RARE DISEASE
Primary sclerosing cholangitis
Primary sclerosing cholangitis
Primary sclerosing cholangitis
Synonyms: PSC
Synonyms: PSC
Synonyms: PSC
Drug discovery
38
drugs
With orphan designations
Overview
Primary Sclerosing Cholangitis (PSC) is a chronic, immune-mediated cholestatic liver disease characterized by progressive inflammation, fibrosis, and stricturing of intra- and extrahepatic bile ducts. It is strongly associated with inflammatory bowel disease (IBD) in 70–80% of cases [1][6][12]. Clinical manifestations include fatigue, pruritus, jaundice, and recurrent cholangitis, with late-stage complications such as cirrhosis, portal hypertension, and hepatobiliary cancers (e.g., cholangiocarcinoma in 10–15% of patients) [1][12][20]. Diagnosis relies on cholangiography (MRCP/ERCP) and exclusion of secondary causes [1][6]. Liver transplantation is the only curative option for advanced disease, though recurrence occurs in 25–30% of cases [12][16].
Burden
Survival: Median transplant-free survival 21 years; 50% mortality at 21 years post-diagnosis [9][12].
Cancer risk: 10–15% lifetime risk of cholangiocarcinoma; 10-fold increased risk of colorectal cancer in IBD patients [12][20].
Quality of life: 48% loss of quality-adjusted life years (QALYs) >25 years post-diagnosis, 25% work productivity loss [9].
Healthcare utilization: Annual costs ~€12,169/patient, with 12.4 hospital contact days/year [9][10].
Therapies
Symptom management: Pruritus treated with cholestyramine, rifampicin, or opioid antagonists; antibiotics for recurrent cholangitis [3][8][13].
Endoscopic intervention: Balloon dilation/stenting for dominant strictures [3][13].
Liver transplantation: Indicated for decompensated cirrhosis or cholangiocarcinoma; 10-year survival post-transplant >80% [4][9][16].
No disease-modifying therapies exist, though high-dose ursodeoxycholic acid (13–15 mg/kg/day) is commonly used [3][5].
Categories: rare hepatic diseases, rare transplant-related disorders
Research Papers
1,462 drug discovery papers about Primary sclerosing cholangitis, with 2 first-in-class and 32 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,462 drug discovery papers about Primary sclerosing cholangitis, with 2 first-in-class and 32 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-07-06 | Mesenchymal stem cells in intrahepatic and extrahepatic biliary diseases: mechanisms and therapeutic applications.
Mesenchymal stem cells (MSCs) have emerged as promising therapeutic candidates for a wide range of intrahepatic and extrahepatic biliary diseases. However, their clinical application remains limited by an incomplete understanding of underlying mechanisms and heterogeneous therapeutic outcomes. This review provides a comprehensive overview of recent advances in MSC-based therapies for biliary system diseases, including primary biliary cholangitis, intrahepatic biliary fibrosis and cirrhosis, biliary atresia, primary sclerosing cholangitis, and cholangiocarcinoma. We summarize both preclinical and clinical evidence and focus on key therapeutic mechanisms, including immunomodulation, antifibrotic activity, regulation of bile acid metabolism, and protection of biliary epithelial cells.
2026-05-25 | Lactobacillus murinus improves liver fibrosis in primary sclerosing cholangitis mice by decreasing taurocholic acid and regulating M2 macrophage polarization.
Hepatic accumulation of bile acids (BAs) contributes to cholestasis-induced liver injury and fibrosis. Our previous studies have shown that Lactobacillus murinus ( L. murinus) alleviates liver fibrosis in primary sclerosing cholangitis (PSC) by modulating bile acid metabolism. In this study, we found that L. murinus intervention alleviated hepatic taurocholic acid (TCA) accumulation, cholestasis, and liver fibrosis in PSC mice. TCA was shown to promote liver fibrosis in PSC mice by enhancing M2 macrophage-mediated secretion of transforming growth factor beta 1 (TGF-β1). Macrophage depletion in PSC mice reduced the proportion of M2 macrophages and TGF-β1 cytokine levels, alleviating liver fibrosis. L. murinus exhibited bile salt hydrolase (BSH) activity, preferentially hydrolyzing glycine-conjugated bile acids. Furthermore, L. murinus reduced TCA reabsorption into the portal circulation by suppressing farnesoid X receptor ( Fxr) gene expression in the ileum, thereby alleviating hepatic TCA accumulation and mitigating liver fibrosis in PSC mice. These findings suggest that L. murinus mitigates PSC-associated liver fibrosis, which is associated with reduced TCA levels and regulation of M2 macrophage polarization, offering a potential therapeutic strategy for PSC.
2026-02-27 | Proctocolectomy with permanent ileostomy is associated with improved transplant-free survival in patients with PSC.
The gut-liver axis is believed to be crucial in the pathogenesis of primary sclerosing cholangitis (PSC). However, the impact of colectomy on liver disease progression is unclear. Our study estimated the effect of colectomy on PSC progression with correction for time dependency and established risk factors by pooling data from several cohorts across different countries. We analysed data from the International PSC Registry (IPSCR), comprising patients from Finland, The Netherlands, Norway, and Sweden. Primary endpoint was defined as liver transplantation (LT) or PSC-related death. Cox proportional hazards regression onto time-dependent colectomy status, with specification for extent, was performed with adjustment for sex, age at diagnosis, large or small duct PSC, features of autoimmune hepatitis, time-dependent inflammatory bowel disease (IBD) status, centre of inclusion, and country of residence. A total of 3,110 participants were included, of whom 470 (15%) had undergone colectomy. During a total follow-up of 32,236 patient-years, 395 deaths and 653 LTs were observed. Compared with patients with PSC with intact colon, the hazard ratio (HR) of reaching LT or PSC-related death was significantly decreased in patients with proctocolectomy with permanent ileostomy (HR 0.41; 95% CI 0.24-0.71). This effect was less pronounced in case of hemi- or subtotal colectomy (HR 0.81; 95% CI: 0.58-1.12) and not observed for proctocolectomy with pouch (HR 1.00; 95% CI: 0.73-1.38). The reduced risk was mainly associated with a lower rate of LT or death resulting from liver failure (HR 0.24; 0.10-0.53). Proctocolectomy with permanent ileostomy was associated with decreased risk for LT and PSC-related death. These findings support the role of the gut-liver axis in the pathophysiology of PSC and call for consideration in counselling patients who face impending colorectal surgery. The impact of the gut-liver axis in the pathophysiology of primary sclerosing cholangitis (PSC) has remained uncertain. In this study, proctocolectomy with ileostomy was associated with improved transplant-free survival, defined as a reduced risk of liver transplantation or PSC-related death, indicating that intestinal factors may influence disease progression. These findings are important for clinicians, researchers, and patients as they suggest that surgical management of colonic disease may have prognostic implications in PSC, and for further studies to clarify mechanisms and guide clinical decision-making.
2026-02-13 | Mesenchymal stromal cell administration promotes macrophage-mediated bile duct regeneration.
Mesenchymal stromal cell (MSC) therapy is used in cirrhosis models of chronic hepatocellular damage and represents a novel therapeutic approach for liver regeneration. However, no studies have examined MSC therapy for bile duct injury and its effects on bile duct regeneration. This study aimed to elucidate the mechanism underlying bile duct regeneration by establishing a regeneration model and administering MSCs. A model of bile duct regeneration was developed by feeding mice a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing diet to induce bile duct injury, followed by a normal diet to promote bile duct regeneration. MSCs were administered concurrently with the normal diet, and the livers were analyzed after 2 days. An experimental system was also developed in which clodronate liposomes were administered alongside MSCs to eliminate the influence of macrophages. MSC administration significantly increased the rate of body weight gain and the liver-to-body weight ratio on day 2 after the change to a normal diet. Immunostaining revealed an increase in the number of CK19+ cholangiocytes. The numbers of Hnf4α+ and Sox9+ cells were significantly elevated in the MSC-treated group. Flow cytometric analysis of liver lymphocytes showed a significant increase in the number of Ly6C- macrophages in the MSC-treated group. Furthermore, analysis of liver lymphocyte populations and cap analysis of gene expression revealed alterations in the immune response and macrophage-related genes, whereas macrophage removal during MSC treatment abolished the bile duct regenerative effects observed with MSC treatment. Macrophages play a crucial role in bile duct regeneration, and MSC administration has regenerative effects. This approach has potential as a novel treatment modality for bile duct injuries.
2025-12-24 | Single-Cell Genetic Mapping of Gasdermin Expression Across Immune-Mediated Inflammatory Diseases.
The gasdermin (GSDM) family mediates pyroptosis and membrane pore formation, but the causal, cell-type-specific roles of individual paralogues in immune-mediated inflammatory diseases (IMIDs) remain poorly defined. We combined single-cell cis-eQTL data from 14 peripheral blood immune subsets (OneK1K) with genome-wide association data from FinnGen release 12 to perform lineage-resolved Mendelian randomization (MR) across eight IMIDs: ankylosing spondylitis, Behçet disease, Crohn disease, hidradenitis suppurativa, primary sclerosing cholangitis, psoriasis, rheumatoid arthritis, and ulcerative colitis (UC). We identified robust genetic instruments for GSDMA, GSDMB, and GSDMD. Higher GSDMA expression in naïve/central-memory CD4+ T cells was protective in UC and Crohn disease, whereas up-regulation in cytotoxic CD8+/natural-killer cells increased the risk for hidradenitis suppurativa and ankylosing spondylitis. GSDMB showed predominantly protective effects: increased expression in multiple T-cell subsets associated with lower risk of UC, Crohn disease, rheumatoid arthritis, and ankylosing spondylitis, but showed an opposite liability in primary sclerosing cholangitis. By contrast, higher GSDMD expression conferred risk in psoriasis and a weaker liability in ankylosing spondylitis, yet was protective in primary sclerosing cholangitis; no instruments were found for GSDMC or GSDME. Consistent with these genetic associations, an independent endoscopic-biopsy cohort (25 UC vs. 25 healthy controls) showed increased mucosal GSDMB protein, suggesting a context-dependent, potentially protective epithelial upregulation. Together, these results establish paralogue- and lineage-specific roles for gasdermins in IMIDs and highlight therapeutic opportunities for cell-targeted modulation of GSDM function.
small molecules
2026-08-14 | Continued concomitant antibiotic or immunosuppression therapies reduce the risk of pouchitis among patients with ileal pouch-anal anastomosis and primary sclerosing cholangitis.
Complications such as intermittent pouchitis (IP) and chronic inflammatory disorders of the pouch (CP) are common after ileal pouch-anal anastomosis (IPAA), particularly among patients with both ulcerative colitis and primary sclerosing cholangitis (PSC). There are no standardized approaches for prophylaxis against these complications for patients with PSC undergoing IPAA. We compared outcomes among patients with PSC and IPAA who received antibiotic or immunosuppressive therapies to those who did not. We designed a retrospective cohort study that included patients with ulcerative colitis and PSC from 7 tertiary care centers that underwent IPAA between 1994 and 2023. Patients were categorized on whether they received medications following IPAA that may provide primary prophylactic benefit, such as antibiotics, probiotics, immunomodulators, or biologic medications; and the proportion of patients developing IP and CP was evaluated. A total of 172 patients were included in the cohort, and 13 (7.6%) patients received antibiotics or immunosuppressant medications. Antibiotics and probiotics were the most common therapy (5 patients, 2.9%), followed by biologics, small-molecule inhibitors, immunomodulators, or mesalamine (all 1 patient, 0.6%). Compared to patients not receiving antibiotics or immunosuppression, patients receiving antibiotics or immunosuppression were significantly less likely to develop IP (69.2% vs 91.2%; P = .03; odds ratio 0.22; 95% CI, 0.06-0.80) and CP (23.1% vs 56.0%, P = 0.04; OR 0.24, 95% CI, 0.06-0.89). In this retrospective cohort of patients with ulcerative colitis and PSC undergoing IPAA, usage of concomitant antibiotics or immunosuppression was low. However, use of concomitant antibiotics or immunosuppression may decrease the burden of inflammatory conditions of the pouch in these high-risk patients.
2026-08-11 | Single-cell landscape of neutrophil activation in primary sclerosing cholangitis.
Primary sclerosing cholangitis (PSC) is a chronic autoimmune cholestatic liver disease characterized by progressive inflammation and fibrosis, but the role of neutrophils in PSC remains poorly understood. To define neutrophil states in the PSC liver microenvironment, we performed single-cell RNA sequencing of leukocytes isolated from liver perfusate obtained from healthy donor grafts and explanted PSC livers. We identified a marked expansion of transcriptionally diverse neutrophil subclusters in PSC liver perfusate. Importantly, PSC livers were enriched for four neutrophil subclusters: RHOB-high, immediate early gene-high, heat shock protein-high, and CXCL8-high liver neutrophil-like subclusters. These PSC-associated neutrophil subclusters showed increased activity of the TNF and IL-17 signaling pathways, consistent with current views of PSC pathogenesis. They also displayed activation of inflammatory transcriptional regulators, including CEBPB, JUN, FOS, and RELA. Pseudotime analysis suggested that RHOB and immediate early gene subsets were derived from immature neutrophils, whereas liver neutrophil-like and heat shock protein-high subsets exhibited more mature and tissue-adapted features. Together, these data reveal previously unrecognized heterogeneity of liver neutrophils in PSC and identify inflammatory neutrophil programs that may contribute to sustained hepatic inflammation and represent potential therapeutic targets.
2026-08-11 | Hepatocyte-intrinsic ER stress and NRF2 initiate primary sclerosing cholangitis, providing therapeutic insights.
primary sclerosing cholangitis (PSC) is a severe liver disease that can progress to cholangiocarcinoma. Therapeutic development has been hindered by the rarity of PSC and by its poorly understood origin, which reflects incompletely defined genetic and environmental risk factors. Here we describe a mouse model that combines two suspected environmental risk factors, hepatocyte-intrinsic ER stress and oxidative stress, which leads to activation of transcription factor NRF2 in both hepatocytes and cholangiocytes. Genetically affected mice, as well as mice treated with an ER stress inducer and an NRF2 activator, progressed to PSC with human-like features. Specifically, hepatocyte-intrinsic ER stress in cooperation with activated NRF2 leads to indirect activation of JNK-JUN signaling, which abrogates HNF1α-stimulated Fxr gene transcription and reduces expression of the bile salt export pump BSEP. These signaling abnormalities, whose clinical relevance is supported by single cell transcriptomics of human PSC tissue, cause cholestasis, hepatocyte and bile canaliculi injury, biliary hyperplasia, and periductular fibrosis, which define PSC. Congruently, alleviation of cholestasis and/or inhibition of biliary hyperplasia resolve PSC in mice.
2026-08-09 | "From Cholestasis to Interface Hepatitis: A Rare Case of Primary Sclerosing Cholangitis-Autoimmune Hepatitis Overlap in a 20-Year-Old Male".
Overlap syndrome refers to the coexistence of more than one immune-mediated liver disease in a single patient. Primary sclerosing cholangitis-autoimmune hepatitis (PSC-AIH) overlap is a rare but clinically important entity, as delayed recognition may lead to progressive liver injury, cirrhosis, and liver failure. Differentiating this condition from isolated PSC or AIH remains challenging due to overlapping clinical, biochemical, and radiological features. A 20-year-old male presented with progressive jaundice, pruritus, acholic stools, and dark urine for one month. Laboratory evaluation revealed marked cholestasis with significantly elevated alkaline phosphatase and transaminases, hyperbilirubinemia, and coagulopathy, while viral and metabolic causes were excluded. Magnetic resonance cholangiopancreatography demonstrated characteristic intrahepatic biliary duct irregularities consistent with primary sclerosing cholangitis. However, disproportionately elevated alanine aminotransferase and serum immunoglobulin G levels prompted further evaluation. Liver biopsy revealed features of both diseases, including interface hepatitis with chronic portal inflammation and plasma cell infiltration, along with bile duct injury, ductopenia, and onion-skin fibrosis. Based on histology and diagnostic scoring, a diagnosis of PSC-AIH overlap syndrome was established. The patient was treated with ursodeoxycholic acid, corticosteroids, and azathioprine, resulting in marked clinical and biochemical improvement on follow-up. This case highlights the importance of considering PSC-AIH overlap syndrome in young patients with cholestatic liver disease and unexpectedly elevated transaminases or immunoglobulin G levels. Early recognition and combined immunosuppressive and supportive therapy can lead to favorable outcomes and may prevent irreversible liver damage.
2026-08-04 | Effect of a single dose antibiotic prophylaxis in scheduled bile duct interventions in Primary Sclerosing Cholangitis.
The recommended duration of antibiotic prophylaxis in scheduled endoscopic retrograde cholangiopancreatography (ERCP) for patients with primary sclerosing cholangitis (PSC) varies greatly across international guidelines. Increasing antibiotic resistance makes a rational use of antibiotics urgently necessary. Therefore, we aimed to investigate the effect of an antibiotic single shot prophylaxis on the rate of postinterventional cholangitis, the antibiotic exposure and potential risk factors for cholangitis in this cohort. A registry-based, non-interventional cohort study was conducted to investigate the effect of a newly introduced standard operating procedure (SOP) with a periinterventional single dose prophylaxis (SOP cohort, n=80 procedures) compared to a historical cohort (n=100 procedures) receiving a multi-day regimen. Tokyo guidelines from 2018 were adapted for diagnosis and severity grading of cholangitis. The duration of the periinterventional antibiotic therapy differed significantly between cohorts, with a median of 0.33 days in the SOP cohort and 3.50 days in the historical cohort (p<0.001), whereas no significant difference in the rate of post-ERCP cholangitis between the cohorts was found, even in procedures with dilation. When cholangitis severity was dichotomized into Grade I vs. Grade II + III, the SOP cohort showed a significantly higher proprotion of moderate to severe cholangits (45.5% vs. 9.1%, p<0.001. Identified significant risk factors (in univariate analysis) for a post-ERCP cholangitis were the presence of a traditional dominant stricture (TDS), and the subsequent performance of a dilation during ERCP (OR 3.360, p=0.034, and OR 3.356, p=0.033, respectively). In our study in patients with PSC, the antibiotic single shot prophylaxis in scheduled ERCPs was not associated with an higher rate of postinterventional cholangitis, but an increase cholangitis grade compared to a multi-day regimen, indicating a potential comparable effectiveness in preventing postinterventional cholangitis.
antibodies
2026-08-01 | Hyaluronan and CD44 targeting reverses early matrix changes, proinflammatory signals and fibrosis in primary sclerosing cholangitis.
Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by biliary inflammation and bile duct strictures and no approved medical therapy. Despite its clinical severity, the pathological mechanisms underlying PSC remain poorly understood, largely due to early diagnostic challenges. Here we provide complementary evidence in human PSC samples, transcriptomic data, mouse models, and 3D cholangiocyte cultures that underscore the importance of hyaluronic acid (HA) and its cognate receptor CD44 in PSC pathogenesis. HA is a glycosaminoglycan abundant in the extracellular matrix in inflammatory disorders, yet its role in PSC has not been well characterized. We demonstrate that in early-stage PSC, cholangiocytes aberrantly produce high molecular weight HA that accumulates in the peribiliary matrix, increasing local tissue stiffness. This mechanical signal is transduced by a CD44/Integrin β1 receptor complex in cholangiocytes, driving cell proliferation, YAP mechanosignaling, pro-inflammatory cytokine production with a transition to a ductular reactive phenotype. CD44 knockdown in cholangiocyte cell lines and mouse models significantly lowered stiffness, and attenuated inflammation. Together, these findings reveal a mechano-inflammatory axis in which HA-driven matrix stiffening perpetuates biliary inflammation and disease progression, identifying HA targeting and CD44 as promising therapeutic strategies. Hyaluronan and CD44 mediate matrix changes and progressive fibrosis in primary sclerosing cholangitis.
2026-06-26 | Multi-Omics Integrative Analysis Identifies the NK Cell-STAT3 Axis as a Shared Immunogenetic Hub Underlying the Comorbidity of Primary Sclerosing Cholangitis and Ulcerative Colitis.
Primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) exhibit a striking clinical comorbidity, with 60-80% of PSC patients concurrently harboring UC, yet the shared immunogenetic mechanisms remain poorly understood. Here, we constructed a multi-omics integrative framework to systematically dissect the cellular and molecular basis of this comorbidity. GWAS meta-analyses were performed for each disease, followed by tissue-level enrichment assessment using QTLEnrich, MAGMA, and gsMap spatial mapping. Single-cell transcriptomic atlases were constructed, and cell-type prioritization was conducted using four complementary methods. Core genes were identified through cross-validation of five algorithms, with subsequent genomic fine-mapping via FUMA and GCTA-COJO. Tissue-level analyses consistently identified the intestine and immune-related tissues as commonly affected. Multi-dimensional evidence integration prioritized natural killer (NK) cells as the core effector cell type for both diseases, supported principally by CELLECT (Cell-type Expression-specific Integration for Complex Traits) heritability enrichment and single-cell differential analysis. Convergence of five gene-level algorithms pinpointed STAT3 as the sole high-confidence comorbidity gene, broadly expressed across immune cell populations and exhibiting tissue-differential alternative splicing. Colocalization identified a high-risk variant (rs3736161) within the STAT3 locus, with conditional analysis revealing 35 additional independent signals. These findings identify the NK cell-STAT3 axis as a central immunogenetic hub connecting PSC and UC, offering potential therapeutic targets for comorbidity management.
2026-05-24 | The Interleukin-17-T helper 17 axis in primary sclerosing cholangitis: A narrative review of an emerging pathogenic frontier.
Interleukin-17 (IL-17) and IL-17+ secretory cells, including T helper 17 (Th17) cells play pivotal roles in autoimmune diseases such as psoriasis. Emerging evidence implicates the IL-17 pathway in primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease lacking approved pharmacological therapies, for which liver transplantation remains the only life-extending option. The IL-17 pathway and Th17 biology is increasingly implicated in PSC pathogenesis through its interactions with hepatic parenchymal and non-parenchymal cells, including cholangiocytes, neutrophils and hepatic stellate cells which promote periductal fibro-inflammation, immune cell recruitment and pro-inflammatory cytokine release. Th17 cells and IL-17+ secreting lymphocytes localise to peribiliary regions, exacerbating biliary injury and fibrosis. Preclinical murine models suggest that inhibition of IL-17 signalling mitigates hepatic fibro-inflammatory responses, providing a compelling rationale for its investigation as a potential therapeutic target in PSC. Whilst licensed IL-17 inhibitors have demonstrated efficacy and safety in a number of autoimmune and immune-mediated diseases, IL-17 has context-dependent roles in tissue homeostasis and host defence underscoring the pathway's complexity. This narrative review synthesises the biology of the IL-17 family, integrating preclinical and translational evidence relevant to PSC, and discusses the translational potential of approved anti-IL-17 agents as novel therapeutic candidates in PSC, whilst highlighting key uncertainties and gastrointestinal safety considerations.
2026-05-21 | Overlapping Cytomegalovirus Infection and Inflammatory Pouchitis After Liver Transplantation: When Antivirals Alone Are Insufficient.
Cytomegalovirus (CMV) is an infrequently reported etiology of secondary pouchitis in patients who have undergone total proctocolectomy with ileal pouch-anal anastomosis. We present the case of a patient with chronic antibiotic-dependent pouchitis, ulcerative pancolitis, primary sclerosing cholangitis, and orthotopic liver transplant who presented with hematochezia. Pouchoscopy showed ulcerated mucosa, and histopathology with immunohistochemistry confirmed CMV pouchitis. The patient was treated with antiviral therapy with improvement in bleeding and viremia. However, persistent refractory pouch inflammation ultimately required guselkumab. This case depicts the importance of considering CMV as a secondary etiology of pouchitis, especially in those with refractory or atypical features.
2026-05-03 | Suppression of Small-Bowel Klebsiella Biofilm in Post-Colectomy Primary Sclerosing Cholangitis
Authored by an Occupational Safety and Health Specialist and Systems Designer (UCD, IT Carlow, Maynooth University) applying formal risk-management architecture to survive their own progressive PSC. Intended purpose: Published for Gastroenterological and Hepatological Critique. This document presents a multi-modal therapeutic framework for post-colectomy Primary Sclerosing Cholangitis, developed out of personal necessity by a patient managing this exact clinical intersection. The protocol outlines a strategic approach to suppressing Klebsiella-driven portal endotoxemia and halting structural hepatic degradation. Because research at this specific anatomical and pathological intersection is scarce, this framework is offered as an actively evolving, open-source architecture. I invite rigorous scrutiny, methodological challenges, and clinical critique from the gastroenterological and research communities to identify evidence gaps and strengthen future revisions.
proteins
2026-07-22 | A Multi-omics and Machine Learning Framework Identifies Plasma SBDS as a Causal Biomarker and Therapeutic Target in Primary Sclerosing Cholangitis.
Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease. Its molecular etiology remains poorly defined, hindering the development of mechanism-based diagnostics and therapies. Therefore, this study aimed to identify key molecular drivers and causal biomarkers of PSC by integrating transcriptomics, machine learning, and genetic causal inference. We deployed a computational framework combining transcriptomics, network biology, machine learning, and genetic causal inference. Peripheral blood transcriptomes from PSC patients and controls were analyzed to identify disease-associated modules. Candidate genes were refined via protein-protein interaction networks and a multi-algorithm machine learning screen. Causal inference was performed using two-sample Mendelian randomization, integrating plasma protein quantitative trait loci with PSC genome-wide association study summary statistics. Transcriptomic analysis revealed a PSC-associated module enriched in ribosome biogenesis and protein homeostasis pathways. A machine learning-optimized nine-gene signature (including PTMA, SUMO1, Shwachman-Bodian-Diamond syndrome (SBDS), RPL7, EIF1AX, ANP32A, PCNA, FAM98A, and MPHOSPH6) achieved high diagnostic accuracy (mean AUC = 0.908) and was consistently downregulated in PSC. This signature was linked to a remodeled immune microenvironment characterized by myeloid skewing and specific transcriptional-immune covariation patterns. Mendelian randomization identified SBDS as a putatively causal protective factor, where genetically instrumented higher plasma SBDS protein levels were robustly associated with a lower PSC risk (inverse variance weighted odds ratio = 0.525, 95% CI: 0.356-0.773, P = 0.001). Sensitivity analyses supported the validity of the Mendelian randomization assumptions. Our study establishes disrupted ribosome homeostasis as a causal pathway in PSC and nominates plasma SBDS as a high-confidence diagnostic biomarker and therapeutic target. The integrative framework provides a generalizable strategy for discovering causal biomarkers in complex diseases.
2026-03-12 | Constructing a protein-protein interaction network for autoimmune liver diseases by integrating pQTL, rQTL, and mediation analyses.
Autoimmune liver diseases (AILDs), including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH), pose significant diagnostic and therapeutic challenges due to poorly understood mechanisms. While most studies focus on absolute protein levels, protein-protein ratios (PPRs), reflecting the relative abundance of paired plasma proteins, emerge as critical yet understudied biomarkers for decoding disease-specific network perturbations. To harness this potential, we integrated protein quantitative trait loci (pQTLs), ratio QTLs (rQTLs), and mediation Mendelian randomization (MR) to map causal proteomic networks, aiming to unravel pathogenic networks and identify therapeutic targets in AILDs. Using two-sample MR, we analyzed 2821 plasma PPRs and 2923 individual proteins from the UK Biobank Pharma Proteomics Project. The primary analysis employed the inverse-variance weighted (IVW) method, complemented by MR-Egger regression, weighted median, simple mode, and weighted mode methods, all within a random-effects model. Sensitivity analyses were performed to validate the findings, including Cochran's Q test, MR-Egger intercept analysis, MR-PRESSO, and Steiger filtering. Cross-trait linkage disequilibrium score regression (LDSC) quantified genetic correlations, while the MR approach based on Bayesian model averaging (MR-BMA) prioritized independent causal PPRs. Two-step mediation MR identified mechanistic pathways. Functional enrichment and protein-protein interaction (PPI) networks were constructed using STRING and the clusterProfiler package. Finally, we investigated the associations between the causal PPRs and AILD-related symptoms/complications, as well as the influence of modifiable lifestyle factors on these PPRs. CD74 exhibited dual roles in AILDs. Elevated plasma CD74 levels were associated with an increased risk of PSC (OR = 1.54, 95% CI 1.24-1.90), whereas CD74-PPRs exhibited robust protection. Specifically, CD74/JAM2 reduced risks of PSC (OR = 0.70, 95% CI 0.59-0.83) and AIH (OR = 0.53, 95% CI 0.39-0.71), while CD74/NPDC1 conferred protection against PSC (OR = 0.66, 95% CI 0.54-0.80). Mediation MR identified TRY3 as the dominant mediator of CD74/JAM2 in AIH (91.52% proportion mediated, P = 0.017), with GREM1 and TEK mediating CD74/NPDC1 effects in PSC. PPI networks implicated interactions among CD74, amyloid precursor protein (APP), and endoglin (ENG). Notably, CD74/JAM2 demonstrated cross-disease relevance, significantly lowering PSC-associated ulcerative colitis risk (OR = 0.35, 95% CI 0.22-0.54). This study pioneers the integration of pQTLs, rQTLs, and mediation MR to map dynamic proteomic interactions in AILDs. Our findings revealed the multifaceted impact of CD74 on AILDs: its direct elevation may promote disease, whereas its protein interactions appear to mitigate risk. These results advance understanding of AILD pathogenesis and pave the way for developing novel biomarkers and targeted therapies.
2025-11-28 | Intestinal barrier in chronic gut and liver diseases: Pathogenesis and therapeutic targets.
The intestinal barrier is the primary defense that separates the host from the external environment, possessing several crucial physiological functions, including nutrient digestion, absorption, and protection against potentially harmful dietary antigens and pathogenic microorganisms. Nevertheless, various factors, such as diet, medications, circadian rhythm disturbances, gut microbiota, microbial metabolites, and genetic predisposition, can disrupt the intestinal barrier. Such disruption may lead to bacterial translocation, subsequently triggering enterohepatic and systemic inflammation. Impaired intestinal barrier has been implicated in the pathogenesis of numerous diseases, particularly chronic gut and liver diseases. In this review, we will summarize the fundamental functions of intestinal barrier and discuss clinical correlations between intestinal barrier dysfunction and diseases such as colitis, colorectal cancer, and chronic liver diseases including metabolic dysfunction-associated steatohepatitis, alcohol-associated liver disease, and primary sclerosing cholangitis. Additionally, we will also highlight some potential therapeutic strategies aimed at restoring barrier integrity to improve disease management.
2025-11-20 | Moderate increase of MET in hepatocytes protects against cholestatic liver injury by promoting an effective antioxidant response.
Hepatocyte growth factor (HGF)/hepatocyte growth factor receptor (MET) signaling plays a critical role during liver regeneration upon acute and chronic damage, and is therefore an interesting target for therapeutic intervention. Nevertheless, the molecular mechanisms underlying the pro-regenerative effects of HGF/MET signaling are not fully elucidated, particularly during cholestatic injury. Our aim was to analyze the impact of moderately enhanced MET on the hepatic response to cholestatic injury, and uncover the mechanisms behind it. For that, Alb-R26Met mice expressing a wild-type Met transgene in albumin-positive liver cells were fed with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-supplemented diet, used as a model simulating human primary sclerosing cholangitis. Results indicate that increased MET expression diminished liver damage in DDC-fed mice, evidenced by lower serum levels of bilirubin and alkaline phosphatase, and decreased cell apoptosis. However, decreased ductular expansion was observed, which together with enhanced hepatocyte proliferation suggests that hepatocytes act as the main cellular defense. Both in vivo and in vitro studies using Alb-R26Met liver-derived hepatocytes under cholestasis-simulated in vitro conditions demonstrated an enhanced upregulation of nuclear factor erythroid 2-related factor 2 (NRF2; encoded by the Nfe2l2 gene), parallel to an upregulation of glutathione biosynthesis enzymes, increased levels of glutathione, and decreased reactive oxygen species, along with decreased activation of transforming growth factor beta (TGF-β)-induced signaling. Consistently, MET transgenic hepatocytes were protected against TGF-β-induced oxidative stress and apoptosis in vitro. In conclusion, our work evidences that moderate upregulation of wild-type MET in hepatocytes is sufficient to promote a strong antioxidant response in the liver that efficiently protects against chronic cholestasis, thus allowing optimal liver regeneration.
2025-11-15 | Regulatory T cell stability determines the efficiency of bile duct regeneration during cholangitis.
Cholangiopathies such as primary sclerosing cholangitis (PSC) cause damage to the bile ducts with no effective cure. Reduction and impairment in the function of regulatory T cells (Tregs) occur in PSC. We investigate whether Tregs regulate bile duct regeneration and the dynamics of Treg turnover during bile duct injury. We use the transgenic Foxp3GFPDTR model to mimic reduced Treg infiltration in PSC and show that Tregs mediate cholangiocyte response to biliary injury. Fate mapping of Tregs reveals that intrahepatic Tregs acquire a pro-inflammatory phenotype, even after interleukin-2 (IL-2)-mediated Treg expansion. Ox40L expression correlates with fibrosis in PSC patients. Enhancing Treg numbers through IL-2 complex administration and blocking Ox40 signaling simultaneously suppresses the inflammatory phenotype of Tregs and reduces bile duct damage and fibrosis. We demonstrate that bile duct regeneration can be enhanced by combining Treg-based therapy and targeting co-stimulatory molecules, such as Ox40L.
other
2025-12-17 | Mechanistic roles and therapeutic potential of bacteriophages in inflammatory gastrointestinal diseases.
The gut virome, particularly its viral and phage components, is increasingly recognized as a key modulator of intestinal microbial dynamics in gastrointestinal inflammatory diseases. Beyond well-characterized bacterial dysbiosis, growing evidence suggests that virome alterations contribute to the development and progression of inflammatory bowel disease, metabolic dysfunction-associated steatohepatitis, alcoholic hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, and pancreatitis. As the most abundant viruses in the gut, bacteriophages influence microbial ecosystem stability and host immune responses through lytic and lysogenic interactions with bacterial populations. Amid the growing burden of multidrug-resistant infections and heightened interest in microbiota-based interventions, phage therapy has re-emerged as a viable strategy in both preclinical and translational contexts. This review synthesizes recent insights into bacteriophage dynamics in the context of major gastrointestinal and hepatopancreatic inflammatory diseases, highlighting potential compositional shifts, proposed mechanisms of phage-microbe interactions, and supportive evidence from animal models and early clinical applications. We also discussed the critical challenges that had to be addressed to enable clinical translation, including host range restrictions, resistance and safety concerns, immunogenicity, and delivery limitations, while emphasizing emerging strategies such as phage engineering, encapsulation technologies, and standardized regulatory frameworks.
2025-11-15 | Numb-exon3 and full length Numb equivalently alleviate cholestatic liver fibrosis by inhibiting ductular reaction.
Cholestasis can occur in various acute and chronic liver diseases, with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) being the most common clinical manifestations. Without appropriate treatment, these conditions may ultimately progress to liver cirrhosis and hepatic failure. Therefore, identifying novel therapeutic targets is of great importance. Our previous research had found a gene target named Numb which is a determinant of stem cell fate can increase the anti-cholestatic liver fibrosis (CLF) effect of bone marrow mesenchymal stem cells (BM-MSCs). However, whether the Numb gene or its exon has direct anti-CLF activity is unclear. In this study, an adeno-associated virus (AAV) was used as a gene delivery vector to overexpress the full-length Numb gene directly in the rat liver. In addition, Exon3 was overexpressed to clarify the effective site of Numb gene for comparison. AAV.Numb can alleviate CLF and suppressed the activation of Notch signaling and the differentiation of hepatic progenitor cells (HPCs) into biliary epithelial cells (BECs), and the anti-CLF effect of Numb-Exon3 was similar to that of full-length Numb. The findings revealed that Numb gene may be a new therapeutic target for PBC and that Exon3 may be an effective site.
2025-01-27 | Liver Lymphatic Dysfunction as a Driver of Fibrosis and Cirrhosis Progression.
The liver lymphatic system plays a critical role in maintaining interstitial fluid balance and immune regulation. Efficient lymphatic drainage is essential for liver homeostasis, but its role in liver disease progression remains poorly understood. In cirrhosis, lymphangiogenesis initially compensates for increased lymph production, but impaired lymphatic drainage in advanced stages may lead to complications such as ascites and portal hypertension. This study aimed to evaluate how liver lymphatic dysfunction affects disease progression and to assess therapeutic strategies. Using a surgical model to block liver lymphatic outflow, we found that impaired drainage accelerates liver injury, fibrosis, and immune cell infiltration, even in healthy livers. Mechanistically, enhanced TGF-β signaling in liver lymphatic endothelial cells (LyECs) contributed to reduced lymphatic vessel (LV) density and function in late-stage decompensated cirrhosis. This dysfunction was linked to the progression from compensated to decompensated cirrhosis, particularly in patients with primary sclerosing cholangitis (PSC). Conversely, liver-specific overexpression of VEGF-C via AAV8 improved lymphatic drainage, restored LV density, reduced fibrosis, mitigated liver injury, and alleviated portal hypertension in cirrhotic rats. These findings establish impaired liver lymphatic function as a pivotal driver of cirrhosis progression and identify VEGF-C as a promising therapeutic target to prevent decompensation.
2024-11-28 | LncRNAs, RNA Therapeutics, and Emerging Technologies in Liver Pathobiology.
The field of ribonucleic acid (RNA) biology has revealed an array of noncoding RNA species, particularly long noncoding RNAs (lncRNAs), which play crucial roles in liver disease pathogenesis. This review explores the diverse functions of lncRNAs in liver pathology, including metabolic-associated steatotic liver disease, hepatocellular carcinoma, alcohol-related liver disease, and cholangiopathies such as primary sclerosing cholangitis and cholangiocarcinoma. We highlight key lncRNAs that regulate lipid metabolism, inflammation, fibrosis, and oncogenesis in the liver, demonstrating their diagnostic and therapeutic potential. Emerging RNA-based therapies, such as mRNA therapy, RNA interference, and antisense oligonucleotides, offer approaches to modulate lncRNA activity and address liver disease at a molecular level. Advances in sequencing technologies and bioinformatics pipelines are simultaneously enabling the identification and functional characterization of novel lncRNAs, driving innovation in personalized medicine. In conclusion, this review highlights the potential of lncRNAs as biomarkers and therapeutic targets in liver disease and emphasizes the need for further research into their regulatory mechanisms and clinical applications.
2024-11-05 | Regulatory T cells-related gene in primary sclerosing cholangitis: evidence from Mendelian randomization and transcriptome data.
The present study utilized large-scale genome-wide association studies (GWAS) summary data (731 immune cell subtypes and three primary sclerosing cholangitis (PSC) GWAS datasets), meta-analysis, and two PSC transcriptome data to elucidate the pivotal role of Tregs proportion imbalance in the occurrence of PSC. Then, we employed weighted gene co-expression network analysis (WGCNA), differential analysis, and 107 combinations of 12 machine-learning algorithms to construct and validate an artificial intelligence-derived diagnostic model (Tregs classifier) according to the average area under curve (AUC) (0.959) in two cohorts. Quantitative real-time polymerase chain reaction (qRT-PCR) verified that compared to control, Akap10, Basp1, Dennd3, Plxnc1, and Tmco3 were significantly up-regulated in the PSC mice model yet the expression level of Klf13, and Scap was significantly lower. Furthermore, immune cell infiltration and functional enrichment analysis revealed significant associations of the hub Tregs-related gene with M2 macrophage, neutrophils, megakaryocyte-erythroid progenitor (MEP), natural killer T cell (NKT), and enrichment scores of the autophagic cell death, complement and coagulation cascades, metabolic disturbance, Fc gamma R-mediated phagocytosis, mitochondrial dysfunction, potentially mediating PSC onset. XGBoost algorithm and SHapley Additive exPlanations (SHAP) identified AKAP10 and KLF13 as optimal genes, which may be an important target for PSC.
cell therapies
2026-07-06 | Mesenchymal stem cells in intrahepatic and extrahepatic biliary diseases: mechanisms and therapeutic applications.
Mesenchymal stem cells (MSCs) have emerged as promising therapeutic candidates for a wide range of intrahepatic and extrahepatic biliary diseases. However, their clinical application remains limited by an incomplete understanding of underlying mechanisms and heterogeneous therapeutic outcomes. This review provides a comprehensive overview of recent advances in MSC-based therapies for biliary system diseases, including primary biliary cholangitis, intrahepatic biliary fibrosis and cirrhosis, biliary atresia, primary sclerosing cholangitis, and cholangiocarcinoma. We summarize both preclinical and clinical evidence and focus on key therapeutic mechanisms, including immunomodulation, antifibrotic activity, regulation of bile acid metabolism, and protection of biliary epithelial cells.
2026-05-25 | Lactobacillus murinus improves liver fibrosis in primary sclerosing cholangitis mice by decreasing taurocholic acid and regulating M2 macrophage polarization.
Hepatic accumulation of bile acids (BAs) contributes to cholestasis-induced liver injury and fibrosis. Our previous studies have shown that Lactobacillus murinus ( L. murinus) alleviates liver fibrosis in primary sclerosing cholangitis (PSC) by modulating bile acid metabolism. In this study, we found that L. murinus intervention alleviated hepatic taurocholic acid (TCA) accumulation, cholestasis, and liver fibrosis in PSC mice. TCA was shown to promote liver fibrosis in PSC mice by enhancing M2 macrophage-mediated secretion of transforming growth factor beta 1 (TGF-β1). Macrophage depletion in PSC mice reduced the proportion of M2 macrophages and TGF-β1 cytokine levels, alleviating liver fibrosis. L. murinus exhibited bile salt hydrolase (BSH) activity, preferentially hydrolyzing glycine-conjugated bile acids. Furthermore, L. murinus reduced TCA reabsorption into the portal circulation by suppressing farnesoid X receptor ( Fxr) gene expression in the ileum, thereby alleviating hepatic TCA accumulation and mitigating liver fibrosis in PSC mice. These findings suggest that L. murinus mitigates PSC-associated liver fibrosis, which is associated with reduced TCA levels and regulation of M2 macrophage polarization, offering a potential therapeutic strategy for PSC.
2026-02-27 | Proctocolectomy with permanent ileostomy is associated with improved transplant-free survival in patients with PSC.
The gut-liver axis is believed to be crucial in the pathogenesis of primary sclerosing cholangitis (PSC). However, the impact of colectomy on liver disease progression is unclear. Our study estimated the effect of colectomy on PSC progression with correction for time dependency and established risk factors by pooling data from several cohorts across different countries. We analysed data from the International PSC Registry (IPSCR), comprising patients from Finland, The Netherlands, Norway, and Sweden. Primary endpoint was defined as liver transplantation (LT) or PSC-related death. Cox proportional hazards regression onto time-dependent colectomy status, with specification for extent, was performed with adjustment for sex, age at diagnosis, large or small duct PSC, features of autoimmune hepatitis, time-dependent inflammatory bowel disease (IBD) status, centre of inclusion, and country of residence. A total of 3,110 participants were included, of whom 470 (15%) had undergone colectomy. During a total follow-up of 32,236 patient-years, 395 deaths and 653 LTs were observed. Compared with patients with PSC with intact colon, the hazard ratio (HR) of reaching LT or PSC-related death was significantly decreased in patients with proctocolectomy with permanent ileostomy (HR 0.41; 95% CI 0.24-0.71). This effect was less pronounced in case of hemi- or subtotal colectomy (HR 0.81; 95% CI: 0.58-1.12) and not observed for proctocolectomy with pouch (HR 1.00; 95% CI: 0.73-1.38). The reduced risk was mainly associated with a lower rate of LT or death resulting from liver failure (HR 0.24; 0.10-0.53). Proctocolectomy with permanent ileostomy was associated with decreased risk for LT and PSC-related death. These findings support the role of the gut-liver axis in the pathophysiology of PSC and call for consideration in counselling patients who face impending colorectal surgery. The impact of the gut-liver axis in the pathophysiology of primary sclerosing cholangitis (PSC) has remained uncertain. In this study, proctocolectomy with ileostomy was associated with improved transplant-free survival, defined as a reduced risk of liver transplantation or PSC-related death, indicating that intestinal factors may influence disease progression. These findings are important for clinicians, researchers, and patients as they suggest that surgical management of colonic disease may have prognostic implications in PSC, and for further studies to clarify mechanisms and guide clinical decision-making.
2026-02-13 | Mesenchymal stromal cell administration promotes macrophage-mediated bile duct regeneration.
Mesenchymal stromal cell (MSC) therapy is used in cirrhosis models of chronic hepatocellular damage and represents a novel therapeutic approach for liver regeneration. However, no studies have examined MSC therapy for bile duct injury and its effects on bile duct regeneration. This study aimed to elucidate the mechanism underlying bile duct regeneration by establishing a regeneration model and administering MSCs. A model of bile duct regeneration was developed by feeding mice a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing diet to induce bile duct injury, followed by a normal diet to promote bile duct regeneration. MSCs were administered concurrently with the normal diet, and the livers were analyzed after 2 days. An experimental system was also developed in which clodronate liposomes were administered alongside MSCs to eliminate the influence of macrophages. MSC administration significantly increased the rate of body weight gain and the liver-to-body weight ratio on day 2 after the change to a normal diet. Immunostaining revealed an increase in the number of CK19+ cholangiocytes. The numbers of Hnf4α+ and Sox9+ cells were significantly elevated in the MSC-treated group. Flow cytometric analysis of liver lymphocytes showed a significant increase in the number of Ly6C- macrophages in the MSC-treated group. Furthermore, analysis of liver lymphocyte populations and cap analysis of gene expression revealed alterations in the immune response and macrophage-related genes, whereas macrophage removal during MSC treatment abolished the bile duct regenerative effects observed with MSC treatment. Macrophages play a crucial role in bile duct regeneration, and MSC administration has regenerative effects. This approach has potential as a novel treatment modality for bile duct injuries.
2025-12-24 | Single-Cell Genetic Mapping of Gasdermin Expression Across Immune-Mediated Inflammatory Diseases.
The gasdermin (GSDM) family mediates pyroptosis and membrane pore formation, but the causal, cell-type-specific roles of individual paralogues in immune-mediated inflammatory diseases (IMIDs) remain poorly defined. We combined single-cell cis-eQTL data from 14 peripheral blood immune subsets (OneK1K) with genome-wide association data from FinnGen release 12 to perform lineage-resolved Mendelian randomization (MR) across eight IMIDs: ankylosing spondylitis, Behçet disease, Crohn disease, hidradenitis suppurativa, primary sclerosing cholangitis, psoriasis, rheumatoid arthritis, and ulcerative colitis (UC). We identified robust genetic instruments for GSDMA, GSDMB, and GSDMD. Higher GSDMA expression in naïve/central-memory CD4+ T cells was protective in UC and Crohn disease, whereas up-regulation in cytotoxic CD8+/natural-killer cells increased the risk for hidradenitis suppurativa and ankylosing spondylitis. GSDMB showed predominantly protective effects: increased expression in multiple T-cell subsets associated with lower risk of UC, Crohn disease, rheumatoid arthritis, and ankylosing spondylitis, but showed an opposite liability in primary sclerosing cholangitis. By contrast, higher GSDMD expression conferred risk in psoriasis and a weaker liability in ankylosing spondylitis, yet was protective in primary sclerosing cholangitis; no instruments were found for GSDMC or GSDME. Consistent with these genetic associations, an independent endoscopic-biopsy cohort (25 UC vs. 25 healthy controls) showed increased mucosal GSDMB protein, suggesting a context-dependent, potentially protective epithelial upregulation. Together, these results establish paralogue- and lineage-specific roles for gasdermins in IMIDs and highlight therapeutic opportunities for cell-targeted modulation of GSDM function.
small molecules
2026-08-14 | Continued concomitant antibiotic or immunosuppression therapies reduce the risk of pouchitis among patients with ileal pouch-anal anastomosis and primary sclerosing cholangitis.
Complications such as intermittent pouchitis (IP) and chronic inflammatory disorders of the pouch (CP) are common after ileal pouch-anal anastomosis (IPAA), particularly among patients with both ulcerative colitis and primary sclerosing cholangitis (PSC). There are no standardized approaches for prophylaxis against these complications for patients with PSC undergoing IPAA. We compared outcomes among patients with PSC and IPAA who received antibiotic or immunosuppressive therapies to those who did not. We designed a retrospective cohort study that included patients with ulcerative colitis and PSC from 7 tertiary care centers that underwent IPAA between 1994 and 2023. Patients were categorized on whether they received medications following IPAA that may provide primary prophylactic benefit, such as antibiotics, probiotics, immunomodulators, or biologic medications; and the proportion of patients developing IP and CP was evaluated. A total of 172 patients were included in the cohort, and 13 (7.6%) patients received antibiotics or immunosuppressant medications. Antibiotics and probiotics were the most common therapy (5 patients, 2.9%), followed by biologics, small-molecule inhibitors, immunomodulators, or mesalamine (all 1 patient, 0.6%). Compared to patients not receiving antibiotics or immunosuppression, patients receiving antibiotics or immunosuppression were significantly less likely to develop IP (69.2% vs 91.2%; P = .03; odds ratio 0.22; 95% CI, 0.06-0.80) and CP (23.1% vs 56.0%, P = 0.04; OR 0.24, 95% CI, 0.06-0.89). In this retrospective cohort of patients with ulcerative colitis and PSC undergoing IPAA, usage of concomitant antibiotics or immunosuppression was low. However, use of concomitant antibiotics or immunosuppression may decrease the burden of inflammatory conditions of the pouch in these high-risk patients.
2026-08-11 | Single-cell landscape of neutrophil activation in primary sclerosing cholangitis.
Primary sclerosing cholangitis (PSC) is a chronic autoimmune cholestatic liver disease characterized by progressive inflammation and fibrosis, but the role of neutrophils in PSC remains poorly understood. To define neutrophil states in the PSC liver microenvironment, we performed single-cell RNA sequencing of leukocytes isolated from liver perfusate obtained from healthy donor grafts and explanted PSC livers. We identified a marked expansion of transcriptionally diverse neutrophil subclusters in PSC liver perfusate. Importantly, PSC livers were enriched for four neutrophil subclusters: RHOB-high, immediate early gene-high, heat shock protein-high, and CXCL8-high liver neutrophil-like subclusters. These PSC-associated neutrophil subclusters showed increased activity of the TNF and IL-17 signaling pathways, consistent with current views of PSC pathogenesis. They also displayed activation of inflammatory transcriptional regulators, including CEBPB, JUN, FOS, and RELA. Pseudotime analysis suggested that RHOB and immediate early gene subsets were derived from immature neutrophils, whereas liver neutrophil-like and heat shock protein-high subsets exhibited more mature and tissue-adapted features. Together, these data reveal previously unrecognized heterogeneity of liver neutrophils in PSC and identify inflammatory neutrophil programs that may contribute to sustained hepatic inflammation and represent potential therapeutic targets.
2026-08-11 | Hepatocyte-intrinsic ER stress and NRF2 initiate primary sclerosing cholangitis, providing therapeutic insights.
primary sclerosing cholangitis (PSC) is a severe liver disease that can progress to cholangiocarcinoma. Therapeutic development has been hindered by the rarity of PSC and by its poorly understood origin, which reflects incompletely defined genetic and environmental risk factors. Here we describe a mouse model that combines two suspected environmental risk factors, hepatocyte-intrinsic ER stress and oxidative stress, which leads to activation of transcription factor NRF2 in both hepatocytes and cholangiocytes. Genetically affected mice, as well as mice treated with an ER stress inducer and an NRF2 activator, progressed to PSC with human-like features. Specifically, hepatocyte-intrinsic ER stress in cooperation with activated NRF2 leads to indirect activation of JNK-JUN signaling, which abrogates HNF1α-stimulated Fxr gene transcription and reduces expression of the bile salt export pump BSEP. These signaling abnormalities, whose clinical relevance is supported by single cell transcriptomics of human PSC tissue, cause cholestasis, hepatocyte and bile canaliculi injury, biliary hyperplasia, and periductular fibrosis, which define PSC. Congruently, alleviation of cholestasis and/or inhibition of biliary hyperplasia resolve PSC in mice.
2026-08-09 | "From Cholestasis to Interface Hepatitis: A Rare Case of Primary Sclerosing Cholangitis-Autoimmune Hepatitis Overlap in a 20-Year-Old Male".
Overlap syndrome refers to the coexistence of more than one immune-mediated liver disease in a single patient. Primary sclerosing cholangitis-autoimmune hepatitis (PSC-AIH) overlap is a rare but clinically important entity, as delayed recognition may lead to progressive liver injury, cirrhosis, and liver failure. Differentiating this condition from isolated PSC or AIH remains challenging due to overlapping clinical, biochemical, and radiological features. A 20-year-old male presented with progressive jaundice, pruritus, acholic stools, and dark urine for one month. Laboratory evaluation revealed marked cholestasis with significantly elevated alkaline phosphatase and transaminases, hyperbilirubinemia, and coagulopathy, while viral and metabolic causes were excluded. Magnetic resonance cholangiopancreatography demonstrated characteristic intrahepatic biliary duct irregularities consistent with primary sclerosing cholangitis. However, disproportionately elevated alanine aminotransferase and serum immunoglobulin G levels prompted further evaluation. Liver biopsy revealed features of both diseases, including interface hepatitis with chronic portal inflammation and plasma cell infiltration, along with bile duct injury, ductopenia, and onion-skin fibrosis. Based on histology and diagnostic scoring, a diagnosis of PSC-AIH overlap syndrome was established. The patient was treated with ursodeoxycholic acid, corticosteroids, and azathioprine, resulting in marked clinical and biochemical improvement on follow-up. This case highlights the importance of considering PSC-AIH overlap syndrome in young patients with cholestatic liver disease and unexpectedly elevated transaminases or immunoglobulin G levels. Early recognition and combined immunosuppressive and supportive therapy can lead to favorable outcomes and may prevent irreversible liver damage.
2026-08-04 | Effect of a single dose antibiotic prophylaxis in scheduled bile duct interventions in Primary Sclerosing Cholangitis.
The recommended duration of antibiotic prophylaxis in scheduled endoscopic retrograde cholangiopancreatography (ERCP) for patients with primary sclerosing cholangitis (PSC) varies greatly across international guidelines. Increasing antibiotic resistance makes a rational use of antibiotics urgently necessary. Therefore, we aimed to investigate the effect of an antibiotic single shot prophylaxis on the rate of postinterventional cholangitis, the antibiotic exposure and potential risk factors for cholangitis in this cohort. A registry-based, non-interventional cohort study was conducted to investigate the effect of a newly introduced standard operating procedure (SOP) with a periinterventional single dose prophylaxis (SOP cohort, n=80 procedures) compared to a historical cohort (n=100 procedures) receiving a multi-day regimen. Tokyo guidelines from 2018 were adapted for diagnosis and severity grading of cholangitis. The duration of the periinterventional antibiotic therapy differed significantly between cohorts, with a median of 0.33 days in the SOP cohort and 3.50 days in the historical cohort (p<0.001), whereas no significant difference in the rate of post-ERCP cholangitis between the cohorts was found, even in procedures with dilation. When cholangitis severity was dichotomized into Grade I vs. Grade II + III, the SOP cohort showed a significantly higher proprotion of moderate to severe cholangits (45.5% vs. 9.1%, p<0.001. Identified significant risk factors (in univariate analysis) for a post-ERCP cholangitis were the presence of a traditional dominant stricture (TDS), and the subsequent performance of a dilation during ERCP (OR 3.360, p=0.034, and OR 3.356, p=0.033, respectively). In our study in patients with PSC, the antibiotic single shot prophylaxis in scheduled ERCPs was not associated with an higher rate of postinterventional cholangitis, but an increase cholangitis grade compared to a multi-day regimen, indicating a potential comparable effectiveness in preventing postinterventional cholangitis.
antibodies
2026-08-01 | Hyaluronan and CD44 targeting reverses early matrix changes, proinflammatory signals and fibrosis in primary sclerosing cholangitis.
Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by biliary inflammation and bile duct strictures and no approved medical therapy. Despite its clinical severity, the pathological mechanisms underlying PSC remain poorly understood, largely due to early diagnostic challenges. Here we provide complementary evidence in human PSC samples, transcriptomic data, mouse models, and 3D cholangiocyte cultures that underscore the importance of hyaluronic acid (HA) and its cognate receptor CD44 in PSC pathogenesis. HA is a glycosaminoglycan abundant in the extracellular matrix in inflammatory disorders, yet its role in PSC has not been well characterized. We demonstrate that in early-stage PSC, cholangiocytes aberrantly produce high molecular weight HA that accumulates in the peribiliary matrix, increasing local tissue stiffness. This mechanical signal is transduced by a CD44/Integrin β1 receptor complex in cholangiocytes, driving cell proliferation, YAP mechanosignaling, pro-inflammatory cytokine production with a transition to a ductular reactive phenotype. CD44 knockdown in cholangiocyte cell lines and mouse models significantly lowered stiffness, and attenuated inflammation. Together, these findings reveal a mechano-inflammatory axis in which HA-driven matrix stiffening perpetuates biliary inflammation and disease progression, identifying HA targeting and CD44 as promising therapeutic strategies. Hyaluronan and CD44 mediate matrix changes and progressive fibrosis in primary sclerosing cholangitis.
2026-06-26 | Multi-Omics Integrative Analysis Identifies the NK Cell-STAT3 Axis as a Shared Immunogenetic Hub Underlying the Comorbidity of Primary Sclerosing Cholangitis and Ulcerative Colitis.
Primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) exhibit a striking clinical comorbidity, with 60-80% of PSC patients concurrently harboring UC, yet the shared immunogenetic mechanisms remain poorly understood. Here, we constructed a multi-omics integrative framework to systematically dissect the cellular and molecular basis of this comorbidity. GWAS meta-analyses were performed for each disease, followed by tissue-level enrichment assessment using QTLEnrich, MAGMA, and gsMap spatial mapping. Single-cell transcriptomic atlases were constructed, and cell-type prioritization was conducted using four complementary methods. Core genes were identified through cross-validation of five algorithms, with subsequent genomic fine-mapping via FUMA and GCTA-COJO. Tissue-level analyses consistently identified the intestine and immune-related tissues as commonly affected. Multi-dimensional evidence integration prioritized natural killer (NK) cells as the core effector cell type for both diseases, supported principally by CELLECT (Cell-type Expression-specific Integration for Complex Traits) heritability enrichment and single-cell differential analysis. Convergence of five gene-level algorithms pinpointed STAT3 as the sole high-confidence comorbidity gene, broadly expressed across immune cell populations and exhibiting tissue-differential alternative splicing. Colocalization identified a high-risk variant (rs3736161) within the STAT3 locus, with conditional analysis revealing 35 additional independent signals. These findings identify the NK cell-STAT3 axis as a central immunogenetic hub connecting PSC and UC, offering potential therapeutic targets for comorbidity management.
2026-05-24 | The Interleukin-17-T helper 17 axis in primary sclerosing cholangitis: A narrative review of an emerging pathogenic frontier.
Interleukin-17 (IL-17) and IL-17+ secretory cells, including T helper 17 (Th17) cells play pivotal roles in autoimmune diseases such as psoriasis. Emerging evidence implicates the IL-17 pathway in primary sclerosing cholangitis (PSC), a chronic cholestatic liver disease lacking approved pharmacological therapies, for which liver transplantation remains the only life-extending option. The IL-17 pathway and Th17 biology is increasingly implicated in PSC pathogenesis through its interactions with hepatic parenchymal and non-parenchymal cells, including cholangiocytes, neutrophils and hepatic stellate cells which promote periductal fibro-inflammation, immune cell recruitment and pro-inflammatory cytokine release. Th17 cells and IL-17+ secreting lymphocytes localise to peribiliary regions, exacerbating biliary injury and fibrosis. Preclinical murine models suggest that inhibition of IL-17 signalling mitigates hepatic fibro-inflammatory responses, providing a compelling rationale for its investigation as a potential therapeutic target in PSC. Whilst licensed IL-17 inhibitors have demonstrated efficacy and safety in a number of autoimmune and immune-mediated diseases, IL-17 has context-dependent roles in tissue homeostasis and host defence underscoring the pathway's complexity. This narrative review synthesises the biology of the IL-17 family, integrating preclinical and translational evidence relevant to PSC, and discusses the translational potential of approved anti-IL-17 agents as novel therapeutic candidates in PSC, whilst highlighting key uncertainties and gastrointestinal safety considerations.
2026-05-21 | Overlapping Cytomegalovirus Infection and Inflammatory Pouchitis After Liver Transplantation: When Antivirals Alone Are Insufficient.
Cytomegalovirus (CMV) is an infrequently reported etiology of secondary pouchitis in patients who have undergone total proctocolectomy with ileal pouch-anal anastomosis. We present the case of a patient with chronic antibiotic-dependent pouchitis, ulcerative pancolitis, primary sclerosing cholangitis, and orthotopic liver transplant who presented with hematochezia. Pouchoscopy showed ulcerated mucosa, and histopathology with immunohistochemistry confirmed CMV pouchitis. The patient was treated with antiviral therapy with improvement in bleeding and viremia. However, persistent refractory pouch inflammation ultimately required guselkumab. This case depicts the importance of considering CMV as a secondary etiology of pouchitis, especially in those with refractory or atypical features.
2026-05-03 | Suppression of Small-Bowel Klebsiella Biofilm in Post-Colectomy Primary Sclerosing Cholangitis
Authored by an Occupational Safety and Health Specialist and Systems Designer (UCD, IT Carlow, Maynooth University) applying formal risk-management architecture to survive their own progressive PSC. Intended purpose: Published for Gastroenterological and Hepatological Critique. This document presents a multi-modal therapeutic framework for post-colectomy Primary Sclerosing Cholangitis, developed out of personal necessity by a patient managing this exact clinical intersection. The protocol outlines a strategic approach to suppressing Klebsiella-driven portal endotoxemia and halting structural hepatic degradation. Because research at this specific anatomical and pathological intersection is scarce, this framework is offered as an actively evolving, open-source architecture. I invite rigorous scrutiny, methodological challenges, and clinical critique from the gastroenterological and research communities to identify evidence gaps and strengthen future revisions.
proteins
2026-07-22 | A Multi-omics and Machine Learning Framework Identifies Plasma SBDS as a Causal Biomarker and Therapeutic Target in Primary Sclerosing Cholangitis.
Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease. Its molecular etiology remains poorly defined, hindering the development of mechanism-based diagnostics and therapies. Therefore, this study aimed to identify key molecular drivers and causal biomarkers of PSC by integrating transcriptomics, machine learning, and genetic causal inference. We deployed a computational framework combining transcriptomics, network biology, machine learning, and genetic causal inference. Peripheral blood transcriptomes from PSC patients and controls were analyzed to identify disease-associated modules. Candidate genes were refined via protein-protein interaction networks and a multi-algorithm machine learning screen. Causal inference was performed using two-sample Mendelian randomization, integrating plasma protein quantitative trait loci with PSC genome-wide association study summary statistics. Transcriptomic analysis revealed a PSC-associated module enriched in ribosome biogenesis and protein homeostasis pathways. A machine learning-optimized nine-gene signature (including PTMA, SUMO1, Shwachman-Bodian-Diamond syndrome (SBDS), RPL7, EIF1AX, ANP32A, PCNA, FAM98A, and MPHOSPH6) achieved high diagnostic accuracy (mean AUC = 0.908) and was consistently downregulated in PSC. This signature was linked to a remodeled immune microenvironment characterized by myeloid skewing and specific transcriptional-immune covariation patterns. Mendelian randomization identified SBDS as a putatively causal protective factor, where genetically instrumented higher plasma SBDS protein levels were robustly associated with a lower PSC risk (inverse variance weighted odds ratio = 0.525, 95% CI: 0.356-0.773, P = 0.001). Sensitivity analyses supported the validity of the Mendelian randomization assumptions. Our study establishes disrupted ribosome homeostasis as a causal pathway in PSC and nominates plasma SBDS as a high-confidence diagnostic biomarker and therapeutic target. The integrative framework provides a generalizable strategy for discovering causal biomarkers in complex diseases.
2026-03-12 | Constructing a protein-protein interaction network for autoimmune liver diseases by integrating pQTL, rQTL, and mediation analyses.
Autoimmune liver diseases (AILDs), including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH), pose significant diagnostic and therapeutic challenges due to poorly understood mechanisms. While most studies focus on absolute protein levels, protein-protein ratios (PPRs), reflecting the relative abundance of paired plasma proteins, emerge as critical yet understudied biomarkers for decoding disease-specific network perturbations. To harness this potential, we integrated protein quantitative trait loci (pQTLs), ratio QTLs (rQTLs), and mediation Mendelian randomization (MR) to map causal proteomic networks, aiming to unravel pathogenic networks and identify therapeutic targets in AILDs. Using two-sample MR, we analyzed 2821 plasma PPRs and 2923 individual proteins from the UK Biobank Pharma Proteomics Project. The primary analysis employed the inverse-variance weighted (IVW) method, complemented by MR-Egger regression, weighted median, simple mode, and weighted mode methods, all within a random-effects model. Sensitivity analyses were performed to validate the findings, including Cochran's Q test, MR-Egger intercept analysis, MR-PRESSO, and Steiger filtering. Cross-trait linkage disequilibrium score regression (LDSC) quantified genetic correlations, while the MR approach based on Bayesian model averaging (MR-BMA) prioritized independent causal PPRs. Two-step mediation MR identified mechanistic pathways. Functional enrichment and protein-protein interaction (PPI) networks were constructed using STRING and the clusterProfiler package. Finally, we investigated the associations between the causal PPRs and AILD-related symptoms/complications, as well as the influence of modifiable lifestyle factors on these PPRs. CD74 exhibited dual roles in AILDs. Elevated plasma CD74 levels were associated with an increased risk of PSC (OR = 1.54, 95% CI 1.24-1.90), whereas CD74-PPRs exhibited robust protection. Specifically, CD74/JAM2 reduced risks of PSC (OR = 0.70, 95% CI 0.59-0.83) and AIH (OR = 0.53, 95% CI 0.39-0.71), while CD74/NPDC1 conferred protection against PSC (OR = 0.66, 95% CI 0.54-0.80). Mediation MR identified TRY3 as the dominant mediator of CD74/JAM2 in AIH (91.52% proportion mediated, P = 0.017), with GREM1 and TEK mediating CD74/NPDC1 effects in PSC. PPI networks implicated interactions among CD74, amyloid precursor protein (APP), and endoglin (ENG). Notably, CD74/JAM2 demonstrated cross-disease relevance, significantly lowering PSC-associated ulcerative colitis risk (OR = 0.35, 95% CI 0.22-0.54). This study pioneers the integration of pQTLs, rQTLs, and mediation MR to map dynamic proteomic interactions in AILDs. Our findings revealed the multifaceted impact of CD74 on AILDs: its direct elevation may promote disease, whereas its protein interactions appear to mitigate risk. These results advance understanding of AILD pathogenesis and pave the way for developing novel biomarkers and targeted therapies.
2025-11-28 | Intestinal barrier in chronic gut and liver diseases: Pathogenesis and therapeutic targets.
The intestinal barrier is the primary defense that separates the host from the external environment, possessing several crucial physiological functions, including nutrient digestion, absorption, and protection against potentially harmful dietary antigens and pathogenic microorganisms. Nevertheless, various factors, such as diet, medications, circadian rhythm disturbances, gut microbiota, microbial metabolites, and genetic predisposition, can disrupt the intestinal barrier. Such disruption may lead to bacterial translocation, subsequently triggering enterohepatic and systemic inflammation. Impaired intestinal barrier has been implicated in the pathogenesis of numerous diseases, particularly chronic gut and liver diseases. In this review, we will summarize the fundamental functions of intestinal barrier and discuss clinical correlations between intestinal barrier dysfunction and diseases such as colitis, colorectal cancer, and chronic liver diseases including metabolic dysfunction-associated steatohepatitis, alcohol-associated liver disease, and primary sclerosing cholangitis. Additionally, we will also highlight some potential therapeutic strategies aimed at restoring barrier integrity to improve disease management.
2025-11-20 | Moderate increase of MET in hepatocytes protects against cholestatic liver injury by promoting an effective antioxidant response.
Hepatocyte growth factor (HGF)/hepatocyte growth factor receptor (MET) signaling plays a critical role during liver regeneration upon acute and chronic damage, and is therefore an interesting target for therapeutic intervention. Nevertheless, the molecular mechanisms underlying the pro-regenerative effects of HGF/MET signaling are not fully elucidated, particularly during cholestatic injury. Our aim was to analyze the impact of moderately enhanced MET on the hepatic response to cholestatic injury, and uncover the mechanisms behind it. For that, Alb-R26Met mice expressing a wild-type Met transgene in albumin-positive liver cells were fed with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-supplemented diet, used as a model simulating human primary sclerosing cholangitis. Results indicate that increased MET expression diminished liver damage in DDC-fed mice, evidenced by lower serum levels of bilirubin and alkaline phosphatase, and decreased cell apoptosis. However, decreased ductular expansion was observed, which together with enhanced hepatocyte proliferation suggests that hepatocytes act as the main cellular defense. Both in vivo and in vitro studies using Alb-R26Met liver-derived hepatocytes under cholestasis-simulated in vitro conditions demonstrated an enhanced upregulation of nuclear factor erythroid 2-related factor 2 (NRF2; encoded by the Nfe2l2 gene), parallel to an upregulation of glutathione biosynthesis enzymes, increased levels of glutathione, and decreased reactive oxygen species, along with decreased activation of transforming growth factor beta (TGF-β)-induced signaling. Consistently, MET transgenic hepatocytes were protected against TGF-β-induced oxidative stress and apoptosis in vitro. In conclusion, our work evidences that moderate upregulation of wild-type MET in hepatocytes is sufficient to promote a strong antioxidant response in the liver that efficiently protects against chronic cholestasis, thus allowing optimal liver regeneration.
2025-11-15 | Regulatory T cell stability determines the efficiency of bile duct regeneration during cholangitis.
Cholangiopathies such as primary sclerosing cholangitis (PSC) cause damage to the bile ducts with no effective cure. Reduction and impairment in the function of regulatory T cells (Tregs) occur in PSC. We investigate whether Tregs regulate bile duct regeneration and the dynamics of Treg turnover during bile duct injury. We use the transgenic Foxp3GFPDTR model to mimic reduced Treg infiltration in PSC and show that Tregs mediate cholangiocyte response to biliary injury. Fate mapping of Tregs reveals that intrahepatic Tregs acquire a pro-inflammatory phenotype, even after interleukin-2 (IL-2)-mediated Treg expansion. Ox40L expression correlates with fibrosis in PSC patients. Enhancing Treg numbers through IL-2 complex administration and blocking Ox40 signaling simultaneously suppresses the inflammatory phenotype of Tregs and reduces bile duct damage and fibrosis. We demonstrate that bile duct regeneration can be enhanced by combining Treg-based therapy and targeting co-stimulatory molecules, such as Ox40L.
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2025-12-17 | Mechanistic roles and therapeutic potential of bacteriophages in inflammatory gastrointestinal diseases.
The gut virome, particularly its viral and phage components, is increasingly recognized as a key modulator of intestinal microbial dynamics in gastrointestinal inflammatory diseases. Beyond well-characterized bacterial dysbiosis, growing evidence suggests that virome alterations contribute to the development and progression of inflammatory bowel disease, metabolic dysfunction-associated steatohepatitis, alcoholic hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, and pancreatitis. As the most abundant viruses in the gut, bacteriophages influence microbial ecosystem stability and host immune responses through lytic and lysogenic interactions with bacterial populations. Amid the growing burden of multidrug-resistant infections and heightened interest in microbiota-based interventions, phage therapy has re-emerged as a viable strategy in both preclinical and translational contexts. This review synthesizes recent insights into bacteriophage dynamics in the context of major gastrointestinal and hepatopancreatic inflammatory diseases, highlighting potential compositional shifts, proposed mechanisms of phage-microbe interactions, and supportive evidence from animal models and early clinical applications. We also discussed the critical challenges that had to be addressed to enable clinical translation, including host range restrictions, resistance and safety concerns, immunogenicity, and delivery limitations, while emphasizing emerging strategies such as phage engineering, encapsulation technologies, and standardized regulatory frameworks.
2025-11-15 | Numb-exon3 and full length Numb equivalently alleviate cholestatic liver fibrosis by inhibiting ductular reaction.
Cholestasis can occur in various acute and chronic liver diseases, with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) being the most common clinical manifestations. Without appropriate treatment, these conditions may ultimately progress to liver cirrhosis and hepatic failure. Therefore, identifying novel therapeutic targets is of great importance. Our previous research had found a gene target named Numb which is a determinant of stem cell fate can increase the anti-cholestatic liver fibrosis (CLF) effect of bone marrow mesenchymal stem cells (BM-MSCs). However, whether the Numb gene or its exon has direct anti-CLF activity is unclear. In this study, an adeno-associated virus (AAV) was used as a gene delivery vector to overexpress the full-length Numb gene directly in the rat liver. In addition, Exon3 was overexpressed to clarify the effective site of Numb gene for comparison. AAV.Numb can alleviate CLF and suppressed the activation of Notch signaling and the differentiation of hepatic progenitor cells (HPCs) into biliary epithelial cells (BECs), and the anti-CLF effect of Numb-Exon3 was similar to that of full-length Numb. The findings revealed that Numb gene may be a new therapeutic target for PBC and that Exon3 may be an effective site.
2025-01-27 | Liver Lymphatic Dysfunction as a Driver of Fibrosis and Cirrhosis Progression.
The liver lymphatic system plays a critical role in maintaining interstitial fluid balance and immune regulation. Efficient lymphatic drainage is essential for liver homeostasis, but its role in liver disease progression remains poorly understood. In cirrhosis, lymphangiogenesis initially compensates for increased lymph production, but impaired lymphatic drainage in advanced stages may lead to complications such as ascites and portal hypertension. This study aimed to evaluate how liver lymphatic dysfunction affects disease progression and to assess therapeutic strategies. Using a surgical model to block liver lymphatic outflow, we found that impaired drainage accelerates liver injury, fibrosis, and immune cell infiltration, even in healthy livers. Mechanistically, enhanced TGF-β signaling in liver lymphatic endothelial cells (LyECs) contributed to reduced lymphatic vessel (LV) density and function in late-stage decompensated cirrhosis. This dysfunction was linked to the progression from compensated to decompensated cirrhosis, particularly in patients with primary sclerosing cholangitis (PSC). Conversely, liver-specific overexpression of VEGF-C via AAV8 improved lymphatic drainage, restored LV density, reduced fibrosis, mitigated liver injury, and alleviated portal hypertension in cirrhotic rats. These findings establish impaired liver lymphatic function as a pivotal driver of cirrhosis progression and identify VEGF-C as a promising therapeutic target to prevent decompensation.
2024-11-28 | LncRNAs, RNA Therapeutics, and Emerging Technologies in Liver Pathobiology.
The field of ribonucleic acid (RNA) biology has revealed an array of noncoding RNA species, particularly long noncoding RNAs (lncRNAs), which play crucial roles in liver disease pathogenesis. This review explores the diverse functions of lncRNAs in liver pathology, including metabolic-associated steatotic liver disease, hepatocellular carcinoma, alcohol-related liver disease, and cholangiopathies such as primary sclerosing cholangitis and cholangiocarcinoma. We highlight key lncRNAs that regulate lipid metabolism, inflammation, fibrosis, and oncogenesis in the liver, demonstrating their diagnostic and therapeutic potential. Emerging RNA-based therapies, such as mRNA therapy, RNA interference, and antisense oligonucleotides, offer approaches to modulate lncRNA activity and address liver disease at a molecular level. Advances in sequencing technologies and bioinformatics pipelines are simultaneously enabling the identification and functional characterization of novel lncRNAs, driving innovation in personalized medicine. In conclusion, this review highlights the potential of lncRNAs as biomarkers and therapeutic targets in liver disease and emphasizes the need for further research into their regulatory mechanisms and clinical applications.
2024-11-05 | Regulatory T cells-related gene in primary sclerosing cholangitis: evidence from Mendelian randomization and transcriptome data.
The present study utilized large-scale genome-wide association studies (GWAS) summary data (731 immune cell subtypes and three primary sclerosing cholangitis (PSC) GWAS datasets), meta-analysis, and two PSC transcriptome data to elucidate the pivotal role of Tregs proportion imbalance in the occurrence of PSC. Then, we employed weighted gene co-expression network analysis (WGCNA), differential analysis, and 107 combinations of 12 machine-learning algorithms to construct and validate an artificial intelligence-derived diagnostic model (Tregs classifier) according to the average area under curve (AUC) (0.959) in two cohorts. Quantitative real-time polymerase chain reaction (qRT-PCR) verified that compared to control, Akap10, Basp1, Dennd3, Plxnc1, and Tmco3 were significantly up-regulated in the PSC mice model yet the expression level of Klf13, and Scap was significantly lower. Furthermore, immune cell infiltration and functional enrichment analysis revealed significant associations of the hub Tregs-related gene with M2 macrophage, neutrophils, megakaryocyte-erythroid progenitor (MEP), natural killer T cell (NKT), and enrichment scores of the autophagic cell death, complement and coagulation cascades, metabolic disturbance, Fc gamma R-mediated phagocytosis, mitochondrial dysfunction, potentially mediating PSC onset. XGBoost algorithm and SHapley Additive exPlanations (SHAP) identified AKAP10 and KLF13 as optimal genes, which may be an important target for PSC.
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Drug Discovery Landscape
38 orphan drug designations for Primary sclerosing cholangitis.
38 orphan drug designations for Primary sclerosing cholangitis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
volixibat | small molecules | FDA | 2026-07-21 | — | Mirum Pharmaceuticals, Inc. |
Leuconostoc citreum, strain G511, Live | other | EMA | 2025-11-21 | — | Harvest Integrated Research Organization Ireland Limited |
Elafibranor | small molecules | EMA | 2025-07-18 | — | Ipsen Pharma |
elafibranor | small molecules | FDA | 2025-07-16 | — | IPSEN Bioscience Inc. |
Beta-lapachone | small molecules | EMA | 2025-06-20 | — | Hungarotrial Zrt. |
Volixibat potassium | small molecules | EMA | 2025-02-26 | — | Mirum Pharmaceuticals International B.V. |
small molecule inhibitor of hyaluronan synthesis | small molecules | FDA | 2024-04-09 | — | Halo Biosciences, Inc. |
Aldafermin | proteins | FDA | 2023-12-21 | — | NGM Biopharmaceuticals Inc. |
Live biotherapeutic product consisting of a single bacterial strain (Leuconostoc citreum [L. citreum]) | cell therapies | FDA | 2022-12-01 | — | LISCure Biosciences Inc. |
3-([3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1Lambda6,2,5-benzothiadiazepin-8-yl]oxy)propanoic acid | small molecules | FDA | 2022-11-15 | — | Albireo AB |
Bezafibrate | small molecules | EMA | 2022-08-10 | — | Amsterdam UMC |
Gly-Trp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu- Gly-Pro-Pro-Pro-Ala-Leu-Ala-Leu-Ala-NH2 | peptides | FDA | 2022-05-24 | — | Sterotherapeutics, LLC |
Bexotegrast | small molecules | EMA | 2022-04-13 | — | Pharma Gateway AB |
Beta-Lapachone | small molecules | FDA | 2022-03-28 | — | Curome Biosciences Co., Ltd. |
Chimeric peptide of human glucagon-like peptide-1, glucagon and gastric inhibitory polypeptide analogues linked to a human immunoglobulin Fc fragment | proteins | EMA | 2021-12-10 | — | JVM Europe B.V. |
3-(4-((3-endo)-3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4- yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one | small molecules | FDA | 2021-09-13 | — | Cascade Pharmaceuticals, Inc |
Norucholic acid | small molecules | FDA | 2021-06-24 | — | Dr. Falk Pharma GmbH |
Humanised IgG1 monoclonal antibody against human eotaxin-2 | antibodies | EMA | 2020-08-21 | — | FGK Representative Service GmbH |
Glucagon-like peptide-1/Glucagon/Gastric inhibitory polypeptide triple agonist linked to human IgG4 Fc fragment | peptides | FDA | 2020-03-04 | — | Hanmi Pharmaceutical Company, Ltd. |
Cilofexor trometamol | small molecules | EMA | 2019-04-01 | — | Gilead Sciences Ireland Unlimited Company |
small molecule inhibitor of integrins avEszett6 and avEszett1 | small molecules | FDA | 2018-11-19 | — | Pliant Therapeutics, Inc. |
2-[3-(2-chloro-4-{[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy}phenyl)-3-hydroxyazetidin-1-yl]pyridine-4-carboxylic acid¿2-amino-2-(hydroxymethyl)propane-1,3-diol (1/1) | small molecules | FDA | 2018-10-25 | — | Gilead Sciences, Inc. |
Monoclonal antibody targeting CCL24 | antibodies | FDA | 2018-10-11 | — | ChemomAb, Ltd. |
(S)-3-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid | small molecules | EMA | 2017-10-16 | — | Pharma Gateway AB |
5-cholesten-3ß, 25-diol 3-sulfate sodium salt (25HC3S) | small molecules | FDA | 2017-07-06 | — | DURECT Corporation |
(S)-3-((S)-2-(2-((2,6-difluorophenyl)amino)-2-oxoacetamido)propanamido-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid | small molecules | FDA | 2017-06-21 | — | Conatus Pharmaceuticals |
Cotsiranib | RNAs | FDA | 2017-06-15 | — | Sirnaomics, Inc. |
berberine ursodeoxycholate | small molecules | FDA | 2016-08-29 | — | HighTide Therapeutics (Hong Kong) Limited |
recombinant, fully-human, IgG4 immunoglobulin with antigen-binding specificity for human vascular adhesion protein-1 (VAP-1) | antibodies | FDA | 2016-08-25 | — | Acorda Therapeutics, Inc. |
Aldafermin | proteins | EMA | 2015-12-14 | — | Propharma Group The Netherlands B.V. |
Recombinant human monoclonal antibody binding to vascular adhesion protein-1 | antibodies | EMA | 2015-03-19 | — | Biotie Therapies Oy |
simtuzumab | antibodies | FDA | 2015-01-05 | — | Gilead Sciences, Inc. |
docosahexaenoic acid, DHA | small molecules | FDA | 2014-12-17 | — | Micelle BioPharma, Inc. |
Norursodeoxycholic acid | small molecules | EMA | 2014-07-04 | — | Dr Falk Pharma GmbH |
Obeticholic acid [Ocaliva] | small molecules | EMA | 2014-01-16 | — | [INACTIVE] Intercept Pharma International Limited |
Maralixibat chloride | small molecules | EMA | 2013-12-18 | — | Mirum Pharmaceuticals International B.V. |
(4R,5R)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-l-azoniabicyclo[2.2.2]octane Chloride | small molecules | FDA | 2013-09-04 | — | Mirum Pharmaceuticals, Inc. |
6-alpha-ethylchenodeoxycholic acid | small molecules | FDA | 2008-04-09 | — | Intercept Pharmaceuticals, Inc. |
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