AI Drug Discovery for Pharma and Biotech

Drug discovery

143

drugs

With orphan designations

Overview

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease characterized by irreversible lung scarring (usual interstitial pneumonia pattern) and declining lung function [1][6]. Median survival is 2–5 years post-diagnosis, with respiratory failure as the primary cause of death [6][16]. Diagnosis requires exclusion of secondary causes and confirmation via HRCT or histopathology [6][16].

Population

  • Primarily affects adults >50 years (mean age 65–70), with incidence rising sharply after age 55 (19.3/100,000 person-years in 55–64 year-olds) [2][17]

  • Male predominance (incidence ratio 1.08 male:female) [2][7]

  • Estimated US prevalence: 42.7–63/100,000 [4][12]

Burden

  • Median survival 2–5 years; comparable to aggressive cancers [6][16]

  • Annual US healthcare costs ~$20,000/patient (2.5–3.5× national average) [4]

  • 61.7/100 mean EQ-5D QoL score, with 24–64% annual hospitalization rates [9][11]

Therapies

  • Antifibrotics (pirfenidone, nintedanib) to slow progression (30% reduction in FVC decline) [5][13]

  • Supportive care: oxygen therapy, pulmonary rehabilitation, symptom management [1][5]

  • Lung transplantation (only curative option; 1,400+ performed at leading centers) [1][6]

Categories: rare respiratory diseases, rare transplant-related disorders

Research Papers

6,425 drug discovery papers about Idiopathic pulmonary fibrosis, with 2 first-in-class and 117 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:

6,425 drug discovery papers about Idiopathic pulmonary fibrosis, with 2 first-in-class and 117 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:

categories:

Small molecules

small molecules
2026-08-13 | Stepwise Translational Validation of the Screening Hit Desipramine Reveals Limits of Fibroblast-State Modulation in Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited treatment options. Depression and anxiety are common comorbidities in patients with IPF, and emerging evidence suggests that neuroactive pathways may also influence fibrotic remodeling. On this basis, we investigated desipramine, a tricyclic antidepressant, as a potential modulator of fibroblast state in lung fibrosis. Desipramine was identified in an FDA-approved compound screen as a pro-lipogenic hit in TGF-β-stimulated fibroblasts and was subsequently evaluated across a stepwise validation pipeline of increasing biological complexity. In WI-38 fibroblasts, desipramine was well tolerated at 10 μM and reduced myofibroblast-associated features while increasing lipid-associated staining. In a fibroblast-supported alveolosphere assay, desipramine altered qualitative organoid clustering and changed the transcript levels of specific mesenchymal markers under profibrotic stimulation, whereas direct treatment of MLE-12 epithelial cells did not elicit a consistent response. While desipramine demonstrated pro-lipogenic and anti-myofibroblastic phenotypic shifts in reductionist 2D cultures, these effects failed to translate robustly into complex 3D human lung tissue slices or in vivo disease models. Ultimately, our findings highlight the critical necessity of utilizing complex translational pipelines to rigorously validate early screening hits before therapeutic efficacy is assumed.

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2026-08-13 | Molecular Systems Architecture of Fibrotic Lung Microenvironment in Idiopathic Pulmonary Fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrosing interstitial lung disease characterized by excessive extracellular matrix (ECM) accumulation, disruption of lung architecture, and progressive loss of pulmonary function. IPF is frequently accompanied by comorbid conditions that exacerbate disease progression and negatively impact prognosis. To address the biological complexity of IPF, this study presents a comprehensive molecular systems architecture that enables a system-level understanding of biomolecular interactions within the fibrotic lung microenvironment in response to external and physiological triggers. Methods: A literature search is conducted using the Medical Subject Headings (MeSH) keywords in PubMed and MEDLINE to identify relevant peer-reviewed articles published from April 2008 to June 2025, with Google Scholar used solely to retrieve full-text versions of articles identified through this search. The systems biology tool CytoSolve® was used to perform the systematic review and to support the curation and development of the molecular systems architecture of IPF pathogenesis. Full-length articles that contained Medical Subject Headings keywords relevant to IPF pathogenesis were selected for a comprehensive review. A total of 150 studies published between April 2008 and June 2025 met the inclusion criteria and were included in the systematic analysis. This systematic review was not registered. Results: Findings were synthesized qualitatively into a multilayered molecular interactome rather than through statistical meta-analysis. The architecture integrates interactions across sixteen lung-associated cell types, including epithelial, endothelial, mesenchymal, immune, and stromal populations. Key external triggers-such as bleomycin (BLM), asbestos, silica, radiation, cigarette smoke, Herpes virus, and genetic mutations (SFTPC I73T), along with hypoxia associated with comorbidities-initiate coordinated cellular responses that converge on three fundamental pathological processes: inflammation, myofibroblast differentiation, and tissue remodeling. These interconnected processes collectively drive the initiation and progression of IPF. Conclusions: This molecular systems architecture unifies triggers, cellular components, molecular pathways, and biological processes into a multilayered framework for identifying therapeutic targets, biomarkers, and rational single- and combination-treatment strategies in IPF.

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2026-08-13 | Discovery of Pyrazole-Containing RGD Mimics with Anti-Fibrotic Efficacy in the Unilateral Ureteral Obstruction Mouse Model.

Fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), metabolic dysfunction-associated steatohepatitis (MASH), and kidney fibrosis represent a major unmet medical need. IPF patients have a mean survival of only 2-5 years, and despite this critical need, only two drugs have been approved in the past decade. These therapies offer limited efficacy and poor tolerability, underscoring the need for better options. Targeting αV integrins has emerged as a promising strategy, supported by strong preclinical data. While αVβ1/6 inhibitors are in clinical trials, our approach focused on developing pan-αV inhibitors with selectivity over αVβ8 and αIIbβ3 and oral pharmacokinetics. Through lead optimization, we identified compound 14, a potent inhibitor of αVβ1, αVβ3, αVβ5, and αVβ6, with high selectivity, oral bioavailability, and low IV clearance. In a mouse unilateral ureteral obstruction model, oral dosing of 14 (10 mg/kg/day for 8 days) reduced total collagen by 25% versus vehicle.

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2026-08-12 | Amprenavir Protects Lung Epithelial Cells From Pepsin Induced Inflammation and Fibrotic Changes.

Chronic reflux-related microaspiration is increasingly recognized as a modifiable risk factor for progressive fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic lung allograft dysfunction (CLAD). Nonacid reflux constituents, including the gastric enzyme pepsin, are thought to be a primary source of aspiration-attributed injury. We previously showed that the FDA-approved HIV protease inhibitor amprenavir reduces pepsin-mediated inflammation and fibrosis in in vivo and in vitro models of the upper airways. Repurposing amprenavir offers a novel strategy to prevent aspiration-related lung disease progression. Our aim was to evaluate time- and dose-dependent effects of pepsin on proinflammatory and fibrotic responses in human bronchial/tracheal epithelial cells (HBECs) and assess the protective role of amprenavir. HBECs were treated in triplicate with 0.1 or 1 mg/mL pepsin and/or 10 μM amprenavir at pH 6.5 for 15 or 30 min, followed by 6 or 24 h rest. Cell secretions were assessed by IL-8 and fibronectin ELISA, and cell lysate was assessed by E-cadherin, β-catenin, and vimentin Western blot. Low-dose pepsin exposure (15 min, 0.1 mg/mL, 6 h rest) induced IL-8 (p < 0.01), reversed by amprenavir (p < 0.01). High-dose pepsin (30 min, 1 mg/mL, 24 h rest) depleted E-cadherin (p < 0.05) and increased vimentin (p < 0.01), both reversed by amprenavir. Pepsin elicited dose- and time-dependent proinflammatory and fibrotic effects in airway epithelial cells in vitro, which were prevented by amprenavir. This supports the capacity of amprenavir to mitigate airway damage caused by chronic reflux-related microaspiration and highlights its potential therapeutic utility for progressive fibrotic lung diseases. N/A.

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2026-08-12 | Covalent Anchoring of Enzyme-Activatable Fluorescent Signals for in Situ Imaging and Longitudinal Staging of Cellular Senescence in Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease caused by the pathological accumulation of senescent cells. In this fibrotic microenvironment, senescence-associated β-galactosidase (SA-β-Gal) serves as a key biomarker. However, existing SA-β-Gal molecular probes suffer from signal diffusion and rapid clearance due to the extracellular leakage, compromising imaging fidelity. To address this issue, an enzyme-activated covalent labelling strategy is proposed, and as a design paradigm developing TCFM-Gal, a imaging tool integrating β-galactosidic fluorophore with an ortho-difluoromethyl leaving group. Upon SA-β-Gal-mediated hydrolysis, TCFM-Gal generates a quinone methide intermediate that covalently anchors to surrounding nucleophiles, confining fluorescence within lysosomes. In senescent cells, TCFM-Gal achieves extended lysosome-retained imaging, maintaining over 85% signal retention within 24 h. In the IPF model, TCFM-Gal enables longitudinal tracking of senescent cells and maintains a high signal intensity after 24 h. Rapid circulatory washout and high interstitial fluid pressure make conventional probes ineffective in the lungs. TCFM-Gal overcomes this not just by sensing, but by anchoring the signals in situ. Moreover, TCFM-Gal facilitates staging assessments of fibrosis progression by quantifying the senescence burden across disease phases. This study establishes an enzyme-activated covalent labeling paradigm for high-fidelity senescence imaging, advancing the spatiotemporal mapping of senescence in lung diseases.

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proteins
2026-08-03 | BCL9 inhibition promotes fibroblast lipogenesis by regulating macrophage-fibroblast interactions to attenuate pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with an urgent need for novel therapeutic strategies. M2 macrophage-derived TGF-β1 promotes fibroblast myogenesis, contributing to IPF pathogenesis. Targeting macrophage polarization and fibroblast function thus represents an effective therapeutic approach for treating IPF. Here, we identify B-cell lymphoma 9 (BCL9) as a key upstream regulator implicated in IPF pathogenesis. We demonstrate that BCL9 drives the macrophage M2 program through the MerTK-ERK-SPP1 axis. Notably, pharmacological inhibition of BCL9 with our novel peptide, hsBCL9Z96, effectively attenuates pulmonary fibrosis by reprogramming macrophage-fibroblast crosstalk. Specifically, BCL9 inhibition promotes fibroblast lipogenesis via TGF-β1 signaling, which in turn supports alveolar type 2 (AT2) cell expansion. This macrophage-orchestrated fibroblast phenotypic switch from myogenic to lipogenic is visually corroborated by spatial transcriptomic analyses and immunofluorescence staining of human lung tissues. Functionally, the pathological role of BCL9 and efficacy of hsBCL9Z96 are validated in human cellular models, including IPF patient-derived cells, confirming its translational significance. Collectively, our findings not only elucidate a novel BCL9-driven macrophage-fibroblast-AT2 cell axis in IPF but also establish hsBCL9Z96 as a promising first-in-class therapeutic candidate, providing a strong rationale for targeting BCL9-mediated Wnt signaling in clinical IPF treatment.

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2026-06-26 | Clearing the Pulmonary Traffic Jam With Dual-Enzyme Inhalable Nanoparticles Restore Airflow and Reverse Fibrotic Remodeling.

Idiopathic pulmonary fibrosis (IPF) is a progressive and life-threatening interstitial lung disorder marked by aberrant mucus hypersecretion and excessive extracellular matrix (ECM) deposition, which together severely limit the effectiveness of current therapies. Although inhalation therapy enables localized pulmonary drug delivery, pathological mucus accumulation and ECM stiffening jointly form a "traffic jam-like" physical obstruction that severely restricts drug penetration and retention. Here, we developed dual-enzyme-modified inhalable nanoparticles (Lipo/PFD-CB) by co-functionalizing the liposomal surface with bromelain and collagenase to synergistically overcome these obstructive barriers and enhance pulmonary delivery of the FDA-approved antifibrotic drug pirfenidone (PFD). Specifically, bromelain cleaves mucin crosslinks to reduce mucus viscosity, while collagenase degrades dense ECM fibers to facilitate deep tissue penetration and prolonged retention. This dual-enzyme remodeling strategy significantly improved aerosol deposition efficiency (86.5%) and optimized the pharmacokinetic profile and tissue distribution of PFD. In both early and advanced bleomycin-induced fibrosis models, Lipo/PFD-CB effectively attenuated profibrotic cellular activation and restored alveolar architecture and airflow. This study introduces an enzyme-mediated, microenvironment-remodeling inhalable nanoplatform that effectively "clears the pulmonary traffic jam," restoring airflow and tissue homeostasis and offering a promising strategy to enhance therapeutic outcomes in IPF.

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2026-06-22 | Epigenetic de-repression of basal cell metaplasia in aging AT2 cells is a risk factor for idiopathic pulmonary fibrosis (IPF).

Idiopathic pulmonary fibrosis (IPF) is a fatal, age-associated lung disease in which alveolar type II (AT2) cells lose regenerative capacity and can adopt aberrant basal-like fates that promote fibrosis. Using 3D organoid co-cultures with primary human fibroblasts, we find that healthy human AT2 cell trans-differentiation into KRT5+/KRT17+ basal cells increases progressively with age, while differentiation into RAGE+ AT1-like cells decreases. We identify a shared gene signature in AT2 cells at downstream targets of p63 characterized both by acquisition of bivalent, poised chromatin marks with age and increased accessibility in IPF, indicating epigenetic "priming" towards a basal cell lineage. In vitro treatment of young AT2 cells with IL-1β recapitulates this priming toward basal differentiation via a NF-kB-regulated histone demethylase, JMJD3. Conversion of primed AT2 cells to a basal fate requires recruitment of a shared transcription factor, KLF5, from AT1-specific to basal-specific promoters by HIF-1α. AT2 cells instead convert to KRT5-/KRT17+ basaloid cells via a non-age-dependent pathway that requires KLF5-SMAD2/3 complexing through TGFβ1 signaling. These findings define an inflammation-driven epigenetic de-repressive mechanism that links aging, inflammatory stress, hypoxia, and dysfunctional epithelial metaplasia, and accounts for the likely origin of aberrant epithelial cell populations in fibrotic lung disease.

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2026-06-20 | MG53-mediated membrane repair attenuates pulmonary fibrosis by antagonizing TGF-β1-driven epithelial mesenchymal transition.

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive disease with limited options for therapy. Mitsugumin 53 (MG53), a key factor involved in cell membrane repair, emerges as a protector in diverse disease models and cell injury. Although its role in pulmonary fibrosis is not well understood, this study focuses on exploring the function of MG53 in IPF and evaluating the therapeutic potential of recombinant MG53 protein. Circulating MG53 levels were quantified in IPF patients and healthy controls. A pulmonary fibrosis model was induced in C57BL/6J mice using bleomycin (BLM), and the mice were then treated with either recombinant human MG53(rhMG53) or saline. In vitro, MLE-12 cells were subjected to TGF-β1 stimulation with or without rhMG53 to explore the affected mechanisms, with a focus on the TGF-β1/Smad signaling pathway and epithelial-mesenchymal transition (EMT). Circulating MG53 levels were significantly decreased in IPF patients and positively correlated with lung function parameters. Similarly, MG53 expression was decreased in the BLM-exposed mice lungs. Treatment with rhMG53 improved survival, attenuated weight loss, and enhanced pulmonary function in BLM-injured mice. Mechanistically, rhMG53 decreased TGF-β1 levels in bronchoalveolar lavage fluid and inhibited Smad2/3 phosphorylation both in vivo and in TGF-β1-stimulated MLE-12 cells. rhMG53 administration did not cause any signs of systemic toxicity. MG53 deficiency is associated with IPF severity, and supplementation with rhMG53 mitigates BLM-induced pulmonary fibrosis by preventing TGF-β1/Smad signaling and EMT. These findings highlight MG53 as a potential protein-based therapy and biomarker of pulmonary fibrosis.

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2026-06-17 | LRP1 activated by AT2 cell-secreted MDK inhibits fibrotic ferroptosis in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by alveolar injury and pathological fibroblast expansion. Our study investigated the aberrant intercellular communication underlying this process. By analyzing single-cell sequencing from GEO database and experimentally validating the results in vivo and in vitro, we demonstrated that the abnormally regulated alveolar type 2 (AT2) cells secrete midkine (MDK) to activate the low-density lipoprotein receptor-related protein 1 (LRP1) receptor in CTHRC1+ fibroblasts, which inhibits fibroblast ferroptosis. Mechanistically, LRP1 signaling upregulates the deubiquitinase OTUB1, which binds to and stabilizes the ferroptosis inhibitor SLC7A11. This molecular pathway was verified in an in vitro cell co-culture model and in vivo mouse models subjected to adenovirus-mediated overexpression and knockdown. Collectively, these results elucidate a novel pathway of disease progression in IPF that could potentially be targeted for the diagnosis or intervention.

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cell therapies
2026-08-12 | Toxicologic Evaluation of RC-0315, a Mesenchymal Stem Cell-Derived Secretome, Following Repeated Intratracheal Administration in Mice.

RC-0315 is a chemotherapy-exposed mesenchymal stem cell-derived secretome developed as a potential advanced therapy for idiopathic pulmonary fibrosis (IPF). A Good Laboratory Practice (GLP)-compliant repeated-dose toxicity study was conducted to evaluate the safety of RC-0315 following intratracheal (ITR) instillation in immunocompetent ICR and SCID mice. Animals received two cycles of three repeated ITR instillations of RC-0315 performed within a 7-day period and separated by a two-week interval. Mice were assigned to saline, vehicle, low-dose, or high-dose groups and were monitored for 3 days (main phase) or 13 weeks (recovery phase) post last administration. No test article-related mortality or toxic clinical signs were observed in either strain. Clinical pathology parameters, body weight, food consumption, and ophthalmologic findings remained within normal limits, with no dose-dependent alterations. Histopathological examination revealed no RC-0315-related adverse findings in the lungs or other organs, and no local toxicity was evident at the site of administration. These findings support the favorable safety profile of RC-0315 when administered via the clinically intended route.

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2026-08-05 | Human Embryonic Stem Cell-Derived Immunity-And-Matrix-Regulatory Cells Attenuate Pulmonary Fibrosis via MMP1-Mediated Collagen Degradation.

Currently, no targeted therapy exists for idiopathic pulmonary fibrosis (IPF). The hallmark pathological feature of excessive extracellular matrix (ECM) deposition severely undermines the efficacy of mesenchymal stem cell (MSC)-based treatments. While existing MSC therapeutic strategies primarily focus on modulating inflammation in early stages, they have not yet established precise interventions addressing the core pathological mechanism-ECM dysregulation. Previous studies demonstrated the therapeutic potential of human embryonic stem cell (hESCs)-derived immunity-and-matrix-regulatory cells (IMRCs) in lung injury and fibrosis models. However, the critical biomarkers and underlying mechanisms mediating IMRCs' efficacy in IPF remain poorly understood. In this study, we generated MMP1 knockout IMRCs (IMRCs-MMP1 KO) using CRISPR-based gene editing. We then characterized whether MMP1 ablation affected key properties of IMRCs, including cell morphology, proliferation, migration, marker protein expression, transcriptomic profile, and cytokine secretion. Subsequently, the ability of IMRCs-MMP1 KO to degrade collagen was tested using in vivo and in vitro pulmonary fibrosis models. MMP1 knockout was successfully achieved and did not compromise typical IMRC characteristics or impair their immunomodulatory capacity. However, MMP1 deficiency significantly attenuated the ability of IMRCs to degrade TGF-β1-induced collagen I deposition in A549 cells. Importantly, wild-type IMRCs demonstrated superior therapeutic efficacy in ameliorating bleomycin-induced lung injury and fibrosis in mice compared with IMRCs-MMP1 KO. Furthermore, IMRCs exhibited significantly greater capability to directly degrade the pericellular collagen I and modulate fibroblasts' activation progression within fibrotic lung tissues in a MMP1-dependent manner. In summary, our data establish that MMP1 plays an essential functional role in IMRC-mediated attenuation of PF. MMP1 thus represents a key therapeutic biomarker for IMRC-based treatment. This work provides a foundation for developing stem cell therapies tailored to the pathological features of IPF, potentially enabling adaptive treatment strategies.

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2026-07-28 | The Gut-Lung Microbiome Axis in Alveolar Stem Cell Regeneration and Lung Repair.

The mammalian respiratory system stands as a frontline barrier, constantly exposed to environmental insults, balancing defensive immunity with gas exchange. Historically considered sterile, the lung harbors a dynamic, low-biomass microbiome that evolves continuously in response to pulmonary pathologies. Accumulating evidence underscores that respiratory health and structural recovery are not autonomous but are critically integrated with distal microbial systems, especially the intestinal tract, through the gut-lung axis (GLA). This review characterizes the GLA as a bidirectional communication highway fueled by immune pathways, microbial metabolites, and direct microbial translocations. During acute or chronic injuries, such as COVID-19, COPD, asthma, idiopathic pulmonary fibrosis (IPF) and lung cancer, the gut microbiota serves as a remote metabolic "rheostat". It delivers pivotal signaling molecules, such as short-chain fatty acids (SCFAs) and tryptophan metabolites (indoles), that could shape the local microenvironment in which the respiratory epithelium undergoes functional repair or maladaptive, fibrotic remodeling. Mechanistically, gut-derived butyrate enhances mitochondrial activity in alveolar epithelial cells, while resident progenitors, such as Alveolar Type 2 (AT2) cells, depend on intact mitochondrial fatty acid oxidation for proper regenerative differentiation. Conversely, critical lung illness disrupts this homeostasis via a "pathological circuit," where severe pulmonary inflammation drives gut permeability, fecal dysbiosis, and the subsequent translocation of pathogen-associated molecular patterns (PAMPs, such as LPS) or gut-associated bacteria back into the pulmonary circulation. This review highlights the systemic nature of lung regeneration, which likely depends heavily on intestinal health through the GLA. Ultimately, leveraging these remote microbial networks through precision postbiotic supplementation, dietary priming, or microbiota transplantation represents a crucial frontier in precision medicine to promote definitive alveolar repair.

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2026-07-13 | Insights into extracellular vesicles in senescence-associated chronic lung diseases.

Chronic lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, obstructive sleep apnea, asthma, bronchiectasis, and lung cancer, are intricately linked to the aging process. These diseases are characterized by a high prevalence rate and a paucity of effective treatment options. Emerging evidence highlights the critical role of extracellular vesicles (EVs) in the pathogenesis and progression of these diseases. EVs, released by senescent cells, mediate intercellular communication and modulate immune responses through their cargo of microRNAs, proteins, and other molecules. These vesicles contribute to disease progression by promoting inflammation, fibrosis, tissue remodeling, and cellular senescence. Specifically, certain microRNAs, such as miR-21, miR-34a, and miR-570-3p, along with several proteins in EVs, have been identified as key factors influencing these processes. Additionally, EVs play significant roles in immune regulation and have potential anti-inflammatory effects, making them promising candidates for therapeutic applications. Recent advances in the use of EVs as therapeutic agents, including their application in nanotechnology for targeted drug delivery, have demonstrated potential in reducing inflammation, modulating immune responses, and enhancing tissue repair. Understanding the role of EVs in these diseases offers insights into potential therapeutic targets to mitigate disease progression and improve patient outcomes. Future research should focus on standardizing EV isolation and characterization methods, verifying the safety and efficacy of EV-based therapies in clinical trials, and elucidating the complex biological mechanisms of EVs in aging and disease.

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2026-07-11 | Alveolar type II cell therapy ameliorates pulmonary fibrosis by reprogramming macrophage activation.

Alveolar type II (ATII) cell transplantation is a promising therapeutic strategy for idiopathic pulmonary fibrosis, although its underlying cellular mechanisms remain incompletely understood. Given that macrophage profibrotic activation is a key driver of fibrosis, we hypothesized that ATII cell therapy exerts antifibrotic effects by reprogramming macrophage activation states during the established fibrotic phase. In a rat model of bleomycin-induced pulmonary fibrosis, we characterized alveolar and interstitial macrophage profiles in control animals, in fibrotic animals, and after intratracheal transplantation of ATII cells performed on day 15 after bleomycin once fibrosis was established. Gene expression analyses were used to define macrophage activation profiles, while in vitro co-cultures of macrophages with ATII cells or fibroblasts assessed paracrine interactions and macrophage activation-state modulation. The CXCL12/CXCR4 signalling axis was further examined to explore potential mechanisms linking macrophage reprogramming to CXCR4⁺ cell dynamics, including recruitment of circulating CXCR4⁺ cells. Disease progression promoted a prominent profibrotic activation profile enriched in M2-associated markers in both alveolar and interstitial macrophages. ATII cell transplantation markedly reduced macrophage infiltration and shifted their activation toward a less profibrotic, more homeostatic profile. In vitro, soluble mediators released by healthy ATII cells contributed to modulation of macrophage activation states, restoring a less profibrotic activation profile. Reciprocal crosstalk between macrophages and fibroblasts was observed: fibrotic macrophages enhanced fibroblast activation, whereas macrophages from control lungs exerted antifibrotic effects. Notably, ATII cell transplantation normalised CXCL12/CXCR4 axis expression and reduced the number of circulating CXCR4⁺ cells, suggesting that modulation of this axis may limit the recruitment of circulating CXCR4⁺ cells and attenuate profibrotic signalling. ATII cell transplantation ameliorates pulmonary fibrosis by restoring a less profibrotic immune microenvironment and modulating macrophage-fibroblast crosstalk. These effects are associated with reduced fibroblast activation and decreased accumulation of circulating CXCR4⁺ cells, consistent with attenuation of fibrotic responses.

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oligonucleotides
2026-08-13 | The telomeric DNA damage response as a therapeutic target in idiopathic pulmonary fibrosis.

Telomere dysfunction and the telomeric DNA damage response (tDDR) activation correlate with aging and age-related diseases, including idiopathic pulmonary fibrosis (IPF). However, a causal role for tDDR in IPF pathogenesis has not been determined. IPF patients frequently bear germline mutations in telomerase genes, critically short telomeres, and markers of tDDR and cellular senescence. We previously demonstrated that telomeric antisense-oligonucleotides (tASOs) targeting telomeric non-coding RNAs are selective tDDR inhibitors. Here, we employed late-generation telomerase knockout mice as a genetic model of IPF. Systemic tASOs treatment reduces DDR-including in stem/progenitor cells-inflammation, and lung fibrosis in young, adult, and old mice. Markers of DDR correlate with lung pathology, and tDDR inhibition normalizes molecular and pathological phenotypes, uncoupling telomere lengths from their deleterious consequences. Transcriptomic changes in telomerase knockout mice recapitulate those observed in normal aged mice and in IPF patients, and they are reversed upon tDDR inhibition. These results highlight the pathogenic causative relevance of tDDR activation in IPF pathogenesis and support tASOs as a promising therapeutic strategy for IPF and for telomere biology diseases.

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2026-08-03 | Mannose-modified tobacco mosaic virus-mediated macrophage regulation inhibits pulmonary fibrosis progression.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease, causing irreversible lung scarring and respiratory failure. CD206+ M2 macrophages play a key role in its progression. In this study, we utilize the pro-inflammatory properties of plant viruses to develop a mannose-modified tobacco mosaic virus nanoparticle (TMV-OEG8-Man), which targets and reprograms profibrotic macrophages to inhibit IPF. TMV-OEG8-Man alters the CD206+ M2 macrophage phenotype in vitro, suppressing profibrotic genes (Mrc1, Spp1, Ccr2) and signaling pathways (MAPK, TGF-beta, PI3K-Akt, mTOR, Wnt), thereby reducing the transition of fibroblasts to myofibroblasts. When administered via aerosol, TMV-OEG8-Man achieves prolonged lung retention with minimal systemic exposure. In mice with bleomycin-induced pulmonary fibrosis, a single dose during fibroproliferation attenuated fibrosis progression, increasing survival rate from 50% to 100%, and preserving lung architecture. This study establishes plant viral nanoparticles as a macrophage reprogramming strategy with therapeutic potential for organ fibrosis.

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2026-06-27 | Golgi casein kinase-mediated phosphorylation of osteopontin orchestrates macrophage- lung-resident mesenchymal stem cells crosstalk and fibrogenesis: a targetable macromolecular axis.

Idiopathic pulmonary fibrosis (IPF) involves aberrant crosstalk between immune cells and mesenchymal compartments. While secreted phosphoproteins are crucial in this process, the upstream kinases regulating their post-translational modifications and biological functions remain poorly understood. Integrating single-cell RNA sequencing and macromolecular interaction analysis, we identified a pro-fibrotic FPR3+ macrophage subset. We utilized co-immunoprecipitation and mass spectrometry to map the interaction between the Golgi kinase Fam20C and its substrate Osteopontin (also known as SPP1). To validate the functional requirement of this kinase in vivo, we employed a Fab'-functionalized macromolecular delivery system to specifically silence Fam20C in macrophages. We demonstrate that Fam20C phosphorylates SPP1, a critical modification that facilitates its secretion and subsequent binding to CD44 receptors on lung-resident mesenchymal stem cells (LR-MSCs). This ligand-receptor interaction inhibits the Hippo pathway, driving LR-MSC differentiation into myofibroblasts. Importantly, specific silencing of Fam20C using the targeted siRNA delivery strategy significantly attenuated fibrotic progression and blocked the macrophage-LR-MSC fibrogenic crosstalk in mouse models. This study reveals the Fam20C-SPP1 phosphorylation axis as a critical macromolecular switch in pulmonary fibrosis. Our findings provide mechanistic insights into immune-stromal communication and highlight Fam20C as a viable target for precision intervention.

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2026-06-15 | A tetrahedral framework DNA-based bioswitchable miR-26a-5p delivery system for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease with severely limited therapeutic options. MicroRNAs, especially miR-26a-5p, have exhibited potent anti-fibrotic effects in preclinical studies. However, their clinical translation has been impeded by intrinsic susceptibility to enzymatic degradation in physiological environments and poor cellular internalization efficiency. In this study, we developed a tetrahedral framework nucleic acid-based bioswitchable miRNA delivery system, termed BiRDS26, for the targeted delivery of miR-26a-5p. BiRDS26 demonstrated robust anti-fibrotic activity in both in vitro and in vivo models, mechanistically mediated by the coordinated suppression of the Hippo and Wnt signaling pathways. Collectively, these results position BiRDS26 as a rationally engineered nanotherapeutic platform with significant translational potential for IPF treatment.

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2026-05-13 | SYISL promotes pulmonary epithelial-mesenchymal transition and fibrosis through DSP-Hippo/YAP pathway.

Long non-coding RNAs (lncRNAs) are pivotal regulators of cellular processes, but their specific functions in pulmonary epithelial homeostasis and idiopathic pulmonary fibrosis (IPF) pathogenesis are not fully defined. Building on our previous finding that SYISL modulates fibroblast behavior, we investigated its role in the epithelial compartment. We discovered that SYISL is significantly upregulated in alveolar epithelial cells from both IPF patients and bleomycin-induced fibrotic mice. Mechanistically, we identified desmoplakin (DSP) as a direct binding partner of SYISL. SYISL promotes DSP degradation, thereby relieving a key constraint on epithelial integrity. This event initiates a downstream signaling cascade, activating the PI3K-AKT pathway and promoting YAP1 dephosphorylation and nuclear translocation. Furthermore, we delineate how this axis reshapes the epigenetic landscape at the vimentin locus, enhancing H3K4me3 and H3K27ac marks to facilitate YAP1-driven transcription, which collectively promotes an EMT-associated state and increased epithelial plasticity. The resultant aberrant epithelial-mesenchymal crosstalk contributes to pathological extracellular matrix (ECM) deposition. Translating these insights into therapy, we show that intratracheal delivery of AAV-shSYISL prevents fibrosis, while SYISL-targeting antisense oligonucleotides (ASOs) can reverse established fibrotic lesions. In summary, our study defines a novel SYISL-DSP-Hippo/YAP regulatory axis that licenses pro-fibrotic epithelial plasticity and nominates SYISL as a promising therapeutic target for IPF.

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other
2026-08-04 | Single-cell RNA sequencing reveals aberrant airway epithelial-immune cell cross-talk in pulmonary fibrosis.

Epithelial-immune cell interactions are crucial in the regulation of pulmonary immune responses. Emerging evidence suggests that cell populations lining the airways may play a pivotal role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a disease characterised by progressive scarring of the lung parenchyma. We profiled the cellular landscape of the airway mucosal niche in incident cases of IPF to understand early-stage events contributing to disease development. Single-cell RNA-sequencing was used to explore cellular heterogeneity in proximal airway brushings from seven healthy controls and nine patients with newly diagnosed IPF. In-depth bioinformatics analysis was used to interrogate changes in cell populations and cell-cell communication in IPF patients compared to controls. We show a relative increase in the abundance of airway macrophage subsets in IPF compared to healthy controls, and disease-specific changes in their transcriptional profile. Increased frequency of airway macrophages and proliferating macrophages was associated with more extensive disease at baseline quantified by the composite physiological index and radiological severity of traction bronchiectasis. Monocyte-derived macrophages were significantly enriched at baseline in IPF patients who had disease progression at 12 months. Using CellChat we exposed differences in cell-cell communication between airway epithelial cells, airway macrophages and T-cells in IPF. We identified dysregulation in signalling pathways such as SEMA3, ANXA1 and DESMOSOME, which modulate airway epithelial-macrophage interactions, potentially driving disease pathology. Airway epithelial cells and macrophages may play a key role in orchestrating the early immunopathology of IPF, and these data support further exploration of novel, airway-focused therapeutic targets in IPF.

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2026-08-01 | FABP5 attenuates pulmonary fibrosis by regulating lipid metabolism in type II alveolar epithelial cells.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease resulting from alveolar epithelial cell injury. Senescence and dysfunction of alveolar epithelial type II (AT2) cells are key drivers of IPF pathogenesis. Given that metabolism underpins cellular homeostasis and AT2 cell function critically depends on lipid metabolism, we investigated the role of fatty acid binding protein 5 (FABP5), a key regulator of intracellular fatty acid trafficking. Using single-cell RNA-sequencing data, we assessed FABP5 expression across primary cellular subpopulations of IPF lung tissue, and validated its expression in IPF patient lungs and bleomycin-induced pulmonary fibrosis (PF) models by western blotting, quantitative PCR and immunofluorescence. We generated FABP5-overexpressing cell lines and human lung precision-cut lung slices (PCLS) via lentiviral transduction, and examined the effects of FABP5 on cell proliferation, apoptosis, mitochondrial function, and lipid droplet formation using staining-based assays. To evaluate in vivo effects, we overexpressed FABP5 in mouse lung tissue via adeno-associated virus (AAV) delivery and evaluated fibrosis by micro-CT and histopathological staining. We found that FABP5 expression was significantly downregulated in AT2 cells from IPF patients and bleomycin-induced models. Overexpression of FABP5 attenuated pathological fibroblast activation and enhanced mitochondrial bioenergetics, thereby protecting alveolar epithelial cells from injury. Furthermore, FABP5 mitigated bleomycin-induced lung fibrosis by increasing global lipid and medium/long-chain fatty acid levels. Our findings identify FABP5 as a critical regulator of pulmonary fibrosis. Downregulation of FABP5 in AT2 cells contributes to disease progression, whereas restoration of FABP5 expression attenuates fibrogenesis by suppressing pathological fibroblast activation, preserving mitochondrial function in AT2 cells, and restoring lipid homeostasis through elevation of medium- and long- chain fatty acids. These results nominate FABP5 as a promising therapeutic target for this devastating disease.

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2026-07-29 | Alveolar Epithelial Cell Loss of the Mitochondrial Regulator TFAM Drives Progressive Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by failed alveolar epithelial repair and progressive fibrotic remodeling. Although aberrant reprogramming of alveolar type 2 (AT2) cells and accumulation of transitional AT2 states are increasing recognized as central features of IPF, the epithelial-intrinsic mechanisms that initiate these pathogenic states remain incompletely understood. Here, we identify mitochondrial transcription factor A (TFAM), a regulator of mitochondrial DNA maintenance, as a critical regulator of AT2 cell homeostasis. TFAM expression was reduced in AT2 cells from human IPF lungs. Inducible AT2 cell-specific Tfam deletion in mice caused spontaneous fibrotic remodeling and increased susceptibility to bleomycin-induced lung injury. TFAM-deficient AT2 cells acquired KRT8+ transitional and p21+ senescence-associated features before the onset of fibrotic transformation, accompanied by impaired oxidative phosphorylation, redox imbalance, mitochondrial superoxide accumulation, repression of mtDNA-encoded respiratory genes, and disrupted mitochondrial ultrastructure. TFAM-deficient AT2 cells developed a profibrotic secretory program that promoted extracellular matrix deposition and fibroblast activation. We further identified insulin-like growth factor-binding protein 2 (IGFBP2) as a secreted mediator induced in TFAM-deficient AT2 cells. IGFBP2 was elevated in AT2 cells in human IPF lung tissue and bronchoalveolar lavage fluid (BALF) from patients with IPF. IGFBP2 was detected in supernatants from fibrotic human precision-cut lung slices (hPCLS). IGFBP2 neutralization attenuated profibrotic remodeling in fibrotic hPCLS. Collectively, our findings identify TFAM-dependent mitochondrial homeostasis as an epithelial checkpoint linking AT2 cell-state stability to impaired epithelial-mesenchymal crosstalk driving pulmonary fibrosis.

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2026-07-28 | SM17, an anti-interleukin-17 receptor B antibody, ameliorates pathogenesis of chronic rhinosinusitis with nasal polyps and idiopathic pulmonary fibrosis via Th2/Th17 dual modulation.

Chronic respiratory diseases (CRDs), driven by dysregulated Th2/Th17 inflammation, represent a global health challenge with limited therapeutic options. Interleukin (IL)-25 has emerged as a key upstream regulator of both pathways, yet its exact role in CRDs' pathogenesis remains underexplored. Here, our aim is to evaluate the efficacies of SM17, a novel anti-IL-25 receptor (IL-17RB) antibody, in preclinical models of chronic rhinosinusitis with nasal polyps (CRSwNP) and idiopathic pulmonary fibrosis (IPF). Eosinophil, peripheral blood mononuclear cell, primary macrophage and lung fibroblast cultures were utilised to define the mechanism of action for how SM17 could ameliorate CRSwNP and IPF related phenotypes in vitro. A CRSwNP murine model was induced by co-administration of ovalbumin and Staphylococcus enterotoxin B for comparing SM17's efficacy with dexamethasone. Furthermore, IPF model was conducted using bleomycin stimulation for differentiating beneficial effects of SM17 with two US Food and Drug Administration (FDA)-approved IPF drugs, nintedanib and pirfenidone. In vitro studies demonstrated that SM17 could attenuate eosinophilic activities via Th2 modulation and Th17 differentiation through inhibition of macrophage activation. Simultaneously, SM17 could also prevent IL-25 driven myofibroblast differentiation. The in vitro efficacies were successfully translated to animal studies. SM17 administration restored olfactory function through suppression of eosinophilic inflammation in the nasal epithelium of the CRSwNP murine model and attenuated lung fibrosis through Th17 modulation in the IPF model. In both animal experiments, SM17 showed trend of improvements than the comparison drugs. Our findings suggest that SM17 is a potential therapeutic agent to treat CRDs such as CRSwNP and IPF through Th2/Th17 dual modulation and antifibrotic function.

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2026-07-27 | Molecular plasticity of LAMA3 across the disease spectrum: pathogenic mechanisms and clinical translation.

The laminin α3 chain, encoded by LAMA3, constitutes a principal component of laminin-332 (LN-332), an essential extracellular matrix (ECM) glycoprotein governing cell adhesion, proliferation, and tissue homeostasis. This systematic review consolidates current evidence on the molecular features and regulatory mechanisms of LAMA3, including its roles in PI3K/Akt, epithelial-mesenchymal transition (EMT), and Hippo-YAP signaling, as well as epigenetic and post-transcriptional modulation. Its context-dependent functions across distinct pathological states are delineated. In malignancies, including colorectal and ovarian cancers, LAMA3 functions as an oncogenic determinant that enhances invasion, metastatic dissemination, and chemotherapeutic resistance. In contrast, in hereditary diseases such as junctional epidermolysis bullosa (JEB) and chronic disorders such as idiopathic pulmonary fibrosis (IPF), LAMA3 deficiency or dysfunction constitutes a structural basis of tissue pathology. From a translational standpoint, elevated LAMA3 expression has been recognized as an independent prognostic indicator in pancreatic ductal adenocarcinoma, whereas LAMA3 promoter methylation is a candidate biomarker for platinum resistance in ovarian cancer. LAMA3-directed gene therapy for JEB has progressed to clinical evaluation. Current limitations in the field are critically examined, and emerging therapeutic approaches, including proteolysis-targeting chimeras (PROTACs), are discussed. Collectively, an integrated framework that connects LAMA3 biology with clinical applications is presented to inform future investigations and precision therapeutic strategies targeting this multifunctional molecule.

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small molecules
2026-08-13 | Stepwise Translational Validation of the Screening Hit Desipramine Reveals Limits of Fibroblast-State Modulation in Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited treatment options. Depression and anxiety are common comorbidities in patients with IPF, and emerging evidence suggests that neuroactive pathways may also influence fibrotic remodeling. On this basis, we investigated desipramine, a tricyclic antidepressant, as a potential modulator of fibroblast state in lung fibrosis. Desipramine was identified in an FDA-approved compound screen as a pro-lipogenic hit in TGF-β-stimulated fibroblasts and was subsequently evaluated across a stepwise validation pipeline of increasing biological complexity. In WI-38 fibroblasts, desipramine was well tolerated at 10 μM and reduced myofibroblast-associated features while increasing lipid-associated staining. In a fibroblast-supported alveolosphere assay, desipramine altered qualitative organoid clustering and changed the transcript levels of specific mesenchymal markers under profibrotic stimulation, whereas direct treatment of MLE-12 epithelial cells did not elicit a consistent response. While desipramine demonstrated pro-lipogenic and anti-myofibroblastic phenotypic shifts in reductionist 2D cultures, these effects failed to translate robustly into complex 3D human lung tissue slices or in vivo disease models. Ultimately, our findings highlight the critical necessity of utilizing complex translational pipelines to rigorously validate early screening hits before therapeutic efficacy is assumed.

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2026-08-13 | Molecular Systems Architecture of Fibrotic Lung Microenvironment in Idiopathic Pulmonary Fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrosing interstitial lung disease characterized by excessive extracellular matrix (ECM) accumulation, disruption of lung architecture, and progressive loss of pulmonary function. IPF is frequently accompanied by comorbid conditions that exacerbate disease progression and negatively impact prognosis. To address the biological complexity of IPF, this study presents a comprehensive molecular systems architecture that enables a system-level understanding of biomolecular interactions within the fibrotic lung microenvironment in response to external and physiological triggers. Methods: A literature search is conducted using the Medical Subject Headings (MeSH) keywords in PubMed and MEDLINE to identify relevant peer-reviewed articles published from April 2008 to June 2025, with Google Scholar used solely to retrieve full-text versions of articles identified through this search. The systems biology tool CytoSolve® was used to perform the systematic review and to support the curation and development of the molecular systems architecture of IPF pathogenesis. Full-length articles that contained Medical Subject Headings keywords relevant to IPF pathogenesis were selected for a comprehensive review. A total of 150 studies published between April 2008 and June 2025 met the inclusion criteria and were included in the systematic analysis. This systematic review was not registered. Results: Findings were synthesized qualitatively into a multilayered molecular interactome rather than through statistical meta-analysis. The architecture integrates interactions across sixteen lung-associated cell types, including epithelial, endothelial, mesenchymal, immune, and stromal populations. Key external triggers-such as bleomycin (BLM), asbestos, silica, radiation, cigarette smoke, Herpes virus, and genetic mutations (SFTPC I73T), along with hypoxia associated with comorbidities-initiate coordinated cellular responses that converge on three fundamental pathological processes: inflammation, myofibroblast differentiation, and tissue remodeling. These interconnected processes collectively drive the initiation and progression of IPF. Conclusions: This molecular systems architecture unifies triggers, cellular components, molecular pathways, and biological processes into a multilayered framework for identifying therapeutic targets, biomarkers, and rational single- and combination-treatment strategies in IPF.

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2026-08-13 | Discovery of Pyrazole-Containing RGD Mimics with Anti-Fibrotic Efficacy in the Unilateral Ureteral Obstruction Mouse Model.

Fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), metabolic dysfunction-associated steatohepatitis (MASH), and kidney fibrosis represent a major unmet medical need. IPF patients have a mean survival of only 2-5 years, and despite this critical need, only two drugs have been approved in the past decade. These therapies offer limited efficacy and poor tolerability, underscoring the need for better options. Targeting αV integrins has emerged as a promising strategy, supported by strong preclinical data. While αVβ1/6 inhibitors are in clinical trials, our approach focused on developing pan-αV inhibitors with selectivity over αVβ8 and αIIbβ3 and oral pharmacokinetics. Through lead optimization, we identified compound 14, a potent inhibitor of αVβ1, αVβ3, αVβ5, and αVβ6, with high selectivity, oral bioavailability, and low IV clearance. In a mouse unilateral ureteral obstruction model, oral dosing of 14 (10 mg/kg/day for 8 days) reduced total collagen by 25% versus vehicle.

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2026-08-12 | Amprenavir Protects Lung Epithelial Cells From Pepsin Induced Inflammation and Fibrotic Changes.

Chronic reflux-related microaspiration is increasingly recognized as a modifiable risk factor for progressive fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic lung allograft dysfunction (CLAD). Nonacid reflux constituents, including the gastric enzyme pepsin, are thought to be a primary source of aspiration-attributed injury. We previously showed that the FDA-approved HIV protease inhibitor amprenavir reduces pepsin-mediated inflammation and fibrosis in in vivo and in vitro models of the upper airways. Repurposing amprenavir offers a novel strategy to prevent aspiration-related lung disease progression. Our aim was to evaluate time- and dose-dependent effects of pepsin on proinflammatory and fibrotic responses in human bronchial/tracheal epithelial cells (HBECs) and assess the protective role of amprenavir. HBECs were treated in triplicate with 0.1 or 1 mg/mL pepsin and/or 10 μM amprenavir at pH 6.5 for 15 or 30 min, followed by 6 or 24 h rest. Cell secretions were assessed by IL-8 and fibronectin ELISA, and cell lysate was assessed by E-cadherin, β-catenin, and vimentin Western blot. Low-dose pepsin exposure (15 min, 0.1 mg/mL, 6 h rest) induced IL-8 (p < 0.01), reversed by amprenavir (p < 0.01). High-dose pepsin (30 min, 1 mg/mL, 24 h rest) depleted E-cadherin (p < 0.05) and increased vimentin (p < 0.01), both reversed by amprenavir. Pepsin elicited dose- and time-dependent proinflammatory and fibrotic effects in airway epithelial cells in vitro, which were prevented by amprenavir. This supports the capacity of amprenavir to mitigate airway damage caused by chronic reflux-related microaspiration and highlights its potential therapeutic utility for progressive fibrotic lung diseases. N/A.

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2026-08-12 | Covalent Anchoring of Enzyme-Activatable Fluorescent Signals for in Situ Imaging and Longitudinal Staging of Cellular Senescence in Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease caused by the pathological accumulation of senescent cells. In this fibrotic microenvironment, senescence-associated β-galactosidase (SA-β-Gal) serves as a key biomarker. However, existing SA-β-Gal molecular probes suffer from signal diffusion and rapid clearance due to the extracellular leakage, compromising imaging fidelity. To address this issue, an enzyme-activated covalent labelling strategy is proposed, and as a design paradigm developing TCFM-Gal, a imaging tool integrating β-galactosidic fluorophore with an ortho-difluoromethyl leaving group. Upon SA-β-Gal-mediated hydrolysis, TCFM-Gal generates a quinone methide intermediate that covalently anchors to surrounding nucleophiles, confining fluorescence within lysosomes. In senescent cells, TCFM-Gal achieves extended lysosome-retained imaging, maintaining over 85% signal retention within 24 h. In the IPF model, TCFM-Gal enables longitudinal tracking of senescent cells and maintains a high signal intensity after 24 h. Rapid circulatory washout and high interstitial fluid pressure make conventional probes ineffective in the lungs. TCFM-Gal overcomes this not just by sensing, but by anchoring the signals in situ. Moreover, TCFM-Gal facilitates staging assessments of fibrosis progression by quantifying the senescence burden across disease phases. This study establishes an enzyme-activated covalent labeling paradigm for high-fidelity senescence imaging, advancing the spatiotemporal mapping of senescence in lung diseases.

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proteins
2026-08-03 | BCL9 inhibition promotes fibroblast lipogenesis by regulating macrophage-fibroblast interactions to attenuate pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with an urgent need for novel therapeutic strategies. M2 macrophage-derived TGF-β1 promotes fibroblast myogenesis, contributing to IPF pathogenesis. Targeting macrophage polarization and fibroblast function thus represents an effective therapeutic approach for treating IPF. Here, we identify B-cell lymphoma 9 (BCL9) as a key upstream regulator implicated in IPF pathogenesis. We demonstrate that BCL9 drives the macrophage M2 program through the MerTK-ERK-SPP1 axis. Notably, pharmacological inhibition of BCL9 with our novel peptide, hsBCL9Z96, effectively attenuates pulmonary fibrosis by reprogramming macrophage-fibroblast crosstalk. Specifically, BCL9 inhibition promotes fibroblast lipogenesis via TGF-β1 signaling, which in turn supports alveolar type 2 (AT2) cell expansion. This macrophage-orchestrated fibroblast phenotypic switch from myogenic to lipogenic is visually corroborated by spatial transcriptomic analyses and immunofluorescence staining of human lung tissues. Functionally, the pathological role of BCL9 and efficacy of hsBCL9Z96 are validated in human cellular models, including IPF patient-derived cells, confirming its translational significance. Collectively, our findings not only elucidate a novel BCL9-driven macrophage-fibroblast-AT2 cell axis in IPF but also establish hsBCL9Z96 as a promising first-in-class therapeutic candidate, providing a strong rationale for targeting BCL9-mediated Wnt signaling in clinical IPF treatment.

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2026-06-26 | Clearing the Pulmonary Traffic Jam With Dual-Enzyme Inhalable Nanoparticles Restore Airflow and Reverse Fibrotic Remodeling.

Idiopathic pulmonary fibrosis (IPF) is a progressive and life-threatening interstitial lung disorder marked by aberrant mucus hypersecretion and excessive extracellular matrix (ECM) deposition, which together severely limit the effectiveness of current therapies. Although inhalation therapy enables localized pulmonary drug delivery, pathological mucus accumulation and ECM stiffening jointly form a "traffic jam-like" physical obstruction that severely restricts drug penetration and retention. Here, we developed dual-enzyme-modified inhalable nanoparticles (Lipo/PFD-CB) by co-functionalizing the liposomal surface with bromelain and collagenase to synergistically overcome these obstructive barriers and enhance pulmonary delivery of the FDA-approved antifibrotic drug pirfenidone (PFD). Specifically, bromelain cleaves mucin crosslinks to reduce mucus viscosity, while collagenase degrades dense ECM fibers to facilitate deep tissue penetration and prolonged retention. This dual-enzyme remodeling strategy significantly improved aerosol deposition efficiency (86.5%) and optimized the pharmacokinetic profile and tissue distribution of PFD. In both early and advanced bleomycin-induced fibrosis models, Lipo/PFD-CB effectively attenuated profibrotic cellular activation and restored alveolar architecture and airflow. This study introduces an enzyme-mediated, microenvironment-remodeling inhalable nanoplatform that effectively "clears the pulmonary traffic jam," restoring airflow and tissue homeostasis and offering a promising strategy to enhance therapeutic outcomes in IPF.

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2026-06-22 | Epigenetic de-repression of basal cell metaplasia in aging AT2 cells is a risk factor for idiopathic pulmonary fibrosis (IPF).

Idiopathic pulmonary fibrosis (IPF) is a fatal, age-associated lung disease in which alveolar type II (AT2) cells lose regenerative capacity and can adopt aberrant basal-like fates that promote fibrosis. Using 3D organoid co-cultures with primary human fibroblasts, we find that healthy human AT2 cell trans-differentiation into KRT5+/KRT17+ basal cells increases progressively with age, while differentiation into RAGE+ AT1-like cells decreases. We identify a shared gene signature in AT2 cells at downstream targets of p63 characterized both by acquisition of bivalent, poised chromatin marks with age and increased accessibility in IPF, indicating epigenetic "priming" towards a basal cell lineage. In vitro treatment of young AT2 cells with IL-1β recapitulates this priming toward basal differentiation via a NF-kB-regulated histone demethylase, JMJD3. Conversion of primed AT2 cells to a basal fate requires recruitment of a shared transcription factor, KLF5, from AT1-specific to basal-specific promoters by HIF-1α. AT2 cells instead convert to KRT5-/KRT17+ basaloid cells via a non-age-dependent pathway that requires KLF5-SMAD2/3 complexing through TGFβ1 signaling. These findings define an inflammation-driven epigenetic de-repressive mechanism that links aging, inflammatory stress, hypoxia, and dysfunctional epithelial metaplasia, and accounts for the likely origin of aberrant epithelial cell populations in fibrotic lung disease.

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2026-06-20 | MG53-mediated membrane repair attenuates pulmonary fibrosis by antagonizing TGF-β1-driven epithelial mesenchymal transition.

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive disease with limited options for therapy. Mitsugumin 53 (MG53), a key factor involved in cell membrane repair, emerges as a protector in diverse disease models and cell injury. Although its role in pulmonary fibrosis is not well understood, this study focuses on exploring the function of MG53 in IPF and evaluating the therapeutic potential of recombinant MG53 protein. Circulating MG53 levels were quantified in IPF patients and healthy controls. A pulmonary fibrosis model was induced in C57BL/6J mice using bleomycin (BLM), and the mice were then treated with either recombinant human MG53(rhMG53) or saline. In vitro, MLE-12 cells were subjected to TGF-β1 stimulation with or without rhMG53 to explore the affected mechanisms, with a focus on the TGF-β1/Smad signaling pathway and epithelial-mesenchymal transition (EMT). Circulating MG53 levels were significantly decreased in IPF patients and positively correlated with lung function parameters. Similarly, MG53 expression was decreased in the BLM-exposed mice lungs. Treatment with rhMG53 improved survival, attenuated weight loss, and enhanced pulmonary function in BLM-injured mice. Mechanistically, rhMG53 decreased TGF-β1 levels in bronchoalveolar lavage fluid and inhibited Smad2/3 phosphorylation both in vivo and in TGF-β1-stimulated MLE-12 cells. rhMG53 administration did not cause any signs of systemic toxicity. MG53 deficiency is associated with IPF severity, and supplementation with rhMG53 mitigates BLM-induced pulmonary fibrosis by preventing TGF-β1/Smad signaling and EMT. These findings highlight MG53 as a potential protein-based therapy and biomarker of pulmonary fibrosis.

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2026-06-17 | LRP1 activated by AT2 cell-secreted MDK inhibits fibrotic ferroptosis in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by alveolar injury and pathological fibroblast expansion. Our study investigated the aberrant intercellular communication underlying this process. By analyzing single-cell sequencing from GEO database and experimentally validating the results in vivo and in vitro, we demonstrated that the abnormally regulated alveolar type 2 (AT2) cells secrete midkine (MDK) to activate the low-density lipoprotein receptor-related protein 1 (LRP1) receptor in CTHRC1+ fibroblasts, which inhibits fibroblast ferroptosis. Mechanistically, LRP1 signaling upregulates the deubiquitinase OTUB1, which binds to and stabilizes the ferroptosis inhibitor SLC7A11. This molecular pathway was verified in an in vitro cell co-culture model and in vivo mouse models subjected to adenovirus-mediated overexpression and knockdown. Collectively, these results elucidate a novel pathway of disease progression in IPF that could potentially be targeted for the diagnosis or intervention.

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cell therapies
2026-08-12 | Toxicologic Evaluation of RC-0315, a Mesenchymal Stem Cell-Derived Secretome, Following Repeated Intratracheal Administration in Mice.

RC-0315 is a chemotherapy-exposed mesenchymal stem cell-derived secretome developed as a potential advanced therapy for idiopathic pulmonary fibrosis (IPF). A Good Laboratory Practice (GLP)-compliant repeated-dose toxicity study was conducted to evaluate the safety of RC-0315 following intratracheal (ITR) instillation in immunocompetent ICR and SCID mice. Animals received two cycles of three repeated ITR instillations of RC-0315 performed within a 7-day period and separated by a two-week interval. Mice were assigned to saline, vehicle, low-dose, or high-dose groups and were monitored for 3 days (main phase) or 13 weeks (recovery phase) post last administration. No test article-related mortality or toxic clinical signs were observed in either strain. Clinical pathology parameters, body weight, food consumption, and ophthalmologic findings remained within normal limits, with no dose-dependent alterations. Histopathological examination revealed no RC-0315-related adverse findings in the lungs or other organs, and no local toxicity was evident at the site of administration. These findings support the favorable safety profile of RC-0315 when administered via the clinically intended route.

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2026-08-05 | Human Embryonic Stem Cell-Derived Immunity-And-Matrix-Regulatory Cells Attenuate Pulmonary Fibrosis via MMP1-Mediated Collagen Degradation.

Currently, no targeted therapy exists for idiopathic pulmonary fibrosis (IPF). The hallmark pathological feature of excessive extracellular matrix (ECM) deposition severely undermines the efficacy of mesenchymal stem cell (MSC)-based treatments. While existing MSC therapeutic strategies primarily focus on modulating inflammation in early stages, they have not yet established precise interventions addressing the core pathological mechanism-ECM dysregulation. Previous studies demonstrated the therapeutic potential of human embryonic stem cell (hESCs)-derived immunity-and-matrix-regulatory cells (IMRCs) in lung injury and fibrosis models. However, the critical biomarkers and underlying mechanisms mediating IMRCs' efficacy in IPF remain poorly understood. In this study, we generated MMP1 knockout IMRCs (IMRCs-MMP1 KO) using CRISPR-based gene editing. We then characterized whether MMP1 ablation affected key properties of IMRCs, including cell morphology, proliferation, migration, marker protein expression, transcriptomic profile, and cytokine secretion. Subsequently, the ability of IMRCs-MMP1 KO to degrade collagen was tested using in vivo and in vitro pulmonary fibrosis models. MMP1 knockout was successfully achieved and did not compromise typical IMRC characteristics or impair their immunomodulatory capacity. However, MMP1 deficiency significantly attenuated the ability of IMRCs to degrade TGF-β1-induced collagen I deposition in A549 cells. Importantly, wild-type IMRCs demonstrated superior therapeutic efficacy in ameliorating bleomycin-induced lung injury and fibrosis in mice compared with IMRCs-MMP1 KO. Furthermore, IMRCs exhibited significantly greater capability to directly degrade the pericellular collagen I and modulate fibroblasts' activation progression within fibrotic lung tissues in a MMP1-dependent manner. In summary, our data establish that MMP1 plays an essential functional role in IMRC-mediated attenuation of PF. MMP1 thus represents a key therapeutic biomarker for IMRC-based treatment. This work provides a foundation for developing stem cell therapies tailored to the pathological features of IPF, potentially enabling adaptive treatment strategies.

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2026-07-28 | The Gut-Lung Microbiome Axis in Alveolar Stem Cell Regeneration and Lung Repair.

The mammalian respiratory system stands as a frontline barrier, constantly exposed to environmental insults, balancing defensive immunity with gas exchange. Historically considered sterile, the lung harbors a dynamic, low-biomass microbiome that evolves continuously in response to pulmonary pathologies. Accumulating evidence underscores that respiratory health and structural recovery are not autonomous but are critically integrated with distal microbial systems, especially the intestinal tract, through the gut-lung axis (GLA). This review characterizes the GLA as a bidirectional communication highway fueled by immune pathways, microbial metabolites, and direct microbial translocations. During acute or chronic injuries, such as COVID-19, COPD, asthma, idiopathic pulmonary fibrosis (IPF) and lung cancer, the gut microbiota serves as a remote metabolic "rheostat". It delivers pivotal signaling molecules, such as short-chain fatty acids (SCFAs) and tryptophan metabolites (indoles), that could shape the local microenvironment in which the respiratory epithelium undergoes functional repair or maladaptive, fibrotic remodeling. Mechanistically, gut-derived butyrate enhances mitochondrial activity in alveolar epithelial cells, while resident progenitors, such as Alveolar Type 2 (AT2) cells, depend on intact mitochondrial fatty acid oxidation for proper regenerative differentiation. Conversely, critical lung illness disrupts this homeostasis via a "pathological circuit," where severe pulmonary inflammation drives gut permeability, fecal dysbiosis, and the subsequent translocation of pathogen-associated molecular patterns (PAMPs, such as LPS) or gut-associated bacteria back into the pulmonary circulation. This review highlights the systemic nature of lung regeneration, which likely depends heavily on intestinal health through the GLA. Ultimately, leveraging these remote microbial networks through precision postbiotic supplementation, dietary priming, or microbiota transplantation represents a crucial frontier in precision medicine to promote definitive alveolar repair.

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2026-07-13 | Insights into extracellular vesicles in senescence-associated chronic lung diseases.

Chronic lung diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, obstructive sleep apnea, asthma, bronchiectasis, and lung cancer, are intricately linked to the aging process. These diseases are characterized by a high prevalence rate and a paucity of effective treatment options. Emerging evidence highlights the critical role of extracellular vesicles (EVs) in the pathogenesis and progression of these diseases. EVs, released by senescent cells, mediate intercellular communication and modulate immune responses through their cargo of microRNAs, proteins, and other molecules. These vesicles contribute to disease progression by promoting inflammation, fibrosis, tissue remodeling, and cellular senescence. Specifically, certain microRNAs, such as miR-21, miR-34a, and miR-570-3p, along with several proteins in EVs, have been identified as key factors influencing these processes. Additionally, EVs play significant roles in immune regulation and have potential anti-inflammatory effects, making them promising candidates for therapeutic applications. Recent advances in the use of EVs as therapeutic agents, including their application in nanotechnology for targeted drug delivery, have demonstrated potential in reducing inflammation, modulating immune responses, and enhancing tissue repair. Understanding the role of EVs in these diseases offers insights into potential therapeutic targets to mitigate disease progression and improve patient outcomes. Future research should focus on standardizing EV isolation and characterization methods, verifying the safety and efficacy of EV-based therapies in clinical trials, and elucidating the complex biological mechanisms of EVs in aging and disease.

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2026-07-11 | Alveolar type II cell therapy ameliorates pulmonary fibrosis by reprogramming macrophage activation.

Alveolar type II (ATII) cell transplantation is a promising therapeutic strategy for idiopathic pulmonary fibrosis, although its underlying cellular mechanisms remain incompletely understood. Given that macrophage profibrotic activation is a key driver of fibrosis, we hypothesized that ATII cell therapy exerts antifibrotic effects by reprogramming macrophage activation states during the established fibrotic phase. In a rat model of bleomycin-induced pulmonary fibrosis, we characterized alveolar and interstitial macrophage profiles in control animals, in fibrotic animals, and after intratracheal transplantation of ATII cells performed on day 15 after bleomycin once fibrosis was established. Gene expression analyses were used to define macrophage activation profiles, while in vitro co-cultures of macrophages with ATII cells or fibroblasts assessed paracrine interactions and macrophage activation-state modulation. The CXCL12/CXCR4 signalling axis was further examined to explore potential mechanisms linking macrophage reprogramming to CXCR4⁺ cell dynamics, including recruitment of circulating CXCR4⁺ cells. Disease progression promoted a prominent profibrotic activation profile enriched in M2-associated markers in both alveolar and interstitial macrophages. ATII cell transplantation markedly reduced macrophage infiltration and shifted their activation toward a less profibrotic, more homeostatic profile. In vitro, soluble mediators released by healthy ATII cells contributed to modulation of macrophage activation states, restoring a less profibrotic activation profile. Reciprocal crosstalk between macrophages and fibroblasts was observed: fibrotic macrophages enhanced fibroblast activation, whereas macrophages from control lungs exerted antifibrotic effects. Notably, ATII cell transplantation normalised CXCL12/CXCR4 axis expression and reduced the number of circulating CXCR4⁺ cells, suggesting that modulation of this axis may limit the recruitment of circulating CXCR4⁺ cells and attenuate profibrotic signalling. ATII cell transplantation ameliorates pulmonary fibrosis by restoring a less profibrotic immune microenvironment and modulating macrophage-fibroblast crosstalk. These effects are associated with reduced fibroblast activation and decreased accumulation of circulating CXCR4⁺ cells, consistent with attenuation of fibrotic responses.

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oligonucleotides
2026-08-13 | The telomeric DNA damage response as a therapeutic target in idiopathic pulmonary fibrosis.

Telomere dysfunction and the telomeric DNA damage response (tDDR) activation correlate with aging and age-related diseases, including idiopathic pulmonary fibrosis (IPF). However, a causal role for tDDR in IPF pathogenesis has not been determined. IPF patients frequently bear germline mutations in telomerase genes, critically short telomeres, and markers of tDDR and cellular senescence. We previously demonstrated that telomeric antisense-oligonucleotides (tASOs) targeting telomeric non-coding RNAs are selective tDDR inhibitors. Here, we employed late-generation telomerase knockout mice as a genetic model of IPF. Systemic tASOs treatment reduces DDR-including in stem/progenitor cells-inflammation, and lung fibrosis in young, adult, and old mice. Markers of DDR correlate with lung pathology, and tDDR inhibition normalizes molecular and pathological phenotypes, uncoupling telomere lengths from their deleterious consequences. Transcriptomic changes in telomerase knockout mice recapitulate those observed in normal aged mice and in IPF patients, and they are reversed upon tDDR inhibition. These results highlight the pathogenic causative relevance of tDDR activation in IPF pathogenesis and support tASOs as a promising therapeutic strategy for IPF and for telomere biology diseases.

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2026-08-03 | Mannose-modified tobacco mosaic virus-mediated macrophage regulation inhibits pulmonary fibrosis progression.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease, causing irreversible lung scarring and respiratory failure. CD206+ M2 macrophages play a key role in its progression. In this study, we utilize the pro-inflammatory properties of plant viruses to develop a mannose-modified tobacco mosaic virus nanoparticle (TMV-OEG8-Man), which targets and reprograms profibrotic macrophages to inhibit IPF. TMV-OEG8-Man alters the CD206+ M2 macrophage phenotype in vitro, suppressing profibrotic genes (Mrc1, Spp1, Ccr2) and signaling pathways (MAPK, TGF-beta, PI3K-Akt, mTOR, Wnt), thereby reducing the transition of fibroblasts to myofibroblasts. When administered via aerosol, TMV-OEG8-Man achieves prolonged lung retention with minimal systemic exposure. In mice with bleomycin-induced pulmonary fibrosis, a single dose during fibroproliferation attenuated fibrosis progression, increasing survival rate from 50% to 100%, and preserving lung architecture. This study establishes plant viral nanoparticles as a macrophage reprogramming strategy with therapeutic potential for organ fibrosis.

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2026-06-27 | Golgi casein kinase-mediated phosphorylation of osteopontin orchestrates macrophage- lung-resident mesenchymal stem cells crosstalk and fibrogenesis: a targetable macromolecular axis.

Idiopathic pulmonary fibrosis (IPF) involves aberrant crosstalk between immune cells and mesenchymal compartments. While secreted phosphoproteins are crucial in this process, the upstream kinases regulating their post-translational modifications and biological functions remain poorly understood. Integrating single-cell RNA sequencing and macromolecular interaction analysis, we identified a pro-fibrotic FPR3+ macrophage subset. We utilized co-immunoprecipitation and mass spectrometry to map the interaction between the Golgi kinase Fam20C and its substrate Osteopontin (also known as SPP1). To validate the functional requirement of this kinase in vivo, we employed a Fab'-functionalized macromolecular delivery system to specifically silence Fam20C in macrophages. We demonstrate that Fam20C phosphorylates SPP1, a critical modification that facilitates its secretion and subsequent binding to CD44 receptors on lung-resident mesenchymal stem cells (LR-MSCs). This ligand-receptor interaction inhibits the Hippo pathway, driving LR-MSC differentiation into myofibroblasts. Importantly, specific silencing of Fam20C using the targeted siRNA delivery strategy significantly attenuated fibrotic progression and blocked the macrophage-LR-MSC fibrogenic crosstalk in mouse models. This study reveals the Fam20C-SPP1 phosphorylation axis as a critical macromolecular switch in pulmonary fibrosis. Our findings provide mechanistic insights into immune-stromal communication and highlight Fam20C as a viable target for precision intervention.

Open article ↗



2026-06-15 | A tetrahedral framework DNA-based bioswitchable miR-26a-5p delivery system for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease with severely limited therapeutic options. MicroRNAs, especially miR-26a-5p, have exhibited potent anti-fibrotic effects in preclinical studies. However, their clinical translation has been impeded by intrinsic susceptibility to enzymatic degradation in physiological environments and poor cellular internalization efficiency. In this study, we developed a tetrahedral framework nucleic acid-based bioswitchable miRNA delivery system, termed BiRDS26, for the targeted delivery of miR-26a-5p. BiRDS26 demonstrated robust anti-fibrotic activity in both in vitro and in vivo models, mechanistically mediated by the coordinated suppression of the Hippo and Wnt signaling pathways. Collectively, these results position BiRDS26 as a rationally engineered nanotherapeutic platform with significant translational potential for IPF treatment.

Open article ↗



2026-05-13 | SYISL promotes pulmonary epithelial-mesenchymal transition and fibrosis through DSP-Hippo/YAP pathway.

Long non-coding RNAs (lncRNAs) are pivotal regulators of cellular processes, but their specific functions in pulmonary epithelial homeostasis and idiopathic pulmonary fibrosis (IPF) pathogenesis are not fully defined. Building on our previous finding that SYISL modulates fibroblast behavior, we investigated its role in the epithelial compartment. We discovered that SYISL is significantly upregulated in alveolar epithelial cells from both IPF patients and bleomycin-induced fibrotic mice. Mechanistically, we identified desmoplakin (DSP) as a direct binding partner of SYISL. SYISL promotes DSP degradation, thereby relieving a key constraint on epithelial integrity. This event initiates a downstream signaling cascade, activating the PI3K-AKT pathway and promoting YAP1 dephosphorylation and nuclear translocation. Furthermore, we delineate how this axis reshapes the epigenetic landscape at the vimentin locus, enhancing H3K4me3 and H3K27ac marks to facilitate YAP1-driven transcription, which collectively promotes an EMT-associated state and increased epithelial plasticity. The resultant aberrant epithelial-mesenchymal crosstalk contributes to pathological extracellular matrix (ECM) deposition. Translating these insights into therapy, we show that intratracheal delivery of AAV-shSYISL prevents fibrosis, while SYISL-targeting antisense oligonucleotides (ASOs) can reverse established fibrotic lesions. In summary, our study defines a novel SYISL-DSP-Hippo/YAP regulatory axis that licenses pro-fibrotic epithelial plasticity and nominates SYISL as a promising therapeutic target for IPF.

Open article ↗



other
2026-08-04 | Single-cell RNA sequencing reveals aberrant airway epithelial-immune cell cross-talk in pulmonary fibrosis.

Epithelial-immune cell interactions are crucial in the regulation of pulmonary immune responses. Emerging evidence suggests that cell populations lining the airways may play a pivotal role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a disease characterised by progressive scarring of the lung parenchyma. We profiled the cellular landscape of the airway mucosal niche in incident cases of IPF to understand early-stage events contributing to disease development. Single-cell RNA-sequencing was used to explore cellular heterogeneity in proximal airway brushings from seven healthy controls and nine patients with newly diagnosed IPF. In-depth bioinformatics analysis was used to interrogate changes in cell populations and cell-cell communication in IPF patients compared to controls. We show a relative increase in the abundance of airway macrophage subsets in IPF compared to healthy controls, and disease-specific changes in their transcriptional profile. Increased frequency of airway macrophages and proliferating macrophages was associated with more extensive disease at baseline quantified by the composite physiological index and radiological severity of traction bronchiectasis. Monocyte-derived macrophages were significantly enriched at baseline in IPF patients who had disease progression at 12 months. Using CellChat we exposed differences in cell-cell communication between airway epithelial cells, airway macrophages and T-cells in IPF. We identified dysregulation in signalling pathways such as SEMA3, ANXA1 and DESMOSOME, which modulate airway epithelial-macrophage interactions, potentially driving disease pathology. Airway epithelial cells and macrophages may play a key role in orchestrating the early immunopathology of IPF, and these data support further exploration of novel, airway-focused therapeutic targets in IPF.

Open article ↗



2026-08-01 | FABP5 attenuates pulmonary fibrosis by regulating lipid metabolism in type II alveolar epithelial cells.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease resulting from alveolar epithelial cell injury. Senescence and dysfunction of alveolar epithelial type II (AT2) cells are key drivers of IPF pathogenesis. Given that metabolism underpins cellular homeostasis and AT2 cell function critically depends on lipid metabolism, we investigated the role of fatty acid binding protein 5 (FABP5), a key regulator of intracellular fatty acid trafficking. Using single-cell RNA-sequencing data, we assessed FABP5 expression across primary cellular subpopulations of IPF lung tissue, and validated its expression in IPF patient lungs and bleomycin-induced pulmonary fibrosis (PF) models by western blotting, quantitative PCR and immunofluorescence. We generated FABP5-overexpressing cell lines and human lung precision-cut lung slices (PCLS) via lentiviral transduction, and examined the effects of FABP5 on cell proliferation, apoptosis, mitochondrial function, and lipid droplet formation using staining-based assays. To evaluate in vivo effects, we overexpressed FABP5 in mouse lung tissue via adeno-associated virus (AAV) delivery and evaluated fibrosis by micro-CT and histopathological staining. We found that FABP5 expression was significantly downregulated in AT2 cells from IPF patients and bleomycin-induced models. Overexpression of FABP5 attenuated pathological fibroblast activation and enhanced mitochondrial bioenergetics, thereby protecting alveolar epithelial cells from injury. Furthermore, FABP5 mitigated bleomycin-induced lung fibrosis by increasing global lipid and medium/long-chain fatty acid levels. Our findings identify FABP5 as a critical regulator of pulmonary fibrosis. Downregulation of FABP5 in AT2 cells contributes to disease progression, whereas restoration of FABP5 expression attenuates fibrogenesis by suppressing pathological fibroblast activation, preserving mitochondrial function in AT2 cells, and restoring lipid homeostasis through elevation of medium- and long- chain fatty acids. These results nominate FABP5 as a promising therapeutic target for this devastating disease.

Open article ↗



2026-07-29 | Alveolar Epithelial Cell Loss of the Mitochondrial Regulator TFAM Drives Progressive Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by failed alveolar epithelial repair and progressive fibrotic remodeling. Although aberrant reprogramming of alveolar type 2 (AT2) cells and accumulation of transitional AT2 states are increasing recognized as central features of IPF, the epithelial-intrinsic mechanisms that initiate these pathogenic states remain incompletely understood. Here, we identify mitochondrial transcription factor A (TFAM), a regulator of mitochondrial DNA maintenance, as a critical regulator of AT2 cell homeostasis. TFAM expression was reduced in AT2 cells from human IPF lungs. Inducible AT2 cell-specific Tfam deletion in mice caused spontaneous fibrotic remodeling and increased susceptibility to bleomycin-induced lung injury. TFAM-deficient AT2 cells acquired KRT8+ transitional and p21+ senescence-associated features before the onset of fibrotic transformation, accompanied by impaired oxidative phosphorylation, redox imbalance, mitochondrial superoxide accumulation, repression of mtDNA-encoded respiratory genes, and disrupted mitochondrial ultrastructure. TFAM-deficient AT2 cells developed a profibrotic secretory program that promoted extracellular matrix deposition and fibroblast activation. We further identified insulin-like growth factor-binding protein 2 (IGFBP2) as a secreted mediator induced in TFAM-deficient AT2 cells. IGFBP2 was elevated in AT2 cells in human IPF lung tissue and bronchoalveolar lavage fluid (BALF) from patients with IPF. IGFBP2 was detected in supernatants from fibrotic human precision-cut lung slices (hPCLS). IGFBP2 neutralization attenuated profibrotic remodeling in fibrotic hPCLS. Collectively, our findings identify TFAM-dependent mitochondrial homeostasis as an epithelial checkpoint linking AT2 cell-state stability to impaired epithelial-mesenchymal crosstalk driving pulmonary fibrosis.

Open article ↗



2026-07-28 | SM17, an anti-interleukin-17 receptor B antibody, ameliorates pathogenesis of chronic rhinosinusitis with nasal polyps and idiopathic pulmonary fibrosis via Th2/Th17 dual modulation.

Chronic respiratory diseases (CRDs), driven by dysregulated Th2/Th17 inflammation, represent a global health challenge with limited therapeutic options. Interleukin (IL)-25 has emerged as a key upstream regulator of both pathways, yet its exact role in CRDs' pathogenesis remains underexplored. Here, our aim is to evaluate the efficacies of SM17, a novel anti-IL-25 receptor (IL-17RB) antibody, in preclinical models of chronic rhinosinusitis with nasal polyps (CRSwNP) and idiopathic pulmonary fibrosis (IPF). Eosinophil, peripheral blood mononuclear cell, primary macrophage and lung fibroblast cultures were utilised to define the mechanism of action for how SM17 could ameliorate CRSwNP and IPF related phenotypes in vitro. A CRSwNP murine model was induced by co-administration of ovalbumin and Staphylococcus enterotoxin B for comparing SM17's efficacy with dexamethasone. Furthermore, IPF model was conducted using bleomycin stimulation for differentiating beneficial effects of SM17 with two US Food and Drug Administration (FDA)-approved IPF drugs, nintedanib and pirfenidone. In vitro studies demonstrated that SM17 could attenuate eosinophilic activities via Th2 modulation and Th17 differentiation through inhibition of macrophage activation. Simultaneously, SM17 could also prevent IL-25 driven myofibroblast differentiation. The in vitro efficacies were successfully translated to animal studies. SM17 administration restored olfactory function through suppression of eosinophilic inflammation in the nasal epithelium of the CRSwNP murine model and attenuated lung fibrosis through Th17 modulation in the IPF model. In both animal experiments, SM17 showed trend of improvements than the comparison drugs. Our findings suggest that SM17 is a potential therapeutic agent to treat CRDs such as CRSwNP and IPF through Th2/Th17 dual modulation and antifibrotic function.

Open article ↗



2026-07-27 | Molecular plasticity of LAMA3 across the disease spectrum: pathogenic mechanisms and clinical translation.

The laminin α3 chain, encoded by LAMA3, constitutes a principal component of laminin-332 (LN-332), an essential extracellular matrix (ECM) glycoprotein governing cell adhesion, proliferation, and tissue homeostasis. This systematic review consolidates current evidence on the molecular features and regulatory mechanisms of LAMA3, including its roles in PI3K/Akt, epithelial-mesenchymal transition (EMT), and Hippo-YAP signaling, as well as epigenetic and post-transcriptional modulation. Its context-dependent functions across distinct pathological states are delineated. In malignancies, including colorectal and ovarian cancers, LAMA3 functions as an oncogenic determinant that enhances invasion, metastatic dissemination, and chemotherapeutic resistance. In contrast, in hereditary diseases such as junctional epidermolysis bullosa (JEB) and chronic disorders such as idiopathic pulmonary fibrosis (IPF), LAMA3 deficiency or dysfunction constitutes a structural basis of tissue pathology. From a translational standpoint, elevated LAMA3 expression has been recognized as an independent prognostic indicator in pancreatic ductal adenocarcinoma, whereas LAMA3 promoter methylation is a candidate biomarker for platinum resistance in ovarian cancer. LAMA3-directed gene therapy for JEB has progressed to clinical evaluation. Current limitations in the field are critically examined, and emerging therapeutic approaches, including proteolysis-targeting chimeras (PROTACs), are discussed. Collectively, an integrated framework that connects LAMA3 biology with clinical applications is presented to inform future investigations and precision therapeutic strategies targeting this multifunctional molecule.

Open article ↗



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Drug Discovery Landscape

143 orphan drug designations for Idiopathic pulmonary fibrosis, including 3 approved therapies.

143 orphan drug designations for Idiopathic pulmonary fibrosis, including 3 approved therapies.

Drug

Therapy type

Regulator

Orphan designation

Approval

Sponsor

4-(4-Bromo-2-oxo-3H-benzimidazol-1-yl)-N-(4-iodophenyl)piperidine-1-carboxamide

small molecules

EMA

2026-08-20

—

Oxcia AB

tazarotene

small molecules

FDA

2026-06-17

—

GRI Bio Operations, Inc.

tadalafil

small molecules

FDA

2026-03-23

—

Shenzhen Hanhui Pharmaceutical Technology Co., Ltd

small molecule inhibitor of ARG-1 and ARG-2

small molecules

FDA

2026-03-09

—

AstraZeneca Pharmaceuticals LP

tranilast lysate

small molecules

FDA

2026-03-09

—

Nuformix Technologies Limited

deupirfenidone

small molecules

FDA

2026-02-19

—

PureTech LYT 100, Inc., a subsidiary of PureTech Health plc

isoquinoline derivative containing diesters that inhibits BCL-xL

small molecules

FDA

2026-01-15

—

Nanjing Reju Therapeutics Co., Ltd.

Phe-Thr-Thr-Phe-Thr-Val-Thr

peptides

EMA

2026-01-09

—

Scendea (NL) B.V.

Deupirfenidone

small molecules

EMA

2026-01-09

—

Granzer Regulatory Consulting & Services GmbH

humanised monoclonal antibody-drug conjugate delivering an mTOR inhibitor payload

antibodies

FDA

2025-12-09

—

Bionevix Ltd

Adeno-associated virus vector serotype 6.2 containing human TERT gene

gene therapies

EMA

2025-12-09

—

Telomere Therapeutics S.L.

zampilimab

antibodies

FDA

2025-11-25

—

Chiesi Farmaceutici S.p.A.

Orvepitant maleate

small molecules

EMA

2025-11-21

—

Granzer Regulatory Consulting & Services GmbH

kynurenic acid

small molecules

FDA

2025-11-14

—

BirchBioMed Inc.

a humanized anti-S100A4 monoclonal antibody of immunoglobulin G4 isotype

antibodies

FDA

2025-10-24

—

Calluna Pharma AS

roflumilast

small molecules

FDA

2025-09-03

—

Transpire Bio Inc

Admilparant

small molecules

EMA

2025-08-22

—

Bristol-Myers Squibb Pharma EEIG

taladegib

small molecules

FDA

2025-06-18

—

Endeavor Biomedicines

Taladegib

small molecules

EMA

2025-05-22

—

Orphix Consulting GmbH

Tranilast

small molecules

EMA

2025-05-22

—

Boyd Consultants Limited

orvepitant

small molecules

FDA

2025-04-04

—

NeRRe Therapeutics Ltd

selective CXCR7 agonist

small molecules

FDA

2025-02-12

—

iLeadBMS Co., Ltd.

an autologous cell product derived from the human airway basal cells without any gene modification

cell therapies

FDA

2025-02-04

—

Regend Therapeutics Co., Ltd.

artesunate

small molecules

FDA

2024-11-18

—

Artasome Therapeutics, LLC

fluoro methyl gallocatechin gallate

small molecules

FDA

2024-07-18

—

Avanti Biosciences, Inc.

Humanized immunoglobulin G1 monoclonal antibody directed against WNT1-inducible signaling pathway protein-1

antibodies

FDA

2024-07-08

—

Mediar Therapeutics, Inc.

Nerandomilast

small molecules

EMA

2024-06-28

—

Boehringer Ingelheim International GmbH

Zinc (2R,3S,4R,5R)-2,3,4,5,6-pentahydroxyhexanoate and (3S,9aS)-3-(1H-imidazol-5-ylmethyl)-octahydro-1H-pyrido[1,2-a]piperazine-1,4-dione

small molecules

FDA

2024-05-30

—

NovMetaPharma Co., Ltd.

lixudebart

antibodies

FDA

2024-05-24

—

Alentis Therapeutics AG

2-(Piperazin-1-yl)ethyl 3-fluoro-5-(2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)benzoate

small molecules

FDA

2024-05-15

—

AgomAb Spain, S.L.

immunomodulatory inhibitor of high mobility group box 1

antibodies

FDA

2024-02-22

—

Spark Biopharma, Inc.

Bersiporocin

small molecules

EMA

2023-12-13

—

Propharma Group The Netherlands B.V.

Pyridine derivative containing pyridazine that inhibits lysophospholipase

small molecules

FDA

2023-11-08

—

Boehringer Ingelheim Pharmaceuticals, Inc.

zelasudil

small molecules

FDA

2023-08-14

—

Redx Pharma Plc

Human Umbilical Cord-derived Mesenchymal Stem Cell Injection

cell therapies

FDA

2023-08-09

—

Wuhan Optics Valley Vcanbiopharma Co., Ltd.

(R)-1-[4'-(5-chloro-3-{[(1-phenylethoxy)carbonyl] amino}thiophen-2-yl)-2'-methoxy-[1,1'-biphenyl]-4-yl]cyclopropanecarboxylic acid

small molecules

FDA

2023-06-12

—

HiLung, Inc.

a humanized, immunoglobulin G subtype 4 anti-Amphiregulin monoclonal antibody

antibodies

FDA

2023-02-16

—

Pulmongene (Hong Kong) Co., Limited

imidazole derivative

small molecules

FDA

2023-02-01

—

InSilico Medicine Hong Kong Limited

Piperidine-containing autotaxin inhibitor

small molecules

FDA

2023-01-19

—

NextGen Bioscience

Ivaltinostat

small molecules

FDA

2023-01-03

—

Machaon Biotherapeutics, Inc.

(H-L-Arginyl-L-Valyl-L-Isoleucyl-L-Arginyl-L-Alanyl-L-Cysteinyl-L-Leucyl-Glycyl-L-Valyl-Glycyl-L-Leucyl-L-Leucyl-Glycyl-L-Asparaginyl-L-Leucyl-D-Alanyl-Glycyl-L-Lysyl-amino-PEG12-propionic acid)2 (Disulfide bond at Cys)

proteins

FDA

2022-12-13

—

CohBar, Inc.

(2S)-4-[2-methoxyethyl-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl]amino]-2-(quinazolin-4-ylamino)butanoic acid

small molecules

EMA

2022-12-09

—

Pharma Gateway AB

ifenprodil

small molecules

FDA

2022-12-01

—

Algernon Pharmaceuticals Inc.

garadacimab

antibodies

FDA

2022-08-16

—

CSL Behring

Ex-vivo conditioned medium from cultured adult human mesenchymal stem cells

other

FDA

2022-08-15

—

Summa Bio-Solutions Inc.

nerandomilast [Jascayd]

small molecules

FDA

2022-08-15

2025-10-07

Boehringer Ingelheim Pharmaceuticals, Inc.

4'-chloro-2'-cyano-N-(trans-4-hydroxy-4-methylcyclohexyl)-biphenyl-4-sulfonamide

small molecules

FDA

2022-08-15

—

Modern Biosciences Ltd

Selective Colony Stimulating Factor-1 Receptor kinase inhibitor

antibodies

FDA

2022-07-27

—

Elixiron Immunotherapeutics Inc.

Pirfenidone

small molecules

EMA

2022-06-24

—

Regintel Limited

(6S,9aS)-N-benzyl-6-(4-hydroxybenzyl)-4,7-dioxo-2-((3-(pyridin-2-yl)isoxazol-5-yl)methyl)-8-(quinolin-5-ylmethyl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide methane sulfonic acid

small molecules

FDA

2022-06-07

—

3Plus2 Pharma, LLC

Chimeric peptide of human glucagon-like peptide-1, glucagon and gastric inhibitory polypeptide analogues linked to a human immunoglobulin Fc fragment

peptides

EMA

2022-05-16

—

JVM Europe B.V.

N-(1¿,2-dihydroxy-[1,2¿-binapthalen]-4¿-yl)-4-methoxybenzenesulfonamide

small molecules

FDA

2022-04-19

—

Tvardi Therapeutics, Inc.

Treprostinil sodium

small molecules

EMA

2022-03-16

—

Ferrer Internacional S.A.

((S)-3-(1-Cyclopentyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamido)-5-(3,3-difluoropiperidin-1-yl)pentanoic acid hydrochloride)

small molecules

FDA

2022-03-08

—

APIE Therapeutics

glucagon-like peptide-1/glucagon/gastric inhibitory polypeptide triple agonist linked to human IgG4 Fc fragment

proteins

FDA

2021-05-10

—

Hanmi Pharmaceutical Co., Ltd.

axatilimab

antibodies

FDA

2021-04-07

—

Syndax Pharmaceuticals, Inc.

lithium carbonate

small molecules

FDA

2021-03-29

—

Lispiro LLC

Sodium-3-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate

small molecules

FDA

2021-02-23

—

Blade Therapeutics, Inc.

Fc-fusion protein comprised of an anti-CXCR4 i-body tethered at its C-terminus to constant domains 2 and 3 of the Fc region of a mutated human IgG1

proteins

FDA

2021-02-22

—

AdAlta Limited

N-(N-(4-(trifluoromethoxy)phenyl) carbamimidoyl)pyrrolidine-1-carboximidamide acetate (Or N1-(4-trifluoromethoxy)phenyl-N5-pyrrolidine biguanide acetate)

small molecules

FDA

2021-02-01

—

ImmunoMet Therapeutics Inc.

Treprostinil

small molecules

FDA

2020-12-07

—

United Therapeutics Corporation

Caveolin-1 Scaffolding Domain 7-Mer

peptides

FDA

2020-09-09

—

Lung Therapeutics, Inc.

Bis-(3-deoxy-3-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)-B-D-galactopyranosyl) sulfane

small molecules

FDA

2020-08-25

—

Galecto Biotech AB

Olitigaltin

small molecules

EMA

2020-08-21

—

Galecto Biotech AB

Sodium cromoglicate

small molecules

EMA

2020-06-26

—

IQVIA RDS Spain S.L.

Benzeneacetamide, 2-[2-[2-[[2-methoxy-4-(1-methyl-4-piperidinyl)phenyl]amino]-5-(trifluoromethyl)-4-pyrimidinyl]ethyl]-

small molecules

FDA

2020-05-18

—

Amplia Therapeutics

4-fluoro-5-((6-methylhexahydropyrrolo[3,4-b] pyrrol-5(1H)-yl) sulfonyl) isoquinoline

small molecules

FDA

2020-02-05

—

The National Institutes of Pharmaceutical R&D Co., Ltd

drug component, inhaled nitric oxide, of the inhaled nitric oxice/INOpulse® Device combination product

small molecules

FDA

2019-09-10

—

Mallinckrodt Pharmaceuticals Ireland Limited

(2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol Hydrogen Chloride

small molecules

FDA

2019-08-05

—

Daewoong Pharmaceutical Co., Ltd.

N-(4-amino-3,4-dioxo-1-phenylbutan-2-yl)-4-(2-fluorophenyl)-2-methyloxazole-5-carboxamide

small molecules

FDA

2019-07-22

—

Blade Therapeutics, Inc.

(R)-N-(1-(1-(1H-indazol-5-yl)-3-methyl-2,4-dioxo-1,3,8-triazaspiro[4,5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide

small molecules

FDA

2019-07-18

—

X-Rx, Inc.

(6-(4-((4-(1H-pyrazol-4-yl)phenyl)amino)pyrimidin-2-yl)-1-methyl-1H-indol-2-yl)(3,3-difluoroazetidin-1-yl)methanone

small molecules

FDA

2019-05-08

—

Beijing Tide Pharmaceutical Co., Ltd

cromolyn solution

small molecules

FDA

2019-04-11

—

Respivant Sciences, Inc.

saracatinib

small molecules

FDA

2019-03-11

—

AstraZeneca Pharmaceuticals, LP

5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine

small molecules

FDA

2019-02-25

—

Molecure S.A. (previously OncoArendi S.A.)

Autotaxin inhibitor

small molecules

FDA

2019-01-14

—

Bridge Biotherapeutics, Inc

small interfering RNA agent that targets human transforming growth factor-Eszett1 messenger RNA

RNAs

FDA

2018-12-19

—

Toray Industries, Inc.

15(S)-hydroxy-(5Z,8Z,11Z,13E,17Z)-eicosapentaenoic acid ethyl ester

small molecules

FDA

2018-12-17

—

Afimmune

(1S,3S)-3-((2-methyl-6-(1-methyl-5-(((methyl(propyl)carbamoyl)oxy)methyl)-1H-1,2,3-triazol-4-yl)pyridin-3-yl)oxy)cyclohexane-1-carboxylic acid

small molecules

FDA

2018-12-17

—

Bristol-Myers Squibb Company

5-(3,5-Dimethyl-4-hydroxybenzylamino)-3-(4-morpholin-4-yl-phenylamino)-1H-pyrazole-4-carboxylic acid amide

small molecules

FDA

2018-12-07

—

Metagone Biotech Inc.

Tilorone

small molecules

EMA

2018-08-24

—

Professor Marjukka Myllärniemi

(S)-(-)-3-(4-aminophenyl)-2-methoxypropanoic acid

small molecules

EMA

2018-08-24

—

Nogra Pharma Limited

small molecule inhibitor of integrins avb6 and avb1

small molecules

FDA

2018-08-01

—

Pliant Therapeutics, Inc.

soidum (5-(3-cyanopyrazolo[1,5-a]pyridin-5-yl)-2-methoxypyridin-3-yl)((2,4-difluorophenyl)sulfonyl)amide

small molecules

FDA

2018-07-09

—

Sunshine Lake Pharma Co., Ltd

small molecule selective inhibitor of c-Jun N-terminal kinase

small molecules

FDA

2018-06-27

—

Celgene Corporation

N-(2-chloro-6-propoxypyridin-4-yl)-2-(2-hydroxyethyl)-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazinecarboxamide

small molecules

FDA

2018-05-23

—

Arroyo Biosciences, LLC

6-(4-(4-(2,3-Dicholorophenyl) piperazin-1-yl) butoxy)-2H-benzo [b] [1,4] oxazin-3(4H)-one hydrochloride

small molecules

FDA

2018-04-04

—

Reviva Pharmaceuticals, Inc.

plasminogen (Human)

proteins

FDA

2017-12-14

—

Kedrion Biopharma Inc.

yinfenidone

small molecules

FDA

2017-08-10

—

Sunshine Lake Pharma Co., Ltd

2-((2-ethyl-6-(4-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)-piperazin-1-yl)-8-methylimidazo[1,2-a]pyridin-3-yl)-(methyl)amino)-4-(4-fluorophenyl)-thiazole-5-carbonitrile

small molecules

FDA

2017-06-08

—

Galapagos NV

small molecule inhibitor of the Wnt pathway

small molecules

FDA

2017-06-06

—

Biosplice Therapeutics, Inc.

nitric oxide

small molecules

FDA

2017-01-31

—

VERO Biotech

3-[4-(lH-imidazol-l-ylmethyl)phenyl]-5-(2-methylpropyl) thiophene-2-[(N-butyloxylcarbamate)-sulphonamide] sodium salt

small molecules

FDA

2017-01-25

—

Vicore Pharma AB

human single domain antibody-like protein inhibitor of the chemokine receptor type 4

antibodies

FDA

2017-01-11

—

AdAlta Limited

Ziritaxestat [GLPG1690]

small molecules

EMA

2016-08-29

—

Lakefront Biotherapeutics

carbon monoxide

small molecules

FDA

2016-08-16

—

Proterris, Inc.

3-[4-(1H-imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)thiophene-2-[(N-butyloxylcarbamate)-sulphonamide] sodium salt

small molecules

EMA

2016-07-14

—

Vicore Pharma AB

monoclonal antibody targeting eotaxin-2

antibodies

FDA

2015-10-29

—

ChemomAb, Ltd.

Setogepram sodium [PBI-4050]

small molecules

EMA

2015-10-09

—

[INACTIVE] Prometic Pharma SMT B.V.

tetra-substituted porphyrin derivative containing manganese (III)

small molecules

FDA

2015-03-16

—

Aeolus Pharmaceuticals

lebrikizumab

antibodies

FDA

2015-03-09

—

Eli Lilly and Company

3-pentylbenzenacetic acid sodium salt

small molecules

FDA

2015-02-11

—

Liminal BioSciences Limited

1-(6-benzothiazolylsulfonyl)-5-chloro-1H-indole-2-butanoic acid

small molecules

EMA

2014-11-19

—

Inventiva

tipelukast

small molecules

FDA

2014-10-20

—

MediciNova, Inc.

pirfenidone

small molecules

FDA

2014-07-31

—

Avalyn Pharma, Inc.

Humanised anti-alpha ν beta 6 monoclonal antibody

antibodies

EMA

2014-07-29

—

Biogen Netherlands B.V.

Nintedanib esylate [Ofev]

small molecules

EMA

2013-04-26

—

Boehringer Ingelheim International GmbH

Tralokinumab [CAT-354]

antibodies

EMA

2012-11-08

—

Medimmune Limited

tralokinumab

antibodies

FDA

2012-07-24

—

MedImmune Ltd.

Recombinant human pentraxin-2

proteins

EMA

2012-07-17

—

Roche Registration GmbH

pamrevlumab

antibodies

FDA

2012-07-06

—

FibroGen, Inc.

recombinant human Pentraxin-2; recombinant human Serum Amyloid P

proteins

FDA

2012-02-17

—

Genentech, Inc.

Tanzisertib [CC-930]

small molecules

EMA

2011-12-09

—

Celgene Europe Limited

4-[[9-(3S)-tetrahydro-3-furanyl]-8-[(2,4,6-trifluorophenyl)amino]-9H-purin-2-yl]amino]-trans-cyclohexanol

small molecules

FDA

2011-09-23

—

Celgene Corporation

bispecific antibody targeting interleukin 4 (IL-4) and interleukin 13 (IL-13)

antibodies

FDA

2011-09-14

—

Sanofi US Services, Inc., A SANOFI COMPANY

nintedanib [OFEV]

small molecules

FDA

2011-06-29

2014-10-15

Boehringer Ingelheim Pharmaceuticals, Inc.

Recombinant humanized anti-LOXL2 monoclonal antibody

antibodies

FDA

2011-04-18

—

Gilead Sciences, Inc.

(R)-1-phenylethyl-5-(4-biphenyl-4-cyclopropanecarboxylic acid)-3-methylisoxazole-4-yl carbamate sodium salt

small molecules

FDA

2011-04-15

—

Bristol-Myers Squibb Company

Sar9, Met(O2)11-Substance P

proteins

FDA

2011-03-16

—

New Amsterdam Sciences

2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione

small molecules

EMA

2010-11-26

—

Calliditas Therapeutics AB

Ambrisentan [ABS-10-001]

small molecules

EMA

2010-10-01

—

Gilead Sciences International Limited

2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-C]pyridine-3,6(2H,5H)-dione

small molecules

FDA

2010-09-21

—

Calliditas Therapeutics AB

humanized monoclonal antibody against human integrin alphaVbeta6

antibodies

FDA

2010-08-05

—

Biogen Idec, Inc.

Cintredekin Besudotox

proteins

FDA

2010-04-30

—

Insys Development Company, Inc.

Macitentan [Opsumit]

small molecules

EMA

2010-01-28

—

Janssen Cilag International

ambrisentan

small molecules

FDA

2009-12-23

—

Gilead Sciences, Inc.

purified bovine type collagen

proteins

FDA

2009-04-27

—

Magnolia Therapeutics LLC

macitentan

small molecules

FDA

2009-04-14

—

Actelion Pharmaceuticals Ltd

bosentan

small molecules

FDA

2008-09-30

—

Actelion Pharmaceuticals Ltd

Bosentan monohydrate [Tracleer]

small molecules

EMA

2008-09-05

—

[INACTIVE] Actelion Registration Limited

ammonium tetrathiomolybdate

small molecules

FDA

2008-05-05

—

Pipex Pharmaceuticals, Inc.

Fresolimumab

antibodies

EMA

2008-04-01

—

[INACTIVE] Sanofi B.V.

carlumab

antibodies

FDA

2007-11-08

—

Janssen Biotech, Inc.

Interferon gamma

proteins

EMA

2007-10-29

—

mondoBIOTECH Laboratories AG

Interferon gamma

proteins

FDA

2007-10-11

—

mondoBIOTECH Laboratories AG

Interferon gamma-1B

proteins

EMA

2005-05-27

—

Intermune UK Limited

Acetylcysteine

small molecules

EMA

2005-01-26

—

Zambon Group S.p.A.

Pirfenidone [Esbriet]

small molecules

EMA

2004-11-16

—

Roche Registration GmbH

Heparin sodium [FibroCure]

other

EMA

2004-09-02

—

Werner Seeger

human anti-transforming growth factor-B1,2,3

antibodies

FDA

2004-07-09

—

Genzyme Corporation

pirfenidone [ESBRIET]

small molecules

FDA

2004-03-05

2014-10-15

Legacy Pharma Inc.

interferon gamma-1b

proteins

FDA

2002-09-12

—

InterMune, Inc.

Interferon beta-1a (recombinant human)

proteins

FDA

1999-01-07

—

Biogen Idec, Inc.

Explority AI logo

228 Park Ave S,
New York, USA.

At Explority, we build first-of-its-kind AI to bring clarity to the earliest and riskiest stages of pharmaceutical research by forecasting which therapies are most likely to succeed. Explority AI web and mobile applications are properties of the Explority AI Inc., a company registered in the United States (File No. 10320493).
For all questions: support@explority.ai

About

Home

Team

Contact

Our AI

Solutions

How it works

Diseases

More

Blog

Terms of Use

Privacy Policy

Copyright © 2026 Explority AI Inc.

Explority AI logo

228 Park Ave S,
New York, USA.

At Explority, we build first-of-its-kind AI to bring clarity to the earliest and riskiest stages of pharmaceutical research by forecasting which therapies are most likely to succeed. Explority AI web and mobile applications are properties of the Explority AI Inc., a company registered in the United States (File No. 10320493).
For all questions: support@explority.ai

About

Home

Team

Contact

Our AI

Solutions

How it works

Diseases

More

Blog

Terms of Use

Privacy Policy

Copyright © 2026 Explority AI Inc.

Explority AI logo

228 Park Ave S,
New York, USA.

At Explority, we build first-of-its-kind AI to bring clarity to the earliest and riskiest stages of pharmaceutical research by forecasting which therapies are most likely to succeed. Explority AI web and mobile applications are properties of the Explority AI Inc., a company registered in the United States (File No. 10320493).
For all questions: support@explority.ai

About

Home

Team

Contact

Our AI

Solutions

How it works

Diseases

More

Blog

Terms of Use

Privacy Policy

Copyright © 2026 Explority AI Inc.