RARE DISEASE
Radiation-induced disorder
Radiation-induced disorder
Radiation-induced disorder
Drug discovery
1
drug
With orphan designation
Overview
Radiation-induced disorders encompass acute and chronic conditions caused by ionizing radiation exposure, affecting cardiovascular, neurological, hematopoietic, and integumentary systems. Acute radiation syndrome (ARS) presents with GI, hematopoietic, and neurovascular symptoms [1][6][11], while chronic effects include vascular disease [2][14], neurocognitive deficits [3][13], and treatment-related cancers [5][12]. Pathophysiology involves DNA damage, oxidative stress, and tissue fibrosis [1][20].
Therapies
Acute: Decontamination, cytokines (G-CSF), blood transfusions, and infection prophylaxis [1][11][16]
Chronic: Hyperbaric oxygen for brain injury [3], ACE inhibitors/statin therapy for cardiac fibrosis [8][20], and neuropathic pain management (gabapentinoids) [4][17]
Preventive: Proton beam therapy, deep-inspiration breath-hold (DIBH) techniques [8][14]
Categories: rare disorders due to toxic effects
Research Papers
2,608 drug discovery papers about Radiation-induced disorder, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,608 drug discovery papers about Radiation-induced disorder, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Distinct Metabolomic and Proteomic Signatures of Early Brain Damage Triggered by the Entrance Plateau Versus the Spread-Out Bragg Peak of Proton Radiation.
Proton therapy spares normal tissues better than photon therapy, potentially reducing toxicity while maintaining tumor control. However, challenges remain due to variations in proton dose distribution, particularly at the distal edge of the spread-out Bragg peak (SOBP); for organs at risk, such variation is crucial. We evaluated the biological effects by comparing two positions of the proton profile, the entrance plateau (EP) and SOBP, in a murine model and investigated distinct metabolomic and proteomic signatures. Mice exposed to the EP beam segment (LETd = 0.8 keV/µm) exhibited less weight reduction than their SOBP-irradiated counterparts (LETd = 2.6 keV/µm). Two hours post-irradiation, the SOBP caused more severe DNA damage in the hippocampus and thalamus. Hematoxylin and eosin staining revealed eosinophil aggregation in both groups, with more surviving neurons in the EP group. Metabolomic profiles differed more between the EP and SOBP groups at 2 h than at 3 days post-irradiation. Relative to EP, SOBP irradiation at 2 h increased fructose-1,6-bisphosphate (FBP), dihydroxyacetone phosphate (DHAP), and inosine but decreased prostaglandin F2α; subsequently, proteomic analysis at day 3 showed that calcium signaling, NF-κB, and endocytosis pathways were enriched in the SOBP group. Combined multi-omics analysis further demonstrated that SOBP irradiation significantly activated the pentose phosphate pathway, purine metabolism, and phospholipase D signaling, while concurrently suppressing arachidonic acid metabolism. Our findings underscore the need for early detection of proton-induced brain toxicity and demonstrate that the higher-LET SOBP segment causes more severe damage than the EP. Targeting these dysregulated multi-omics pathways may offer a promising strategy for mitigating radiation-induced brain injury during proton therapy.
2026-08-13 | Adipose Dysfunction Caused by Obesity and Radiation Therapy Rewires the Prostate Stroma Toward Tumor Progression.
Obesity is associated with chronic adipose dysfunction characterized by oxidative stress, inflammation, senescence, and fibrosis, which can promote tumor progression. In prostate cancer, periprostatic adipose tissue may directly influence the prostate microenvironment. Radiation therapy is widely used in prostate cancer, but radiation-induced adipose dysfunction in obesity and its impact on the prostate microenvironment remain poorly understood. In the present study, we investigated the impact of obese and irradiated obese adipose microenvironments on prostate stromal remodeling, as well as the activation of prostate fibroblasts mediating prostate cancer progression. We utilized a high-fat diet obesity model with localized adipose irradiation in animal and in vitro studies using obese and irradiated obese adipocytes. Prostates from obese and irradiated obese mice exhibited epithelial hyperplasia, increased stromal activation markers, oxidative damage, and senescence. Interestingly, radiation maintained the obesity-induced pathological behavior in the prostate, rather than elevating it. The conditioned media from obese and irradiated obese adipocytes induced stromal activation markers, senescence, extracellular H2O2 production, pro-survival signaling, and inflammation. Notably, the only significant changes observed with the addition of radiation to obesity were enhancement of fibrosis-associated features and infiltration of CD4+ T cells. Functionally, prostate myofibroblasts or senescent fibroblasts promoted prostate cancer migration and induced epithelial-to-mesenchymal transition and elevated pro-tumorigenic pathways. Cytokine profiling identified elevated levels of CXCL10 and CXCL11 from myofibroblasts, and pharmacological inhibition of CXCR3 significantly reduced prostate cancer migration, implicating this signaling axis in activated fibroblast-driven tumor-promoting crosstalk. Collectively, these findings demonstrate obesity-associated adipose dysfunction reprograms the prostate microenvironment toward a pro-tumorigenic state, while radiation sustains rather than markedly amplifies these pathological changes, identifying obese adipose-stromal crosstalk and the CXCL10/CXCL11-CXCR3 axis as potential therapeutic targets to inhibit prostate cancer progression.
2026-08-13 | Bronchial Chondronecrosis After Proton Beam Therapy Successfully Treated With Hyperbaric Oxygen Therapy.
Airway chondronecrosis is a rare but serious manifestation of late radiation-induced toxicity. We report the case of a 67-year-old woman with epidermal growth factor receptor mutation-positive lung adenocarcinoma who developed bronchial chondronecrosis 8 years after proton-beam therapy (PBT) to the right upper lobe nodule. For 2 years, she was treated for cough-variant asthma owing to a persistent cough. Chest computed tomography (CT) showed only a subtle irregularity of the right main bronchial wall. Bronchoscopy revealed yellow necrotic deposits in the right main bronchi. Although a conventional forceps biopsy was nondiagnostic, transbronchial lung cryobiopsy (TBLC) obtained cartilage specimens, confirming bronchial chondronecrosis without malignancy. Hyperbaric oxygen therapy (HBOT) (90 sessions in total) led to symptomatic and bronchoscopic improvement. This case highlights that very-late-onset airway chondronecrosis following PBT must be considered, even with minimal CT findings. TBLC is a valuable tool for diagnosing submucosal lesions and HBOT appears to be an effective therapy.
2026-08-07 | Lysyl oxidase (LOX) family proteins in extracellular matrix homeostasis: roles in disease and radiation-induced pathogenesis.
The extracellular matrix (ECM) not only provides structural support in tissues but also regulates cellular processes and tissue homeostasis. The lysyl oxidase (LOX) family of enzymes, consisting of LOX and lysyl oxidase-like enzymes (LOXL1-4), is involved in ECM remodeling by catalyzing the crosslinking of collagen and elastin. Dysregulation of these enzymes is implicated in the pathogenesis of various diseases, including organ fibrosis and tumor development. Furthermore, LOX family members have been shown to affect radiotherapy responses, with specific involvement in radioresistance and radiation-induced fibrosis. This review summarizes the structural and functional characteristics of the LOX family, highlighting their roles in fibrotic diseases such as pulmonary fibrosis, liver fibrosis, and cardiac diseases, their roles in tumor progression, relevance in radiotherapy, and treatment targeting LOX and LOXLs. Understanding the underlying mechanisms and potential therapies is critical for developing novel strategies in both disease identification and management.
2026-08-07 | Late-onset radiation-induced myocardial fibrosis after lung cancer radiotherapy: correlation of cardiac MRI with radiation treatment planning CT.
A 55-year-old male with history of prior LCx STEMI and remote chest external beam radiation underwent cardiac MRI(CMR) for aortic regurgitation. CMR demonstrated Nonischemic late gadolinium enhancement (LGE), valvular thickening, and pericardial effusion. Correlation with radiation treatment planning CT supported the diagnosis of radiation-induced myocardial fibrosis despite a history of prior STEMI.
antibodies
2026-08-17 | Hypo-fractionated radiotherapy combined with PD-1 inhibitor for relapsed/refractory B-cell lymphoma after failure to CD19 CAR-T therapy.
B-cell lymphoma relapsed after chimeric antigen receptor (CAR) T-cell therapy lacks effective standard treatment options and generally has a poor prognosis, largely due to mechanisms such as immune escape and tumor heterogeneity. Radiotherapy combined with immune checkpoint inhibitors (ICIs) may exert synergistic effects, including local tumor control through radiation-induced DNA damage and systemic immune activation via modulation of the tumor immune microenvironment. This case report describes a patient with relapsed/refractory (R/R) B-cell lymphoma who experienced multiple relapses and treatment failures, including CD19 CAR-T therapy. Almost 7 years after CAR-T treatment, the patient developed disease relapse and was diagnosed with follicular lymphoma (FL). The patient received a personalized treatment strategy combining hypo-fractionated radiotherapy (30 Gy/5 fractions) and the Programmed Death-1 (PD-1) inhibitor camrelizumab, achieving complete remission (CR) and remaining disease-free for over 43 months. This case highlights the potential efficacy of this combination strategy in R/R lymphoma, particularly in patients with limited treatment options.
2026-08-14 | Radiation-induced CD200+ tumor-associated macrophages suppress eosinophil-mediated antitumor immunity through CD200R signaling in hepatocellular carcinoma.
Radiotherapy elicits dual immunomodulatory effects in cancer, activating antitumor immunity while paradoxically inducing immunosuppression, which limits therapeutic efficacy. The molecular pathways mediating postradiation immune escape in hepatocellular carcinoma (HCC) remain poorly defined. Here, we elucidate a previously uncharacterized mechanism whereby radiotherapy drives the accumulation of CD200+ tumor-associated macrophages (TAMs) that suppress eosinophil-mediated antitumor immunity in patients with HCC. Through single-cell RNA sequencing of postradiotherapy HCC specimens, we demonstrated that radiation-induced DNA damage activated the cytosolic DNA-sensing STING pathway in TAMs, triggering NF-κB-dependent CD200 upregulation independent of canonical type I interferon signaling. These radiation-induced CD200+ TAMs exhibited an immunosuppressive phenotype and correlated with adverse clinical outcomes in HCC patients. Mechanistically, CD200+ TAMs established an immunosuppressive axis by recruiting CCR1+ eosinophils through CCL3-mediated chemotaxis, subsequently inhibiting their antitumor functions via CD200-CD200R engagement. This interaction comprehensively suppressed NF-κB activation in eosinophils, impaired their antigen-presenting capacity and Th2 cytokine secretion and abrogated their ability to support CD8+ T-cell-mediated cytotoxicity. Therapeutic blockade of CD200R following radiotherapy restored eosinophil effector functions, promoted central memory T-cell formation, and significantly enhanced tumor control across multiple preclinical HCC models. Remarkably, CD200R antagonism sensitized PD-1-refractory "cold" tumors to radioimmunotherapy combinations, overcoming primary resistance. Our findings establish STING-driven CD200+ TAM accumulation and subsequent eosinophil dysfunction as critical determinants of radioresistance, positioning CD200R blockade as a promising therapeutic strategy to potentiate radioimmunotherapy responses in patients with HCC. Graphical abstract of the study findings. Radiotherapy-induced STING signaling activation promotes the accumulation of CD200+ TAMs. These CD200+ TAMs facilitate the recruitment of eosinophils via the CCL3-CCR1 chemotaxis axis while simultaneously suppressing eosinophil-mediated antitumor activity through CD200-CD200R engagement (left panel). Targeted blockade of CD200R following radiotherapy unleashed the antitumor potential of eosinophils, leading to enhanced infiltration and effector function of CTLs (right panel).
2026-08-07 | Giant retinal telangiectasia after ophthalmic plaque radiation therapy.
Radiation retinopathy is a known complication of plaque brachytherapy, characterized by progressive retinal vasculature damage. This study describes the clinical course of two cases of late post-radiation giant retinal telangiectasias, discovered in patients treated with radiation for choroidal melanomas. A single center chart review revealed two patients with giant retinal telangiectasis. Each patient had been treated with palladium-103 (103Pd) plaque brachytherapy for choroidal melanoma. Clinical data revealed their presentation, clinical course and treatment. Giant retinal telangiectasias were associated with pre-retinal hemorrhages, exudates, and edema occurring 7 and 9 years after irradiation, with macular telangiectasia exhibiting a more fulminant course. It required both laser photocoagulation and periodic intravitreal steroid therapy; both received intravitreal anti-vascular endothelial growth factor injections. Treatment was given based on both telangiectasia activity and other radiation-induced ocular morbidities. Giant retinal telangiectasias are a rare complication that may occur after ophthalmic plaque radiation therapy.
2026-07-25 | Induction toripalimab plus chemotherapy sequential concurrent chemoradiotherapy with nimotuzumab followed by toripalimab maintenance in stage IVB hypopharyngeal squamous cell carcinoma: a single-arm phase 2 study.
Optimal induction chemoimmunotherapy sequential concurrent chemoradiotherapy (cCRT) in locally advanced hypopharyngeal squamous cell carcinoma (HSCC) remains undefined. This study aimed to evaluate toripalimab plus chemotherapy sequential cCRT with nimotuzumab, followed by toripalimab maintenance in unresectable stage IVB HSCC. In this single-arm, open-label, phase 2 study, untreated patients received two 21-day cycles of induction toripalimab 240 mg (d1) plus nab-paclitaxel 230 mg/m2 (d1) and cisplatin/nedaplatin 40 mg/m2 (d1-2) sequential cCRT (helical tomotherapy; nab-paclitaxel 230 mg/m2 (d1, 22, 43)) with nimotuzumab 200 mg weekly for 7 weeks. Subsequently, toripalimab maintenance was administered for eight cycles. Primary endpoint was progression-free survival (PFS). From March 16, 2022 to April 24, 2024, 31 patients completed induction chemoimmunotherapy. With a median follow-up of 31 months, median PFS and overall survival (OS) were not reached; 2-year PFS and OS rates were 67.7% and 86.4%. The 2-year larynx preservation rate was 93.3%. 30 (96.8%) patients achieved the best objective response, with 28 (90.3%) complete responses and 2 (6.5%) partial responses. The most common grade 3-4 treatment-related adverse events (TRAEs) were radiation-induced oropharyngeal mucositis and decreased appetite (each 46.9%). No grade 5 and fatal TRAEs occurred. No difficulties in speech and swallowing functions were reported in 96.8% of patients. There was no significant association between PFS and PD-L1 combined positive score, epidermal growth factor receptor expression, tumor-infiltrating T-lymphocytes, tumor mutational burden, or genetic alterations. High baseline peripheral CD3+ and CD8+CD28+ T-cell levels were associated with favorable PFS. Exploratory biomarker analyses identified that patients without disease progression after maintenance exhibited significantly higher levels of CD8+CD28⁻ T cells with a memory phenotype and lower B-cell levels. This exploratory study demonstrated preliminary efficacy and larynx preservation with manageable toxicity, possibly supporting further evaluation of induction toripalimab plus chemotherapy sequential cCRT with nimotuzumab, followed by toripalimab maintenance in stage IVB HSCC. Peripheral lymphocytes may warrant further investigation as candidate biomarkers in locally advanced disease. NCT05860335; ChiCTR2300074672.
2026-05-29 | Effect and safety of tislelizumab combined with anlotinib and radiotherapy in advanced hepatocellular carcinoma: A single-arm, single-center, phase II clinical study.
Immune checkpoint inhibitors plus targeted therapy remains the mainstay of treatment for advanced hepatocellular carcinoma (HCC), yet its efficacy is limited. This study aimed to evaluate the efficacy and safety of tislelizumab combined with anlotinib and radiotherapy as first-line therapy for advanced HCC. This was a single-arm, single-center, phase II clinical trial. A total of 45 patients with advanced HCC were enrolled and administered first-line therapy consisting of tislelizumab plus anlotinib combined with radiotherapy. Stratification was performed according to pretreatment portal vein tumor thrombus (PVTT) status, Barcelona Clinic Liver Cancer (BCLC) stage, and median biologically effective dose (BED) of the gross tumor volume (GTV). Treatment response was assessed using the modified Response Evaluation Criteria in Solid Tumors, and adverse events (AEs) were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety profiles reflected by AEs. The median BED of the GTV was 47.9 Gy (Gy). The ORR and DCR were 62.2% (28/45) and 75.6% (34/45), respectively. Median PFS and OS were 11.0 months (95% CI 1.444-14.081) and 26.7 months (95% CI 1.749-25.178), respectively. ORR and DCR were comparable across subgroups defined by PVTT status, BCLC stage, and BED level (all p > 0.05). No significant differences in PFS or OS were observed among these subgroups (all p > 0.05). Most AEs (82.2%, 37/45) were grade 1/2 and well tolerated. Grade 3/4 AEs occurred in 13.3% (6/45) of patients. No grade 5 events, radiation-induced liver disease, or treatment-related deaths were reported. Tislelizumab combined with anlotinib and radiotherapy demonstrates promising efficacy and acceptable safety as first-line treatment for advanced HCC. Clinical outcomes appear to be independent of PVTT status, BCLC stage, or radiation BED level.Registration Number in the Chinese Clinical Trial Registry: ChiCTR2000039022 (10/13/2020). https://www.chictr.org.cn/index.html.
proteins
2026-08-02 | A self-sustaining repair circuit drives the progression of pulmonary fibrosis.
Pulmonary fibrosis is a progressive and often fatal lung disorder whose clinical behavior is not fully explained by conventional injury-driven models. Fibrosis frequently progresses after the initiating insult has resolved, anti-inflammatory therapies have shown limited benefit in idiopathic pulmonary fibrosis, and current antifibrotic drugs slow but rarely reverse disease progression. Moreover, diverse conditions including idiopathic pulmonary fibrosis, post-ARDS or post-infectious fibrosis, radiation-induced injury, drug toxicity, and bronchopulmonary dysplasia arise from distinct causes yet may converge toward shared features of persistent fibrotic remodeling. Here we propose that pulmonary fibrosis represents a self-sustaining pathological tissue-repair state rather than a continuously injury-dependent process. Failure of alveolar epithelial regeneration produces persistent cellular senescence and chronic distress signaling that recruits reparative immune responses. These signals promote fibroblast survival and myofibroblast persistence, leading to extracellular matrix deposition and progressive tissue stiffening. Increased matrix stiffness further disrupts epithelial recovery through mechanotransduction pathways, creating a feedback loop linking epithelial dysfunction, immune mis-repair, stromal stabilization, and mechanical reinforcement. Within this framework, fibrosis persists because the lung behaves as a chronically unhealed wound. This model may help explain disease progression and heterogeneity and suggests that effective therapies must restore epithelial regeneration and disrupt system-level feedback rather than target single profibrotic pathways.
2026-07-14 | Advances in the prevention and treatment of radiation-induced brain necrosis: a narrative review.
Radiation-induced brain necrosis (RBN) is a serious and often debilitating complication of radiotherapy for intracranial and head and neck malignancies, with an incidence of 5-25%. It can lead to significant cognitive impairment, neurological deficits, and increased mortality. As radiotherapy techniques advance and patient survival improves, effective prevention and management of RBN have become critical clinical priorities. This review systematically summarizes the current understanding of RBN pathogenesis, highlighting the central roles of vascular injury (endothelial damage, HIF-1α/VEGF dysregulation) and neuroinflammation (microglial activation, cytokine release). We discuss recent advances in preventive strategies, including refined radiotherapy modalities such as intensity-modulated radiotherapy (IMRT), fractionated stereotactic radiosurgery (fSRS), and FLASH ultra-high-dose-rate radiotherapy, as well as pharmacological prophylaxis using bevacizumab and neuroprotective agents (NGF, GM1, edaravone). Established and emerging treatment options are reviewed, including corticosteroids, bevacizumab, hyperbaric oxygen therapy (HBOT), laser interstitial thermal therapy (LITT), and Colony Stimulating Factor 1 Receptor(CSF1R) inhibitors. We also cover innovations in imaging for early detection and differential diagnosis, including magnetic resonance spectroscopy (MRS), perfusion-weighted imaging (PWI), and Positron Emission Tomography-Computed Tomography(PET/CT) with advanced tracers (11C-methionine, 18F-FET). Finally, we summarize updates to international management guidelines, particularly the 2022 DEGRO guidelines, and propose future directions for research and therapeutic optimization.
2026-07-13 | Hematopoietic stem cell transplantation-associated partial lipodystrophy.
Hematopoietic stem cell transplantation (HSCT)-associated partial lipodystrophy (HSCT-PL) is a serious metabolic complication that develops in remote period among childhood cancer survivors treated with HSCT with total body irradiation (TBI). Since the first proposal in 2013, HSCT-PL seems to be increasingly recognized as a distinct disease entity. The patients with HSCT-PL show profound metabolic dysfunction including insulin resistance, diabetes, elevated triglycerides, and hepatic steatosis. Their body mass index is low-normal, although they show visceral fat accumulation and increased waist-to-hip ratio. In addition, HSCT-PL is characterized by Dunnigan phenotype: lipoatrophy in buttock and extremities combined with lipohypertrophy in face and neck. Although the precise pathogenesis is still obscure, radiation-induced damage to adipose progenitor cells, leading to accelerated senescence, seems to be a main pathway. Literature survey identified 17 patients of HSCT-PL with sufficient information from 12 reports. Among them, clear female predominance (15 females) and possible ethnic difference in disease prevalence (11 Japanese) were ascertained. Genetic factors may be involved in those epidemiological traits. There remains much to be clarified, including establishment of reliable diagnostic procedure, elucidation of long-term prognosis, and invention of effective treatment. Metreleptin is one of the promising options, and the accumulation of its therapeutic efficacy are warranted.
2026-07-06 | Tissue Resilience in Radiation-Induced Injury: A Hypothesis-Generating Review of Heat Shock Protein 27 in Osteoradionecrosis of the Jaw
Osteoradionecrosis of the jaw (ORNJ) remains one of the most severe late complications of head and neck radiotherapy. Current evidence suggests that ORNJ is a progressive and biologically heterogeneous disorder driven by microvascular injury, chronic hypoxia, oxidative stress, fibro-atrophic remodeling, impaired bone turnover, immune dysregulation, and systemic susceptibility factors. Within this complex pathogenic network, heat shock protein 27 (HSP27) emerges as a biologically plausible but unexplored mediator. HSP27 regulates multiple stress-response pathways, including redox homeostasis, cytoskeletal stabilization, endothelial protection, apoptosis control, fibroblast activation, and osteoblast–osteoclast function, all of which overlap with key mechanisms implicated in ORNJ. However, no studies have directly investigated HSP27 expression, activation, or functional significance in irradiated mandibular tissues or ORNJ-specific cohorts. This review summarizes current knowledge of ORNJ pathobiology, examines potential mechanistic links with HSP27, and outlines future research priorities involving biomarker development, tissue-level characterization, preclinical modeling, and therapeutic targeting. Integrating HSP27 into ORNJ research may improve understanding of pathogenesis, risk stratification, and the development of novel preventive and therapeutic strategies.
2026-05-27 | Protective Efficacy of Met-Ser-Arg Against Irradiation-Related Testicular Injury†.
Ionizing radiation poses a significant risk to male fertility by inducing testicular damage, yet effective protective strategies remain limited. The tripeptide Met-Ser-Arg (MSA) has demonstrated potential in alleviating radiation-induced oxidative stress and lipid metabolic disorders, prompting investigation into its protective effects on the male reproductive system. Male BALB/c mice were exposed to X-ray irradiation (0.5 Gy/day for 5 days) to establish a testicular injury model, followed by MSA treatment. Testicular structure and function were evaluated through histology, electron microscopy, computer-assisted sperm analysis (CASA), and quantitative PCR. MSA significantly alleviated radiation-induced testicular damage, restoring the structural integrity and function of spermatogenesis tubules while increasing both the height of the spermatogenic epithelium and germ cell number. Sperm quality and motility were markedly improved, and the expression of several sperm cell molecular markers was favorably adjusted. Mechanistic investigations revealed that MSA regulated lipid metabolism by upregulating fatty acid β-oxidation enzymes, including ACSL3 and CPT1A, while downregulating the lipid synthase DGAT2, thereby reducing lipid droplet accumulation. MSA also attenuated radiation-induced reactive oxygen species and malondialdehyde levels, enhanced antioxidant capacity through upregulation of NRF2 and HO-1, and preserved mitochondrial structure and function via upregulation of PGC1A. Furthermore, MSA reduced apoptosis by lowering the levels of Cleaved-caspase 3 and γH2AX. Collectively, these findings demonstrate that MSA ameliorates radiation-induced testicular injury and improves sperm quality through coordinated regulation of lipid metabolism, antioxidant pathway activation, mitochondrial protection, and apoptosis inhibition, providing a theoretical basis for its potential clinical application in the context of radiotherapy.
cell therapies
2026-08-02 | Muse cell transplantation attenuates neuroinflammation and preserves endothelial reparative responses after radiation-induced brain injury.
Radiation-induced brain injury (RIBI) is a serious complication of cranial radiotherapy and currently lacks effective disease-modifying treatment. Persistent neuroinflammation and neurovascular dysfunction are considered central to RIBI progression, making them attractive therapeutic targets for regenerative intervention. Multilineage-differentiating stress-enduring (Muse) cells are a non-tumorigenic pluripotent-like cell population with reported reparative and immunomodulatory properties, but their therapeutic potential in RIBI has not been defined. In this study, we evaluated the effects of Muse cell transplantation in experimental RIBI using in vitro neurovascular co-culture systems and in an vivo rat model. Irradiation induced marked activation of inflammasome-related signaling, endothelial injury, and neurological impairment. Muse cells suppressed the expression of NLRP3, AIM2, ASC, Caspase-1, IL-1β, and IL-18 in irradiated co-culture systems, while preserving endothelial proliferative and angiogenic responses. Transcriptomic analysis identified stress-related pathways associated with Muse cell-mediated protection, and PPAN emerged as a candidate regulator linked to the reparative phenotype. In vivo, intracarotid transplantation of Muse cells reduced [18F] DPA-714 uptake in irradiated brain tissue and was accompanied by supportive behavioral trends suggestive of functional improvement. These findings provide exploratory preclinical evidence that Muse cell transplantation attenuates neuroinflammatory activation and preserves endothelial reparative responses after radiation-induced brain injury. Muse cells may therefore represent a potential cell-based strategy for RIBI, although their therapeutic efficacy, neurovascular repair-related effects, and long-term functional benefits require further validation in larger and more comprehensive preclinical studies.
2026-05-04 | Therapeutic advances in ureteral stricture: lessons from radiation-induced fibrosis to regenerative strategies-a narrative review.
Radiation-induced ureteral stricture (RIUS) is a rare but refractory late complication of pelvic radiotherapy, driven by severe fibrosis and microvascular injury that undermines the effectiveness of conventional interventions such as balloon dilation, ureteral stenting, and reconstructive surgery. This review summarizes the pathophysiological basis of treatment resistance in RIUS and critically appraises current management strategies. Beyond its clinical relevance, RIUS is discussed as a paradigmatic model of advanced fibrotic ureteral disease, offering broader insights into the limitations of purely mechanical approaches. We further examine emerging biologically oriented strategies, including mesenchymal stem cell-derived extracellular vesicle-based regenerative therapies, next-generation ureteral stents incorporating advanced biomaterials, and drug-eluting stent platforms for localized antifibrotic and antimicrobial delivery. Although largely investigational, these approaches collectively signal a conceptual shift from palliative drainage toward biologically informed, restorative management of RIUS and related refractory ureteral strictures.
2026-04-24 | Regenerative potential of MSC-derived secretomes in radiation-induced xerostomia: Role of SDF-1, IL-10, and VEGF.
This study aims to analyze the potential of MSC-derived secretomes, specifically SDF-1, IL-10, and VEGF, as an alternative therapy for xerostomia or other disorders caused by ionizing radiation. This research is an experimental laboratory-based analytical study. The samples were secretomes derived from mesenchymal stem cells (MSCs) isolated from human umbilical cords. The MSCs were divided into two groups: the control group (K), which consisted of MSC cultures without X-ray exposure, and the treatment group (P), consisting of MSC cultures exposed to X-rays. Each cell culture was incubated until day 3 and day 7. The secretion levels of SDF-1, IL-10, and VEGF were then measured using a sandwich ELISA test. The study showed that the average secretion levels of SDF-1, IL-10, and VEGF increased significantly after exposure to 0.16 mSv ionizing radiation, both on day 3 and day 7, compared to the control group without radiation exposure. However, the average secretion levels of SDF-1, IL-10, and VEGF in the treatment group on day 7 (P.7) were lower than those on day 3 (P.3). Secretomes from MSC cultures have great potential as an alternative therapy for xerostomia or other disorders caused by ionizing radiation, serving as a cell-free therapy. Secretomes contain various bioactive molecules such as cytokines, chemokines, antioxidants, and growth factors that play a crucial role in cell and tissue regeneration.
2026-04-24 | Histological Remodeling of Irradiated Postmastectomy Breast Tissue After Autologous Fat Grafting: A Prospective Paired Tru-Cut Biopsy Study.
Background/Objectives: Radiotherapy following mastectomy induces persistent structural alterations in the chest wall, including fibrosis, extracellular matrix disorganization, and vascular changes that compromise reconstructive outcomes. Although autologous fat grafting is widely used to improve tissue quality in irradiated breasts, direct human histological evidence remains limited. The aim of this prospective pilot study was to evaluate intra-patient histological remodeling in irradiated postmastectomy breast tissue before and 4 months after autologous fat grafting using paired core needle biopsies. This study should be considered a hypothesis-generating histological pilot study. Methods: Five female patients with prior mastectomy and adjuvant radiotherapy underwent Tru-Cut core needle biopsy of irradiated chest wall tissue before lipofilling and at approximately four months (range between 3 and 12 months) post-procedure. Specimens were processed using formalin fixation, paraffin embedding, and hematoxylin and eosin staining. Histological assessment focused on collagen density, stromal organization, vascular structures, inflammatory infiltrate, and adipocyte integration. Comparative intra-patient analysis was performed descriptively. Results: Baseline biopsies demonstrated consistent post-radiation alterations, including collagen compaction, stromal disorganization, perivascular fibrosis, and variable inflammatory infiltrate. Post-lipofilling specimens showed heterogeneous remodeling characterized by focal collagen fiber insertion between adipocytes, areas of immature connective tissue formation, and variable preservation of adipose architecture. The extent and pattern of remodeling differed among patients. Inflammatory activity decreased or remained mild in most cases. Conclusions: Autologous fat grafting in irradiated postmastectomy tissue is associated with measurable histological remodeling. Structural adaptation appears heterogeneous and patient-specific, suggesting a dynamic multi-stage process rather than uniform regeneration. Further studies incorporating quantitative and molecular analyses are required to clarify the mechanisms underlying these changes.
2026-03-29 | Genetically engineered Escherichia coli Nissle 1917 enabling on-site melanin synthesis attenuates radiation enteritis through ferroptosis inhibition and gut microbiota modulation.
Radiation enteritis (RE) poses a clinically-relevant therapeutic challenge with limited effective interventions. Engineered probiotic drug delivery systems offer innovative strategies for precise treatment of inflammatory disease. However, both the practical efficacy and therapeutic mechanism of engineered probiotic agents for RE alleviation remains largely unclear. Herein, the melanin with natural radioprotective function was applied to modify engineered Escherichia coli Nissle 1917 that contains the tyrosinase gene (EcN-Tyr), which were further formulated into orally administrable microspheres (EcN-Tyr (A/C)1) with natural sodium alginate and chitosan coatings via microfluidic approach. Notably, EcN-Tyr (A/C)1 microspheres could successfully withstand gastric acid and actively target inflammatory lesions in the intestine. Mechanistically, EcN-Tyr (A/C)1 microspheres enabled ferroptosis inhibition through reducing lipid peroxidation to protect the host from radiation damage. As a result, EcN-Tyr (A/C)1 effectively alleviated radiation-induced intestinal inflammation, and reduced DNA damage. Furthermore, the administration of EcN-Tyr (A/C)1 increased the abundance of beneficial bacteria, such as Akkermansia and Ligilactobacillus, while reducing the abundance of harmful bacteria, such as Escherichia-Shigella, clearly indicating the positive effects on the balance of gut microbiota. In summary, EcN-Tyr (A/C)1, as a novel probiotic carrier, shows great potential in the treatment of RE, and pioneers new avenues for leveraging natural biomaterials to treat RE.
other
2026-08-14 | circNCX1-nanogel mitigates radiation-induced heart disease.
Radiation-induced heart disease (RIHD) is a significant late complication of radiotherapy for thoracic malignancies, limiting cancer control and patient well-being. Although RIHD has been extensively studied, its precise molecular mechanisms remain poorly defined, and effective therapeutic agents are lacking. Herein, we demonstrate that circNCX1, a circular RNA of SLC8A1 that regulates cytoplasmic calcium levels and muscle excitation-contraction coupling, was inhibited by radiation. To investigate this in vitro, human cardiomyocyte AC16 cells exposed to 4 Gy X-ray irradiation were used as a model. In irradiated AC16 cells, circNCX1 functions as a miR-133a-3p-sequestering competing endogenous RNA (ceRNA) that derepresses PIK3C2A, thereby augmenting PI3K/AKT/mTOR signaling and limiting radiation-induced apoptosis. Building upon this observation, a cardiac-targeted circNCX1-nanogel is assembled by incorporating circNCX1 expression plasmid into a polyethylene glycol-sodium alginate (SA) nanogel matrix, and subsequently modified with targeting PCM and TAT peptides to augment cardiac accumulation. For the in vivo study, male C57BL/6J mice receiving a single localized 20 Gy heart dose were used as a model for evaluating RIHD for 12 weeks. Intravenously administered circNCX1 nanogel rapidly accumulated in the heart prior to irradiation and conferred robust cardiac protection, evidenced by preserved cardiac function and reduced myocardial fibrosis and apoptosis. Histological analyses and serum biochemical markers of major organs demonstrated undetectable off-target injury. Collectively, these findings demonstrate that circNCX1 nanogel, particularly when administered prior to radiation, mitigates RIHD by improving ventricular function, reducing myocardial fibrosis and cardiomyocyte apoptosis, and reactivating the PI3K/AKT/mTOR survival pathway.
2026-07-06 | Ion Channel Dysfunction and Therapeutic Targeting in Salivary Gland Disorders.
Salivary gland hypofunction and xerostomia represent major clinical complications of radiation therapy, autoimmune disorders such as Sjögren's disease, and inherited epithelial ion transport defects. This review integrates current knowledge on ion channel dysfunction as a central mechanistic driver of salivary gland pathology and evaluates promising ion channel-targeted therapeutic strategies. A comprehensive narrative review was performed using PubMed, Scopus, and Web of Science to identify experimental, translational, and clinical studies on ion channel regulation in salivary gland physiology and disease. Salivary secretion depends on coordinated Ca2+ signaling and polarized ion transport in acinar and ductal cells. Across radiation injury, Sjögren's disease, and cystic fibrosis, disease-specific disruptions of calcium entry, chloride conductance, and water channel trafficking converge on impaired fluid secretion through distinct but mechanistically overlapping pathways. These insights have driven targeted therapies, including muscarinic agonists, ANO1 and CFTR modulators, anti-inflammatory strategies, and AAV2-hAQP1 gene therapy, which shows sustained benefit in radiation-induced xerostomia. Ion channels are central regulators of salivary gland physiology and promising therapeutic targets, and combining pharmacologic, gene, and regenerative approaches provides a precision strategy to restore salivary gland function.
2026-07-04 | Aquaporin-1 gene therapy as a novel method to treat radiation-induced salivary gland damage: The case for adeno-associated virus vectors.
Head and neck cancer imposes a substantial disease burden, with approximately 65,000 new cases annually in the United States and 500,000 cases worldwide. Radiation therapy remains a primary treatment modality for many patients with head and neck cancer. Despite advances aimed at limiting exposure of normal tissues within the field of radiation, salivary gland injury is a common and often unavoidable consequence of treatment. Although the mechanisms underlying radiation-induced salivary gland dysfunction remain incompletely understood, the resulting reduction in salivary flow is clinically evident and can cause substantial morbidity, including increased risk of oral infections, oral mucositis, dysphagia, and difficulty eating and speaking. Current therapeutic options are largely palliative, and durable, effective, and patient-acceptable treatments remain limited. Gene therapy offers a potential strategy for sustained functional improvement in irradiated salivary glands. The purpose of this work is to review the historical development of modified viral vectors for delivery of aquaporin-1, a water channel, to the salivary glands. We first summarize early studies using adenoviral vectors for gene delivery, which provided the basis for a Phase I clinical trial of adenoviral aquaporin-1 transfer for radiation-induced salivary gland dysfunction. We then describe the justification for our subsequent clinical trial using modified adeno-associated virus vectors for aquaporin-1 gene transfer. Finally, we outline the design of this trial, including subject recruitment, study procedures, and outcome measures.
2026-05-14 | Tetrahedral framework nucleic acids as a promising vehicle for small molecule drugs of traditional Chinese medicine: application to disease prevention and treatment.
The modernization of Traditional Chinese Medicine (TCM) faces considerable challenges, primarily due to the poor water solubility, low chemical stability, and limited oral bioavailability of its active components. These limitations hinder the translation of Natural Compounds from Chinese Herbal Medicine (NCCHMs) from basic research to clinical applications. Recently, the advent of DNA nanotechnology has provided innovative solutions to address these challenges. Among these, tetrahedral framework nucleic acids (tFNAs), a novel class of programmable nanomaterials, show significant promise as ideal drug delivery carriers. Their precisely controllable three-dimensional structure, excellent biocompatibility, low immunogenicity, efficient cellular uptake, and remarkable ability to penetrate biological barriers contribute to their potential. This review systematically examines the latest advancements in using tFNAs as efficient delivery platforms to enhance the therapeutic efficacy of NCCHMs against various diseases. It begins with an overview of tFNA synthesis, key physicochemical properties, and inherent biological effects, before exploring the passive targeting capability of tFNAs. This capability allows for efficient drug delivery to target organs, such as the liver, kidneys, brain, and joints, through various administration routes. The core section focuses on strategies for conjugating tFNAs with various natural compounds and active components from TCM, including groove binding, intercalation, and covalent linkage. Drawing on studies from diverse disease models-such as obesity, radiation-induced cystitis, osteoarthritis, acute kidney injury, and diabetic retinopathy-the review demonstrates that tFNA-NCCHMs significantly enhance drug stability, increase target-site concentration, reduce toxic side effects, and provide synergistic therapeutic effects.Finally, this review provides future perspectives, highlighting the potential of tFNA-NCCHMs in advancing TCM from an "empirical medicine" to an "evidence-based" precision medicine approach. With precise functionalization modifications (e.g., targeting peptides, stimulus-responsive elements), stability optimization, and interdisciplinary integration with fields such as artificial intelligence and immunotherapy, the tFNA-NCCHMs delivery system holds great promise for the modernization and global integration of TCM.
2026-05-04 | Accounting for out-of-field dose and second cancer risk in classical Hodgkin lymphoma: A comprehensive comparison of proton and photon therapy using whole-body phantom.
Although out-of-field radiation doses are lower than in-field doses, they may still contribute to late toxicities and second cancer risk in classical Hodgkin lymphoma (cHL) patients. Moreover, treatment planning systems (TPS) often underestimate these doses, especially in healthy tissues. Dosimetric parameters were compared between pencil beam scanning proton therapy (PBS) and volumetric modulated arc therapy (VMAT) in a cohort of 20 patients from the PRO-Hodgkin study. Planning CT scans were reconstructed into virtual whole-body CTs using the IS2aR software. Out-of-field doses were estimated with analytical models and Monte Carlo simulations in whole-body phantoms, then integrated with TPS in-field doses to calculate total equivalent dose. Dose distributions, dose-volume histograms (DVHs), non-target tissue integral dose equivalent (NTIHs), mean organ doses, and lifetime attributable risks of Second cancer (LARs) were evaluated for critical healthy tissues. PBS consistently resulted in lower out-of-field doses than VMAT. In both modalities, contributions were relatively small, not exceeding 5% of the prescribed dose. For organs near the target such as thyroid, lungs, breasts, heart, and esophagus, mean dose differences between PBS and VMAT ranged from 1.3 to 4.5 Sv, while for distant organs differences remained below 0.3 Sv. Incorporating out-of-field doses into LAR estimates increased predicted risks, but PBS reduced these values by up to 40% compared to VMAT. The radiation burden in high-precision radiotherapy, particularly from out-of-field radiation, should be accounted for in epidemiological studies and incorporated into treatment planning optimization to minimize second cancer risks in cHL patients.
small molecules
2026-08-13 | Distinct Metabolomic and Proteomic Signatures of Early Brain Damage Triggered by the Entrance Plateau Versus the Spread-Out Bragg Peak of Proton Radiation.
Proton therapy spares normal tissues better than photon therapy, potentially reducing toxicity while maintaining tumor control. However, challenges remain due to variations in proton dose distribution, particularly at the distal edge of the spread-out Bragg peak (SOBP); for organs at risk, such variation is crucial. We evaluated the biological effects by comparing two positions of the proton profile, the entrance plateau (EP) and SOBP, in a murine model and investigated distinct metabolomic and proteomic signatures. Mice exposed to the EP beam segment (LETd = 0.8 keV/µm) exhibited less weight reduction than their SOBP-irradiated counterparts (LETd = 2.6 keV/µm). Two hours post-irradiation, the SOBP caused more severe DNA damage in the hippocampus and thalamus. Hematoxylin and eosin staining revealed eosinophil aggregation in both groups, with more surviving neurons in the EP group. Metabolomic profiles differed more between the EP and SOBP groups at 2 h than at 3 days post-irradiation. Relative to EP, SOBP irradiation at 2 h increased fructose-1,6-bisphosphate (FBP), dihydroxyacetone phosphate (DHAP), and inosine but decreased prostaglandin F2α; subsequently, proteomic analysis at day 3 showed that calcium signaling, NF-κB, and endocytosis pathways were enriched in the SOBP group. Combined multi-omics analysis further demonstrated that SOBP irradiation significantly activated the pentose phosphate pathway, purine metabolism, and phospholipase D signaling, while concurrently suppressing arachidonic acid metabolism. Our findings underscore the need for early detection of proton-induced brain toxicity and demonstrate that the higher-LET SOBP segment causes more severe damage than the EP. Targeting these dysregulated multi-omics pathways may offer a promising strategy for mitigating radiation-induced brain injury during proton therapy.
2026-08-13 | Adipose Dysfunction Caused by Obesity and Radiation Therapy Rewires the Prostate Stroma Toward Tumor Progression.
Obesity is associated with chronic adipose dysfunction characterized by oxidative stress, inflammation, senescence, and fibrosis, which can promote tumor progression. In prostate cancer, periprostatic adipose tissue may directly influence the prostate microenvironment. Radiation therapy is widely used in prostate cancer, but radiation-induced adipose dysfunction in obesity and its impact on the prostate microenvironment remain poorly understood. In the present study, we investigated the impact of obese and irradiated obese adipose microenvironments on prostate stromal remodeling, as well as the activation of prostate fibroblasts mediating prostate cancer progression. We utilized a high-fat diet obesity model with localized adipose irradiation in animal and in vitro studies using obese and irradiated obese adipocytes. Prostates from obese and irradiated obese mice exhibited epithelial hyperplasia, increased stromal activation markers, oxidative damage, and senescence. Interestingly, radiation maintained the obesity-induced pathological behavior in the prostate, rather than elevating it. The conditioned media from obese and irradiated obese adipocytes induced stromal activation markers, senescence, extracellular H2O2 production, pro-survival signaling, and inflammation. Notably, the only significant changes observed with the addition of radiation to obesity were enhancement of fibrosis-associated features and infiltration of CD4+ T cells. Functionally, prostate myofibroblasts or senescent fibroblasts promoted prostate cancer migration and induced epithelial-to-mesenchymal transition and elevated pro-tumorigenic pathways. Cytokine profiling identified elevated levels of CXCL10 and CXCL11 from myofibroblasts, and pharmacological inhibition of CXCR3 significantly reduced prostate cancer migration, implicating this signaling axis in activated fibroblast-driven tumor-promoting crosstalk. Collectively, these findings demonstrate obesity-associated adipose dysfunction reprograms the prostate microenvironment toward a pro-tumorigenic state, while radiation sustains rather than markedly amplifies these pathological changes, identifying obese adipose-stromal crosstalk and the CXCL10/CXCL11-CXCR3 axis as potential therapeutic targets to inhibit prostate cancer progression.
2026-08-13 | Bronchial Chondronecrosis After Proton Beam Therapy Successfully Treated With Hyperbaric Oxygen Therapy.
Airway chondronecrosis is a rare but serious manifestation of late radiation-induced toxicity. We report the case of a 67-year-old woman with epidermal growth factor receptor mutation-positive lung adenocarcinoma who developed bronchial chondronecrosis 8 years after proton-beam therapy (PBT) to the right upper lobe nodule. For 2 years, she was treated for cough-variant asthma owing to a persistent cough. Chest computed tomography (CT) showed only a subtle irregularity of the right main bronchial wall. Bronchoscopy revealed yellow necrotic deposits in the right main bronchi. Although a conventional forceps biopsy was nondiagnostic, transbronchial lung cryobiopsy (TBLC) obtained cartilage specimens, confirming bronchial chondronecrosis without malignancy. Hyperbaric oxygen therapy (HBOT) (90 sessions in total) led to symptomatic and bronchoscopic improvement. This case highlights that very-late-onset airway chondronecrosis following PBT must be considered, even with minimal CT findings. TBLC is a valuable tool for diagnosing submucosal lesions and HBOT appears to be an effective therapy.
2026-08-07 | Lysyl oxidase (LOX) family proteins in extracellular matrix homeostasis: roles in disease and radiation-induced pathogenesis.
The extracellular matrix (ECM) not only provides structural support in tissues but also regulates cellular processes and tissue homeostasis. The lysyl oxidase (LOX) family of enzymes, consisting of LOX and lysyl oxidase-like enzymes (LOXL1-4), is involved in ECM remodeling by catalyzing the crosslinking of collagen and elastin. Dysregulation of these enzymes is implicated in the pathogenesis of various diseases, including organ fibrosis and tumor development. Furthermore, LOX family members have been shown to affect radiotherapy responses, with specific involvement in radioresistance and radiation-induced fibrosis. This review summarizes the structural and functional characteristics of the LOX family, highlighting their roles in fibrotic diseases such as pulmonary fibrosis, liver fibrosis, and cardiac diseases, their roles in tumor progression, relevance in radiotherapy, and treatment targeting LOX and LOXLs. Understanding the underlying mechanisms and potential therapies is critical for developing novel strategies in both disease identification and management.
2026-08-07 | Late-onset radiation-induced myocardial fibrosis after lung cancer radiotherapy: correlation of cardiac MRI with radiation treatment planning CT.
A 55-year-old male with history of prior LCx STEMI and remote chest external beam radiation underwent cardiac MRI(CMR) for aortic regurgitation. CMR demonstrated Nonischemic late gadolinium enhancement (LGE), valvular thickening, and pericardial effusion. Correlation with radiation treatment planning CT supported the diagnosis of radiation-induced myocardial fibrosis despite a history of prior STEMI.
antibodies
2026-08-17 | Hypo-fractionated radiotherapy combined with PD-1 inhibitor for relapsed/refractory B-cell lymphoma after failure to CD19 CAR-T therapy.
B-cell lymphoma relapsed after chimeric antigen receptor (CAR) T-cell therapy lacks effective standard treatment options and generally has a poor prognosis, largely due to mechanisms such as immune escape and tumor heterogeneity. Radiotherapy combined with immune checkpoint inhibitors (ICIs) may exert synergistic effects, including local tumor control through radiation-induced DNA damage and systemic immune activation via modulation of the tumor immune microenvironment. This case report describes a patient with relapsed/refractory (R/R) B-cell lymphoma who experienced multiple relapses and treatment failures, including CD19 CAR-T therapy. Almost 7 years after CAR-T treatment, the patient developed disease relapse and was diagnosed with follicular lymphoma (FL). The patient received a personalized treatment strategy combining hypo-fractionated radiotherapy (30 Gy/5 fractions) and the Programmed Death-1 (PD-1) inhibitor camrelizumab, achieving complete remission (CR) and remaining disease-free for over 43 months. This case highlights the potential efficacy of this combination strategy in R/R lymphoma, particularly in patients with limited treatment options.
2026-08-14 | Radiation-induced CD200+ tumor-associated macrophages suppress eosinophil-mediated antitumor immunity through CD200R signaling in hepatocellular carcinoma.
Radiotherapy elicits dual immunomodulatory effects in cancer, activating antitumor immunity while paradoxically inducing immunosuppression, which limits therapeutic efficacy. The molecular pathways mediating postradiation immune escape in hepatocellular carcinoma (HCC) remain poorly defined. Here, we elucidate a previously uncharacterized mechanism whereby radiotherapy drives the accumulation of CD200+ tumor-associated macrophages (TAMs) that suppress eosinophil-mediated antitumor immunity in patients with HCC. Through single-cell RNA sequencing of postradiotherapy HCC specimens, we demonstrated that radiation-induced DNA damage activated the cytosolic DNA-sensing STING pathway in TAMs, triggering NF-κB-dependent CD200 upregulation independent of canonical type I interferon signaling. These radiation-induced CD200+ TAMs exhibited an immunosuppressive phenotype and correlated with adverse clinical outcomes in HCC patients. Mechanistically, CD200+ TAMs established an immunosuppressive axis by recruiting CCR1+ eosinophils through CCL3-mediated chemotaxis, subsequently inhibiting their antitumor functions via CD200-CD200R engagement. This interaction comprehensively suppressed NF-κB activation in eosinophils, impaired their antigen-presenting capacity and Th2 cytokine secretion and abrogated their ability to support CD8+ T-cell-mediated cytotoxicity. Therapeutic blockade of CD200R following radiotherapy restored eosinophil effector functions, promoted central memory T-cell formation, and significantly enhanced tumor control across multiple preclinical HCC models. Remarkably, CD200R antagonism sensitized PD-1-refractory "cold" tumors to radioimmunotherapy combinations, overcoming primary resistance. Our findings establish STING-driven CD200+ TAM accumulation and subsequent eosinophil dysfunction as critical determinants of radioresistance, positioning CD200R blockade as a promising therapeutic strategy to potentiate radioimmunotherapy responses in patients with HCC. Graphical abstract of the study findings. Radiotherapy-induced STING signaling activation promotes the accumulation of CD200+ TAMs. These CD200+ TAMs facilitate the recruitment of eosinophils via the CCL3-CCR1 chemotaxis axis while simultaneously suppressing eosinophil-mediated antitumor activity through CD200-CD200R engagement (left panel). Targeted blockade of CD200R following radiotherapy unleashed the antitumor potential of eosinophils, leading to enhanced infiltration and effector function of CTLs (right panel).
2026-08-07 | Giant retinal telangiectasia after ophthalmic plaque radiation therapy.
Radiation retinopathy is a known complication of plaque brachytherapy, characterized by progressive retinal vasculature damage. This study describes the clinical course of two cases of late post-radiation giant retinal telangiectasias, discovered in patients treated with radiation for choroidal melanomas. A single center chart review revealed two patients with giant retinal telangiectasis. Each patient had been treated with palladium-103 (103Pd) plaque brachytherapy for choroidal melanoma. Clinical data revealed their presentation, clinical course and treatment. Giant retinal telangiectasias were associated with pre-retinal hemorrhages, exudates, and edema occurring 7 and 9 years after irradiation, with macular telangiectasia exhibiting a more fulminant course. It required both laser photocoagulation and periodic intravitreal steroid therapy; both received intravitreal anti-vascular endothelial growth factor injections. Treatment was given based on both telangiectasia activity and other radiation-induced ocular morbidities. Giant retinal telangiectasias are a rare complication that may occur after ophthalmic plaque radiation therapy.
2026-07-25 | Induction toripalimab plus chemotherapy sequential concurrent chemoradiotherapy with nimotuzumab followed by toripalimab maintenance in stage IVB hypopharyngeal squamous cell carcinoma: a single-arm phase 2 study.
Optimal induction chemoimmunotherapy sequential concurrent chemoradiotherapy (cCRT) in locally advanced hypopharyngeal squamous cell carcinoma (HSCC) remains undefined. This study aimed to evaluate toripalimab plus chemotherapy sequential cCRT with nimotuzumab, followed by toripalimab maintenance in unresectable stage IVB HSCC. In this single-arm, open-label, phase 2 study, untreated patients received two 21-day cycles of induction toripalimab 240 mg (d1) plus nab-paclitaxel 230 mg/m2 (d1) and cisplatin/nedaplatin 40 mg/m2 (d1-2) sequential cCRT (helical tomotherapy; nab-paclitaxel 230 mg/m2 (d1, 22, 43)) with nimotuzumab 200 mg weekly for 7 weeks. Subsequently, toripalimab maintenance was administered for eight cycles. Primary endpoint was progression-free survival (PFS). From March 16, 2022 to April 24, 2024, 31 patients completed induction chemoimmunotherapy. With a median follow-up of 31 months, median PFS and overall survival (OS) were not reached; 2-year PFS and OS rates were 67.7% and 86.4%. The 2-year larynx preservation rate was 93.3%. 30 (96.8%) patients achieved the best objective response, with 28 (90.3%) complete responses and 2 (6.5%) partial responses. The most common grade 3-4 treatment-related adverse events (TRAEs) were radiation-induced oropharyngeal mucositis and decreased appetite (each 46.9%). No grade 5 and fatal TRAEs occurred. No difficulties in speech and swallowing functions were reported in 96.8% of patients. There was no significant association between PFS and PD-L1 combined positive score, epidermal growth factor receptor expression, tumor-infiltrating T-lymphocytes, tumor mutational burden, or genetic alterations. High baseline peripheral CD3+ and CD8+CD28+ T-cell levels were associated with favorable PFS. Exploratory biomarker analyses identified that patients without disease progression after maintenance exhibited significantly higher levels of CD8+CD28⁻ T cells with a memory phenotype and lower B-cell levels. This exploratory study demonstrated preliminary efficacy and larynx preservation with manageable toxicity, possibly supporting further evaluation of induction toripalimab plus chemotherapy sequential cCRT with nimotuzumab, followed by toripalimab maintenance in stage IVB HSCC. Peripheral lymphocytes may warrant further investigation as candidate biomarkers in locally advanced disease. NCT05860335; ChiCTR2300074672.
2026-05-29 | Effect and safety of tislelizumab combined with anlotinib and radiotherapy in advanced hepatocellular carcinoma: A single-arm, single-center, phase II clinical study.
Immune checkpoint inhibitors plus targeted therapy remains the mainstay of treatment for advanced hepatocellular carcinoma (HCC), yet its efficacy is limited. This study aimed to evaluate the efficacy and safety of tislelizumab combined with anlotinib and radiotherapy as first-line therapy for advanced HCC. This was a single-arm, single-center, phase II clinical trial. A total of 45 patients with advanced HCC were enrolled and administered first-line therapy consisting of tislelizumab plus anlotinib combined with radiotherapy. Stratification was performed according to pretreatment portal vein tumor thrombus (PVTT) status, Barcelona Clinic Liver Cancer (BCLC) stage, and median biologically effective dose (BED) of the gross tumor volume (GTV). Treatment response was assessed using the modified Response Evaluation Criteria in Solid Tumors, and adverse events (AEs) were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety profiles reflected by AEs. The median BED of the GTV was 47.9 Gy (Gy). The ORR and DCR were 62.2% (28/45) and 75.6% (34/45), respectively. Median PFS and OS were 11.0 months (95% CI 1.444-14.081) and 26.7 months (95% CI 1.749-25.178), respectively. ORR and DCR were comparable across subgroups defined by PVTT status, BCLC stage, and BED level (all p > 0.05). No significant differences in PFS or OS were observed among these subgroups (all p > 0.05). Most AEs (82.2%, 37/45) were grade 1/2 and well tolerated. Grade 3/4 AEs occurred in 13.3% (6/45) of patients. No grade 5 events, radiation-induced liver disease, or treatment-related deaths were reported. Tislelizumab combined with anlotinib and radiotherapy demonstrates promising efficacy and acceptable safety as first-line treatment for advanced HCC. Clinical outcomes appear to be independent of PVTT status, BCLC stage, or radiation BED level.Registration Number in the Chinese Clinical Trial Registry: ChiCTR2000039022 (10/13/2020). https://www.chictr.org.cn/index.html.
proteins
2026-08-02 | A self-sustaining repair circuit drives the progression of pulmonary fibrosis.
Pulmonary fibrosis is a progressive and often fatal lung disorder whose clinical behavior is not fully explained by conventional injury-driven models. Fibrosis frequently progresses after the initiating insult has resolved, anti-inflammatory therapies have shown limited benefit in idiopathic pulmonary fibrosis, and current antifibrotic drugs slow but rarely reverse disease progression. Moreover, diverse conditions including idiopathic pulmonary fibrosis, post-ARDS or post-infectious fibrosis, radiation-induced injury, drug toxicity, and bronchopulmonary dysplasia arise from distinct causes yet may converge toward shared features of persistent fibrotic remodeling. Here we propose that pulmonary fibrosis represents a self-sustaining pathological tissue-repair state rather than a continuously injury-dependent process. Failure of alveolar epithelial regeneration produces persistent cellular senescence and chronic distress signaling that recruits reparative immune responses. These signals promote fibroblast survival and myofibroblast persistence, leading to extracellular matrix deposition and progressive tissue stiffening. Increased matrix stiffness further disrupts epithelial recovery through mechanotransduction pathways, creating a feedback loop linking epithelial dysfunction, immune mis-repair, stromal stabilization, and mechanical reinforcement. Within this framework, fibrosis persists because the lung behaves as a chronically unhealed wound. This model may help explain disease progression and heterogeneity and suggests that effective therapies must restore epithelial regeneration and disrupt system-level feedback rather than target single profibrotic pathways.
2026-07-14 | Advances in the prevention and treatment of radiation-induced brain necrosis: a narrative review.
Radiation-induced brain necrosis (RBN) is a serious and often debilitating complication of radiotherapy for intracranial and head and neck malignancies, with an incidence of 5-25%. It can lead to significant cognitive impairment, neurological deficits, and increased mortality. As radiotherapy techniques advance and patient survival improves, effective prevention and management of RBN have become critical clinical priorities. This review systematically summarizes the current understanding of RBN pathogenesis, highlighting the central roles of vascular injury (endothelial damage, HIF-1α/VEGF dysregulation) and neuroinflammation (microglial activation, cytokine release). We discuss recent advances in preventive strategies, including refined radiotherapy modalities such as intensity-modulated radiotherapy (IMRT), fractionated stereotactic radiosurgery (fSRS), and FLASH ultra-high-dose-rate radiotherapy, as well as pharmacological prophylaxis using bevacizumab and neuroprotective agents (NGF, GM1, edaravone). Established and emerging treatment options are reviewed, including corticosteroids, bevacizumab, hyperbaric oxygen therapy (HBOT), laser interstitial thermal therapy (LITT), and Colony Stimulating Factor 1 Receptor(CSF1R) inhibitors. We also cover innovations in imaging for early detection and differential diagnosis, including magnetic resonance spectroscopy (MRS), perfusion-weighted imaging (PWI), and Positron Emission Tomography-Computed Tomography(PET/CT) with advanced tracers (11C-methionine, 18F-FET). Finally, we summarize updates to international management guidelines, particularly the 2022 DEGRO guidelines, and propose future directions for research and therapeutic optimization.
2026-07-13 | Hematopoietic stem cell transplantation-associated partial lipodystrophy.
Hematopoietic stem cell transplantation (HSCT)-associated partial lipodystrophy (HSCT-PL) is a serious metabolic complication that develops in remote period among childhood cancer survivors treated with HSCT with total body irradiation (TBI). Since the first proposal in 2013, HSCT-PL seems to be increasingly recognized as a distinct disease entity. The patients with HSCT-PL show profound metabolic dysfunction including insulin resistance, diabetes, elevated triglycerides, and hepatic steatosis. Their body mass index is low-normal, although they show visceral fat accumulation and increased waist-to-hip ratio. In addition, HSCT-PL is characterized by Dunnigan phenotype: lipoatrophy in buttock and extremities combined with lipohypertrophy in face and neck. Although the precise pathogenesis is still obscure, radiation-induced damage to adipose progenitor cells, leading to accelerated senescence, seems to be a main pathway. Literature survey identified 17 patients of HSCT-PL with sufficient information from 12 reports. Among them, clear female predominance (15 females) and possible ethnic difference in disease prevalence (11 Japanese) were ascertained. Genetic factors may be involved in those epidemiological traits. There remains much to be clarified, including establishment of reliable diagnostic procedure, elucidation of long-term prognosis, and invention of effective treatment. Metreleptin is one of the promising options, and the accumulation of its therapeutic efficacy are warranted.
2026-07-06 | Tissue Resilience in Radiation-Induced Injury: A Hypothesis-Generating Review of Heat Shock Protein 27 in Osteoradionecrosis of the Jaw
Osteoradionecrosis of the jaw (ORNJ) remains one of the most severe late complications of head and neck radiotherapy. Current evidence suggests that ORNJ is a progressive and biologically heterogeneous disorder driven by microvascular injury, chronic hypoxia, oxidative stress, fibro-atrophic remodeling, impaired bone turnover, immune dysregulation, and systemic susceptibility factors. Within this complex pathogenic network, heat shock protein 27 (HSP27) emerges as a biologically plausible but unexplored mediator. HSP27 regulates multiple stress-response pathways, including redox homeostasis, cytoskeletal stabilization, endothelial protection, apoptosis control, fibroblast activation, and osteoblast–osteoclast function, all of which overlap with key mechanisms implicated in ORNJ. However, no studies have directly investigated HSP27 expression, activation, or functional significance in irradiated mandibular tissues or ORNJ-specific cohorts. This review summarizes current knowledge of ORNJ pathobiology, examines potential mechanistic links with HSP27, and outlines future research priorities involving biomarker development, tissue-level characterization, preclinical modeling, and therapeutic targeting. Integrating HSP27 into ORNJ research may improve understanding of pathogenesis, risk stratification, and the development of novel preventive and therapeutic strategies.
2026-05-27 | Protective Efficacy of Met-Ser-Arg Against Irradiation-Related Testicular Injury†.
Ionizing radiation poses a significant risk to male fertility by inducing testicular damage, yet effective protective strategies remain limited. The tripeptide Met-Ser-Arg (MSA) has demonstrated potential in alleviating radiation-induced oxidative stress and lipid metabolic disorders, prompting investigation into its protective effects on the male reproductive system. Male BALB/c mice were exposed to X-ray irradiation (0.5 Gy/day for 5 days) to establish a testicular injury model, followed by MSA treatment. Testicular structure and function were evaluated through histology, electron microscopy, computer-assisted sperm analysis (CASA), and quantitative PCR. MSA significantly alleviated radiation-induced testicular damage, restoring the structural integrity and function of spermatogenesis tubules while increasing both the height of the spermatogenic epithelium and germ cell number. Sperm quality and motility were markedly improved, and the expression of several sperm cell molecular markers was favorably adjusted. Mechanistic investigations revealed that MSA regulated lipid metabolism by upregulating fatty acid β-oxidation enzymes, including ACSL3 and CPT1A, while downregulating the lipid synthase DGAT2, thereby reducing lipid droplet accumulation. MSA also attenuated radiation-induced reactive oxygen species and malondialdehyde levels, enhanced antioxidant capacity through upregulation of NRF2 and HO-1, and preserved mitochondrial structure and function via upregulation of PGC1A. Furthermore, MSA reduced apoptosis by lowering the levels of Cleaved-caspase 3 and γH2AX. Collectively, these findings demonstrate that MSA ameliorates radiation-induced testicular injury and improves sperm quality through coordinated regulation of lipid metabolism, antioxidant pathway activation, mitochondrial protection, and apoptosis inhibition, providing a theoretical basis for its potential clinical application in the context of radiotherapy.
cell therapies
2026-08-02 | Muse cell transplantation attenuates neuroinflammation and preserves endothelial reparative responses after radiation-induced brain injury.
Radiation-induced brain injury (RIBI) is a serious complication of cranial radiotherapy and currently lacks effective disease-modifying treatment. Persistent neuroinflammation and neurovascular dysfunction are considered central to RIBI progression, making them attractive therapeutic targets for regenerative intervention. Multilineage-differentiating stress-enduring (Muse) cells are a non-tumorigenic pluripotent-like cell population with reported reparative and immunomodulatory properties, but their therapeutic potential in RIBI has not been defined. In this study, we evaluated the effects of Muse cell transplantation in experimental RIBI using in vitro neurovascular co-culture systems and in an vivo rat model. Irradiation induced marked activation of inflammasome-related signaling, endothelial injury, and neurological impairment. Muse cells suppressed the expression of NLRP3, AIM2, ASC, Caspase-1, IL-1β, and IL-18 in irradiated co-culture systems, while preserving endothelial proliferative and angiogenic responses. Transcriptomic analysis identified stress-related pathways associated with Muse cell-mediated protection, and PPAN emerged as a candidate regulator linked to the reparative phenotype. In vivo, intracarotid transplantation of Muse cells reduced [18F] DPA-714 uptake in irradiated brain tissue and was accompanied by supportive behavioral trends suggestive of functional improvement. These findings provide exploratory preclinical evidence that Muse cell transplantation attenuates neuroinflammatory activation and preserves endothelial reparative responses after radiation-induced brain injury. Muse cells may therefore represent a potential cell-based strategy for RIBI, although their therapeutic efficacy, neurovascular repair-related effects, and long-term functional benefits require further validation in larger and more comprehensive preclinical studies.
2026-05-04 | Therapeutic advances in ureteral stricture: lessons from radiation-induced fibrosis to regenerative strategies-a narrative review.
Radiation-induced ureteral stricture (RIUS) is a rare but refractory late complication of pelvic radiotherapy, driven by severe fibrosis and microvascular injury that undermines the effectiveness of conventional interventions such as balloon dilation, ureteral stenting, and reconstructive surgery. This review summarizes the pathophysiological basis of treatment resistance in RIUS and critically appraises current management strategies. Beyond its clinical relevance, RIUS is discussed as a paradigmatic model of advanced fibrotic ureteral disease, offering broader insights into the limitations of purely mechanical approaches. We further examine emerging biologically oriented strategies, including mesenchymal stem cell-derived extracellular vesicle-based regenerative therapies, next-generation ureteral stents incorporating advanced biomaterials, and drug-eluting stent platforms for localized antifibrotic and antimicrobial delivery. Although largely investigational, these approaches collectively signal a conceptual shift from palliative drainage toward biologically informed, restorative management of RIUS and related refractory ureteral strictures.
2026-04-24 | Regenerative potential of MSC-derived secretomes in radiation-induced xerostomia: Role of SDF-1, IL-10, and VEGF.
This study aims to analyze the potential of MSC-derived secretomes, specifically SDF-1, IL-10, and VEGF, as an alternative therapy for xerostomia or other disorders caused by ionizing radiation. This research is an experimental laboratory-based analytical study. The samples were secretomes derived from mesenchymal stem cells (MSCs) isolated from human umbilical cords. The MSCs were divided into two groups: the control group (K), which consisted of MSC cultures without X-ray exposure, and the treatment group (P), consisting of MSC cultures exposed to X-rays. Each cell culture was incubated until day 3 and day 7. The secretion levels of SDF-1, IL-10, and VEGF were then measured using a sandwich ELISA test. The study showed that the average secretion levels of SDF-1, IL-10, and VEGF increased significantly after exposure to 0.16 mSv ionizing radiation, both on day 3 and day 7, compared to the control group without radiation exposure. However, the average secretion levels of SDF-1, IL-10, and VEGF in the treatment group on day 7 (P.7) were lower than those on day 3 (P.3). Secretomes from MSC cultures have great potential as an alternative therapy for xerostomia or other disorders caused by ionizing radiation, serving as a cell-free therapy. Secretomes contain various bioactive molecules such as cytokines, chemokines, antioxidants, and growth factors that play a crucial role in cell and tissue regeneration.
2026-04-24 | Histological Remodeling of Irradiated Postmastectomy Breast Tissue After Autologous Fat Grafting: A Prospective Paired Tru-Cut Biopsy Study.
Background/Objectives: Radiotherapy following mastectomy induces persistent structural alterations in the chest wall, including fibrosis, extracellular matrix disorganization, and vascular changes that compromise reconstructive outcomes. Although autologous fat grafting is widely used to improve tissue quality in irradiated breasts, direct human histological evidence remains limited. The aim of this prospective pilot study was to evaluate intra-patient histological remodeling in irradiated postmastectomy breast tissue before and 4 months after autologous fat grafting using paired core needle biopsies. This study should be considered a hypothesis-generating histological pilot study. Methods: Five female patients with prior mastectomy and adjuvant radiotherapy underwent Tru-Cut core needle biopsy of irradiated chest wall tissue before lipofilling and at approximately four months (range between 3 and 12 months) post-procedure. Specimens were processed using formalin fixation, paraffin embedding, and hematoxylin and eosin staining. Histological assessment focused on collagen density, stromal organization, vascular structures, inflammatory infiltrate, and adipocyte integration. Comparative intra-patient analysis was performed descriptively. Results: Baseline biopsies demonstrated consistent post-radiation alterations, including collagen compaction, stromal disorganization, perivascular fibrosis, and variable inflammatory infiltrate. Post-lipofilling specimens showed heterogeneous remodeling characterized by focal collagen fiber insertion between adipocytes, areas of immature connective tissue formation, and variable preservation of adipose architecture. The extent and pattern of remodeling differed among patients. Inflammatory activity decreased or remained mild in most cases. Conclusions: Autologous fat grafting in irradiated postmastectomy tissue is associated with measurable histological remodeling. Structural adaptation appears heterogeneous and patient-specific, suggesting a dynamic multi-stage process rather than uniform regeneration. Further studies incorporating quantitative and molecular analyses are required to clarify the mechanisms underlying these changes.
2026-03-29 | Genetically engineered Escherichia coli Nissle 1917 enabling on-site melanin synthesis attenuates radiation enteritis through ferroptosis inhibition and gut microbiota modulation.
Radiation enteritis (RE) poses a clinically-relevant therapeutic challenge with limited effective interventions. Engineered probiotic drug delivery systems offer innovative strategies for precise treatment of inflammatory disease. However, both the practical efficacy and therapeutic mechanism of engineered probiotic agents for RE alleviation remains largely unclear. Herein, the melanin with natural radioprotective function was applied to modify engineered Escherichia coli Nissle 1917 that contains the tyrosinase gene (EcN-Tyr), which were further formulated into orally administrable microspheres (EcN-Tyr (A/C)1) with natural sodium alginate and chitosan coatings via microfluidic approach. Notably, EcN-Tyr (A/C)1 microspheres could successfully withstand gastric acid and actively target inflammatory lesions in the intestine. Mechanistically, EcN-Tyr (A/C)1 microspheres enabled ferroptosis inhibition through reducing lipid peroxidation to protect the host from radiation damage. As a result, EcN-Tyr (A/C)1 effectively alleviated radiation-induced intestinal inflammation, and reduced DNA damage. Furthermore, the administration of EcN-Tyr (A/C)1 increased the abundance of beneficial bacteria, such as Akkermansia and Ligilactobacillus, while reducing the abundance of harmful bacteria, such as Escherichia-Shigella, clearly indicating the positive effects on the balance of gut microbiota. In summary, EcN-Tyr (A/C)1, as a novel probiotic carrier, shows great potential in the treatment of RE, and pioneers new avenues for leveraging natural biomaterials to treat RE.
other
2026-08-14 | circNCX1-nanogel mitigates radiation-induced heart disease.
Radiation-induced heart disease (RIHD) is a significant late complication of radiotherapy for thoracic malignancies, limiting cancer control and patient well-being. Although RIHD has been extensively studied, its precise molecular mechanisms remain poorly defined, and effective therapeutic agents are lacking. Herein, we demonstrate that circNCX1, a circular RNA of SLC8A1 that regulates cytoplasmic calcium levels and muscle excitation-contraction coupling, was inhibited by radiation. To investigate this in vitro, human cardiomyocyte AC16 cells exposed to 4 Gy X-ray irradiation were used as a model. In irradiated AC16 cells, circNCX1 functions as a miR-133a-3p-sequestering competing endogenous RNA (ceRNA) that derepresses PIK3C2A, thereby augmenting PI3K/AKT/mTOR signaling and limiting radiation-induced apoptosis. Building upon this observation, a cardiac-targeted circNCX1-nanogel is assembled by incorporating circNCX1 expression plasmid into a polyethylene glycol-sodium alginate (SA) nanogel matrix, and subsequently modified with targeting PCM and TAT peptides to augment cardiac accumulation. For the in vivo study, male C57BL/6J mice receiving a single localized 20 Gy heart dose were used as a model for evaluating RIHD for 12 weeks. Intravenously administered circNCX1 nanogel rapidly accumulated in the heart prior to irradiation and conferred robust cardiac protection, evidenced by preserved cardiac function and reduced myocardial fibrosis and apoptosis. Histological analyses and serum biochemical markers of major organs demonstrated undetectable off-target injury. Collectively, these findings demonstrate that circNCX1 nanogel, particularly when administered prior to radiation, mitigates RIHD by improving ventricular function, reducing myocardial fibrosis and cardiomyocyte apoptosis, and reactivating the PI3K/AKT/mTOR survival pathway.
2026-07-06 | Ion Channel Dysfunction and Therapeutic Targeting in Salivary Gland Disorders.
Salivary gland hypofunction and xerostomia represent major clinical complications of radiation therapy, autoimmune disorders such as Sjögren's disease, and inherited epithelial ion transport defects. This review integrates current knowledge on ion channel dysfunction as a central mechanistic driver of salivary gland pathology and evaluates promising ion channel-targeted therapeutic strategies. A comprehensive narrative review was performed using PubMed, Scopus, and Web of Science to identify experimental, translational, and clinical studies on ion channel regulation in salivary gland physiology and disease. Salivary secretion depends on coordinated Ca2+ signaling and polarized ion transport in acinar and ductal cells. Across radiation injury, Sjögren's disease, and cystic fibrosis, disease-specific disruptions of calcium entry, chloride conductance, and water channel trafficking converge on impaired fluid secretion through distinct but mechanistically overlapping pathways. These insights have driven targeted therapies, including muscarinic agonists, ANO1 and CFTR modulators, anti-inflammatory strategies, and AAV2-hAQP1 gene therapy, which shows sustained benefit in radiation-induced xerostomia. Ion channels are central regulators of salivary gland physiology and promising therapeutic targets, and combining pharmacologic, gene, and regenerative approaches provides a precision strategy to restore salivary gland function.
2026-07-04 | Aquaporin-1 gene therapy as a novel method to treat radiation-induced salivary gland damage: The case for adeno-associated virus vectors.
Head and neck cancer imposes a substantial disease burden, with approximately 65,000 new cases annually in the United States and 500,000 cases worldwide. Radiation therapy remains a primary treatment modality for many patients with head and neck cancer. Despite advances aimed at limiting exposure of normal tissues within the field of radiation, salivary gland injury is a common and often unavoidable consequence of treatment. Although the mechanisms underlying radiation-induced salivary gland dysfunction remain incompletely understood, the resulting reduction in salivary flow is clinically evident and can cause substantial morbidity, including increased risk of oral infections, oral mucositis, dysphagia, and difficulty eating and speaking. Current therapeutic options are largely palliative, and durable, effective, and patient-acceptable treatments remain limited. Gene therapy offers a potential strategy for sustained functional improvement in irradiated salivary glands. The purpose of this work is to review the historical development of modified viral vectors for delivery of aquaporin-1, a water channel, to the salivary glands. We first summarize early studies using adenoviral vectors for gene delivery, which provided the basis for a Phase I clinical trial of adenoviral aquaporin-1 transfer for radiation-induced salivary gland dysfunction. We then describe the justification for our subsequent clinical trial using modified adeno-associated virus vectors for aquaporin-1 gene transfer. Finally, we outline the design of this trial, including subject recruitment, study procedures, and outcome measures.
2026-05-14 | Tetrahedral framework nucleic acids as a promising vehicle for small molecule drugs of traditional Chinese medicine: application to disease prevention and treatment.
The modernization of Traditional Chinese Medicine (TCM) faces considerable challenges, primarily due to the poor water solubility, low chemical stability, and limited oral bioavailability of its active components. These limitations hinder the translation of Natural Compounds from Chinese Herbal Medicine (NCCHMs) from basic research to clinical applications. Recently, the advent of DNA nanotechnology has provided innovative solutions to address these challenges. Among these, tetrahedral framework nucleic acids (tFNAs), a novel class of programmable nanomaterials, show significant promise as ideal drug delivery carriers. Their precisely controllable three-dimensional structure, excellent biocompatibility, low immunogenicity, efficient cellular uptake, and remarkable ability to penetrate biological barriers contribute to their potential. This review systematically examines the latest advancements in using tFNAs as efficient delivery platforms to enhance the therapeutic efficacy of NCCHMs against various diseases. It begins with an overview of tFNA synthesis, key physicochemical properties, and inherent biological effects, before exploring the passive targeting capability of tFNAs. This capability allows for efficient drug delivery to target organs, such as the liver, kidneys, brain, and joints, through various administration routes. The core section focuses on strategies for conjugating tFNAs with various natural compounds and active components from TCM, including groove binding, intercalation, and covalent linkage. Drawing on studies from diverse disease models-such as obesity, radiation-induced cystitis, osteoarthritis, acute kidney injury, and diabetic retinopathy-the review demonstrates that tFNA-NCCHMs significantly enhance drug stability, increase target-site concentration, reduce toxic side effects, and provide synergistic therapeutic effects.Finally, this review provides future perspectives, highlighting the potential of tFNA-NCCHMs in advancing TCM from an "empirical medicine" to an "evidence-based" precision medicine approach. With precise functionalization modifications (e.g., targeting peptides, stimulus-responsive elements), stability optimization, and interdisciplinary integration with fields such as artificial intelligence and immunotherapy, the tFNA-NCCHMs delivery system holds great promise for the modernization and global integration of TCM.
2026-05-04 | Accounting for out-of-field dose and second cancer risk in classical Hodgkin lymphoma: A comprehensive comparison of proton and photon therapy using whole-body phantom.
Although out-of-field radiation doses are lower than in-field doses, they may still contribute to late toxicities and second cancer risk in classical Hodgkin lymphoma (cHL) patients. Moreover, treatment planning systems (TPS) often underestimate these doses, especially in healthy tissues. Dosimetric parameters were compared between pencil beam scanning proton therapy (PBS) and volumetric modulated arc therapy (VMAT) in a cohort of 20 patients from the PRO-Hodgkin study. Planning CT scans were reconstructed into virtual whole-body CTs using the IS2aR software. Out-of-field doses were estimated with analytical models and Monte Carlo simulations in whole-body phantoms, then integrated with TPS in-field doses to calculate total equivalent dose. Dose distributions, dose-volume histograms (DVHs), non-target tissue integral dose equivalent (NTIHs), mean organ doses, and lifetime attributable risks of Second cancer (LARs) were evaluated for critical healthy tissues. PBS consistently resulted in lower out-of-field doses than VMAT. In both modalities, contributions were relatively small, not exceeding 5% of the prescribed dose. For organs near the target such as thyroid, lungs, breasts, heart, and esophagus, mean dose differences between PBS and VMAT ranged from 1.3 to 4.5 Sv, while for distant organs differences remained below 0.3 Sv. Incorporating out-of-field doses into LAR estimates increased predicted risks, but PBS reduced these values by up to 40% compared to VMAT. The radiation burden in high-precision radiotherapy, particularly from out-of-field radiation, should be accounted for in epidemiological studies and incorporated into treatment planning optimization to minimize second cancer risks in cHL patients.
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Drug Discovery Landscape
1 orphan drug designation for Radiation-induced disorder.
1 orphan drug designation for Radiation-induced disorder.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Recombinant human keratinocyte growth factor | proteins | FDA | 1999-12-20 | — | Swedish Orphan Biovitrum AB (publ) (SOBI) |
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