Autoimmune hepatitis (AIH) is a rare, complex and chronic immune-mediated disease in which loss of tolerance to hepatocyte antigens leads to T-cell-driven liver inflammation, typically associated with autoantibodies and elevated IgG. The understanding of disease mechanisms is limited, patient presentations are heterogeneous, and clinical care varies. Predniso(lo)ne and azathioprine or mycophenolate mofetil are the first-line treatments. These medications are life-saving, but lack specificity, and are marred by side-effect profiles that negatively affect adherence and quality of life. Less than 70% of patients achieve a complete biochemical response (normalization of aminotransferases and IgG) by 6 months, and more than 20% develop side effects that require discontinuation. In addition, current medications have high rates of relapse after discontinuation. Evidence of second- and third-line treatments is mainly built on real-world studies without control groups. In addition, people with AIH experience symptoms that affect their well-being, such as fatigue, depression, anxiety, cognitive dysfunction and mood changes. Several gaps in AIH management persist, including a lack of validated questionnaires to capture specific symptoms and complaints, lack of recognized endpoints for clinical trials supported by regulatory agencies, and special AIH populations are understudied and outcomes beyond liver enzymes are underrepresented. In this review, we provide a detailed appraisal of current gaps in the management, discuss special populations, and recent advancements of new agents for AIH, summarizing evidence regarding how these agents could reduce the side effects of current treatment, potentially improving the quality of life of people living with AIH.
Hepatic encephalopathy remains an underserved complication of chronic liver disease. Reliable diagnostic and prognostic biomarkers linked to disease pathophysiology are currently lacking, as are options for treatment that reduce mortality beyond lactulose and rifaximin. However, with the advent of high-throughput sequencing and multi-omics techniques to interrogate microbial taxonomy and metabolic pathways, our understanding of the gut-liver-brain-axis has moved beyond the ammonia-inflammation hypothesis. This review summarises recent studies that have aimed to characterise the role of the gut-liver-brain axis in hepatic encephalopathy and how this can be leveraged to create novel diagnostic, prognostic and therapeutic agents.
BACKGROUND & AIMS:The recent approval of pharmacological therapies for fibrotic metabolic dysfunction-associated steatohepatitis (MASH) has increased the need for accurate identification of treatment-eligible patients. Current recommendations increasingly rely on non-invasive tests (NITs), including vibration-controlled transient elastography (VCTE), while multiparametric ultrasound (MPUS) may provide additional opportunities for non-invasive assessment. However, agreement between histology and imaging-based approaches remains uncertain. We compared treatment eligibility based on histology, VCTE, and MPUS in two international biopsy-proven cohorts of metabolic dysfunction-associated steatotic liver disease (MASLD). METHODS:We analysed two biopsy-proven MASLD cohorts: CAP-IPDMA (n=1029), including VCTE and controlled attenuation parameter (CAP), and iLEAD (n=124), including MPUS. Treatment eligibility was assessed using histologically confirmed F2/F3 MASH and NIT-based recommendations from international expert panels. RESULTS:In CAP-IPDMA, 277/1029 patients (26.9%) met the histological definition of "at-risk MASH". Depending on the VCTE cut-off, 13.2-32.0% qualified for treatment. Overlap between histological "at-risk MASH" and VCTE thresholds was limited, reaching 27.8% when using VCTE 8-15 kPa, and decreasing when narrower or higher thresholds were applied. Among patients identified only by VCTE 8-15 kPa, males had lower median AST and ALT than those fulfilling only the histological indication (35 vs 48 IU/L p=0.034 and 45 vs 62 IU/L p=0.0072, respectively). In iLEAD, 21/124 patients (16.9%) met the histological definition, while 13.7-16.1% were eligible based on SWE thresholds, again with a similarly limited overlap. CONCLUSIONS:Histology and non-invasive tests capture partly distinct patient populations, meaning that both the number and type of patients selected for therapy depend on the chosen modality and cutoffs. As vibration-controlled transient elastography and multiparametric ultrasound become increasingly accessible in clinical practice, prospective validation is essential for establishing reliable non-invasive treatment pathways. IMPACT AND IMPLICATIONS:The current literature reflects a paradigm shift away from biopsy-based approaches toward NIT-based assessment of treatment eligibility in metabolic dysfunction-associated steatotic liver disease (MASLD), which may substantially affect which patients receive newly approved therapies. Our results are important for clinicians, researchers, and guideline developers because histology and current NIT cut-offs identify only partially overlapping patient populations, implying that different diagnostic strategies select different risk profiles. In practice, these findings support thoughtful implementation of NIT-based treatment pathways, the use of repeated measurements, and prospective validation of NIT thresholds to guide clinical care, trial design, and health policy decisions.
Curative-intent treatments for hepatocellular carcinoma (HCC), including liver resection and transplantation, are limited by high recurrence rates and strict patient selection criteria. The success of immune checkpoint inhibitors (ICIs) in advanced disease has driven their integration into the perioperative setting, with the aim of improving long-term outcomes and expanding access to curative strategies. Neoadjuvant immunotherapy represents a biologically attractive approach, leveraging the intact tumour microenvironment to enhance systemic antitumour immunity and eradicate micrometastatic disease. Early-phase trials have demonstrated feasibility and promising efficacy outcomes, while recent phase 2/3 data suggest improved event-free survival with perioperative ICI-based combinations (CARES-009 trial), but no survival benefit with adjuvant ICI alone (IMbrave050 trial). In parallel, conversion strategies incorporating ICIs with tyrosine kinase inhibitors and locoregional therapies are increasing resectability rates in selected patients with initially unresectable disease. In the transplant setting, ICIs show potential as a bridging or downstaging strategy, although concerns regarding allograft rejection and optimal washout intervals remain. Emerging biomarkers, including pathological response and circulating tumour DNA, may refine patient selection and guide the design of adaptive clinical trials. Collectively, these advances support a shift toward biomarker-driven, perioperative immunotherapy strategies to optimise curative-intent management of HCC.
BACKGROUND & AIMS:Metabolic dysfunction-associated steatotic liver disease (MASLD) affects women and men differently, and both perceived and self-stigma may contribute to care avoidance. This study aimed to assess gender-specific patterns of stigma and their associations with care avoidance in MASLD. METHODS:A cross-sectional, international survey was administered in 2023 by the Global MASH/NASH Council (GNC) among adults with a confirmed diagnosis of MASLD. The survey collected sociodemographic and clinical data, assessed perceived stigma and self-stigma using the validated Self-Stigma Scale-Short Form, generating domain-specific and total scores. Severe self-stigma (simply named self-stigma) was defined as a total score above the 75th percentile, stratified by gender. Care avoidance in primary or secondary care (gastroenterology, hepatology, and endocrinology) was reported. RESULTS:Among 1,313 respondents with MASLD (51% men; 50% aged ≥55 years; 28% Europe, 26% USA/Canada, 30% South East/West Asia, 16% MENA), care avoidance was more frequent among men (23.6% vs. 18.9%, p=0.04), occurring predominantly in the primary care. Women reported higher self-stigma scores (all p<0.001) and more discrimination-related perceived stigma (27.8% vs. 19.1%). In adjusted analyses, both perceived stigma [adjusted OR(95%CI): 1.84(1.07-3.18)] and self-stigma [1.84(1.19-2.85)] were associated with care avoidance in men, whereas only perceived stigma was associated with care avoidance in women [2.29(1.25-4.22)]. In women, perceived stigma was linked to younger age, multimorbidity, and history of medical weight loss (p<0.05), while no predictors were identified in men. Lower socioeconomic status and advanced fibrosis predicted self-stigma in both genders. CONCLUSIONS:Stigma emerges as a major, gender-specific barrier to care in MASLD, with distinct mechanisms in men and women. Integrating gender-sensitive, stigma-informed strategies into MASLD care may improve access and continuity of care. IMPACT AND IMPLICATIONS:The presence of stigma due to liver disease is associated with avoiding care. However, despite women reporting a higher degree of stigma than men, men more often avoided healthcare visits especially when self-stigma was present. These differences in stigma and care avoidance by gender necessitates that healthcare providers who treat patients with MASLD develop gender-sensitive interventions to help ensure continued engagement with the healthcare system.
Background & Aims Noninvasive tests to identify pediatric metabolic dysfunction-associated steatohepatitis (MASH) remain a critical need. We aimed to develop and validate a screening panel that identifies biopsy-confirmed MASH in children and adolescents using clinical and metabolomics data. Methods Fasting serum from youth in NASH CRN studies and healthy participants underwent untargeted metabolomics by liquid chromatography-mass spectrometry (LC-MS). Clinical data included anthropometrics, lipids, liver enzymes, and markers of insulin resistance. MASH was determined by biopsy in NASH CRN participants and hepatic steatosis by MRI-PDFF in healthy participants. Clinical features were selected by Kolmogorov-Smirnov testing (p < 0.05), and metabolomics data were reduced to 52 features with non-zero LASSO coefficients. Feature importance was ranked using CatBoost. The final model included eight clinical features and the top 10 annotated metabolites. Data were split into training and test sets, with longitudinal validation in a sub-cohort with 96-week follow-up biopsies. Results The cohort included 586 children (ages 5-18, 70% male, mean BMI z-score of 2.35 ± 0.84, 72% Hispanic). Of these, 390 had MASH (21% Zone 3, 41% Zone 1, 38% definite MASH), and 196 were non-MASH. The model incorporated ALT, AST, GGT, platelets, HOMA-IR, BMI z-score, TG:HDL ratio, and alkaline phosphatase. Key metabolic features included amino acid derivatives (e.g., glutamic acid, argininosuccinic acid), indole, diacetylspermine, and lipid metabolites. The model achieved an AUROC of 0.88 (92% sensitivity, 71% specificity) in the test set and 0.81 (69% sensitivity, 86% specificity) in the longitudinal cohort. Conclusions This 18-variable panel of eight clinical measures and 10 metabolites showed strong performance for noninvasive screening of biopsy-confirmed MASH in children and potential utility for longitudinal monitoring. Impact and implications Currently, there are no clinically approved non-invasive biomarkers for diagnosing or monitoring pediatric MASH, despite its growing prevalence and long-term health risks. This study developed and validated a machine-learning-based panel that combines clinical and high-resolution metabolomics data, demonstrating strong performance for classifying MASH and monitoring disease status in a longitudinal cohort. These findings are particularly relevant for improving the care of children with MASH and could inform both clinical practice and research. With further validation, this approach could reduce reliance on liver biopsy, enable earlier detection, and support clinical decision-making for physicians and researchers.
Background and aims The liver is an immune privileged organ, yet it needs to overcome infections. We aimed to explore the role of the liver-specific microRNA miR-122 in liver immune tolerance. Methods We developed a miR-122 knockout (KO) mouse model and assessed immune, inflammatory, and fibrogenic responses from early postnatal stages. Innate and adaptive immune alterations were studied in miR-122 KO mice. Transcriptomic profiles from autoimmune hepatitis (AIH) patients were compared to these KO mice. Results MiR-122 KO mice developed liver inflammation and fibrosis as early as two weeks of age. An inverse correlation between miR-122 expression and inflammation/fibrosis was observed in both KO mice (p<0.01in both at weeks two (n=6) and three (n=6) of KO mice age) and human AIH samples (p<0.01, n=9). KO mice shared transcriptomic and phenotypic features with human AIH. RNA sequencing identified over 5,000 differentially expressed genes between wt and KO mice, including upregulated chemokines, immune checkpoints, and pro-fibrotic markers. IRF2, a TLR3 transcription factor, was identified as a novel direct target of miR-122. Conclusions MiR-122 is a key regulator of liver immune tolerance, modulating inflammation and fibrosis via distinct pathways. Its absence enhances immune activation and accelerates fibrosis. These findings identify miR-122 as a promising therapeutic target for autoimmune liver diseases. Impact and implication The liver is an immune-privileged organ, an adaptation likely evolved to prevent robust immune responses against material absorbed from the gastrointestinal tract. This tolerance creates a sanctuary for pathogens—including bacteria, hepatitis viruses, and parasites such as Plasmodium—within the liver parenchyma, and similarly permits the development of primary liver malignancy and metastatic seeding. We found that miR-122 regulates hepatic immune tolerance, positioning miR-122 modulation as a potential therapeutic strategy for infectious, autoimmune, malignant, and metastatic liver diseases.
BACKGROUND & AIMS:Extrahepatic cholangiocarcinoma (eCCA) is an aggressive biliary tract cancer (BTC) with limited therapeutic options and actionable genetic alterations. Although PTEN loss and PI3K pathway activation are common in eCCA, their roles in disease pathogenesis and therapeutic vulnerability remain unclear. Therefore, we aimed to establish clinically relevant mouse models of PTEN loss-driven eCCA and identify novel therapeutic strategies. METHODS:To investigate eCCA development and the underlying mechanisms, we generated CK19-CreERT-based genetically engineered mouse models with biliary epithelial cell-specific PTEN deletion combined with either TGFβR2 loss or oncogenic Kras activation. RESULTS:PTEN loss alone was insufficient for tumorigenesis, whereas combined deletion of PTEN and TGFβR2 induced periductal infiltrating-type eCCA originating from the peribiliary glands. In contrast, PTEN loss and oncogenic Kras activation predominantly generated intraductal-growing tumors with broader biliary involvement. These included intrahepatic cholangiocarcinoma (iCCA) and gallbladder cancer (GBC). RNA sequencing revealed that SCAP/SREBP-mediated lipogenesis was consistently activated in the PTEN loss-driven eCCA models. Genetic ablation of SCAP markedly suppressed eCCA development (p < 0.0001) but exacerbated iCCA, indicating the need for alternative therapeutic approaches. SREBP-driven lipogenesis increased the synthesis of polyunsaturated phospholipids and concomitantly induced GPX4, thereby conferring resistance to ferroptosis. GPX4 inhibition suppressed eCCA (p = 0.002) and GBC development without exacerbating iCCA. Consistently, PTEN-deficient human BTC cell lines, including CRISPR-Cas9-engineered models, exhibited increased vulnerability to GPX4 inhibition. Furthermore, clinical eCCA samples (n = 182) confirmed the coordinated activation of the PI3K, SREBP, and ferroptosis pathways. CONCLUSIONS:Distinct oncogenic alterations shape the histological and anatomical diversity of BTC. PTEN loss-driven eCCA critically depends on SCAP/SREBP-mediated lipid reprogramming and GPX4-dependent ferroptosis resistance, indicating the therapeutic potential of ferroptosis induction. IMPACT AND IMPLICATIONS:This study provides a scientific rationale for the stratification of extrahepatic cholangiocarcinoma (eCCA) based on oncogenic context. Our findings demonstrate that PTEN loss is associated with shared lipid metabolic features, whereas additional genetic alterations determine histological growth patterns and anatomical distribution. We identified ferroptosis resistance as a key downstream feature of PTEN-deficient eCCA. Although further validation is required, these findings provide a theoretical basis for further exploration of ferroptosis-based therapeutic approaches for genetically defined subsets of biliary tract cancer.
Background & Aims Genetic testing for Lynch and BRCA1/2-associated hereditary cancer syndromes is recommended in colon or pancreatic cancer patients, but their association with hepatocellular carcinoma (HCC) risk is unknown. We evaluated associations between rare germline variants in DNA-repair genes and HCC risk across ancestrally diverse cohorts. Methods We analyzed whole exome (WES) and whole genome sequencing (WGS) data from 2,594 HCC cases and 290,547 cancer-free controls from diverse biobanks and cohorts: Penn Medicine BioBank, All of Us, Mayo Clinic, ESCALON, and the Million Veteran Program. Participants were classified into six population groups. We focused on six DNA-repair genes previously implicated in HCC: BRCA2, BRIP1, MSH6, PMS2, CHEK2, and FANCA. Gene-level burden analyses of rare predicted loss-of-function (pLoF) and damaging missense variants were performed in European and African populations, and across all six ancestry groups. Results In the European population, MSH6, a Lynch syndrome-associated gene, had the strongest association with HCC, with a 2.75-fold increased HCC risk at 1% minor-allele frequency (MAF) (OR= 2.75 [1.50, 5.04], P=0.001, FDR q=0.02), while PMS2, showed a nominally significant association at the same MAF threshold (OR=1.90 [1.08, 3.34], P=0.03, FDR q=0.09). Combined analysis across all populations strengthened the MSH6 finding (OR=2.53 [1.43, 4.49], P=0.001, FDR q=0.01) at a MAF of 0.1%. A significant BRCA2 association was also observed in the combined analysis at a MAF of 0.1% (OR=2.26 [1.39, 3.67], P=0.001, FDR q=0.01). Conclusions Rare variants in MSH6 and BRCA2 are significantly associated with increased HCC risk, revealing a previously unconfirmed role for DNA repair genes in HCC susceptibility across ancestrally diverse populations. These findings may inform genetic risk stratification and surveillance strategies. Impact and Implications Rare variants in MSH6 and BRCA2 genes are associated with 2.3 to 2.8-fold higher HCC risk. These findings may warrant further evaluation of liver cancer risk in individuals with MSH6-associated Lynch syndrome or BRCA2-associated hereditary cancer syndromes.
BACKGROUND & AIMS:The temporal relationship between hepatic decompensation and portal vein thrombosis (PVT) in compensated advanced chronic liver disease (cACLD) remains unclear. We investigated their temporal sequence, prognostic significance, and molecular signatures and developed a biologically grounded predictive model for decompensation. METHODS:In this prospective study, 367 rigorously defined patients with cACLD without previous decompensation or PVT were followed for up to 11 years. Baseline assessment included hepatic venous pressure gradient, liver stiffness, upper endoscopy, Doppler ultrasound, and serum measurement of 35 biomarkers spanning angiogenesis, inflammation, endothelial injury, hypoxia, and gut permeability. Temporal associations were analysed using Kaplan-Meier and time-dependent Cox models. Biomarkers independently associated with decompensation were integrated to derive the VAIL score, which was compared with established prognostic scores. RESULTS:During follow-up, 102/367 (27.7%) patients developed hepatic decompensation and 22/367 (6.0%) developed non-malignant PVT. Among patients experiencing both events, decompensation preceded PVT in 53.3% whereas PVT preceded decompensation in 33.3%. Time-dependent Cox analysis showed that hepatic decompensation was the strongest determinant of mortality (HR 11.86, 95% CI 5.68 to 24.78; p<0.001), whereas PVT was not independently associated with mortality (HR 0.56, 95% CI 0.12 to 2.46; p=0.443). Biomarker profiling showed a restricted signature for isolated PVT (Tie2, mesothelin) but broad multisystem dysregulation preceding decompensation. The VAIL score showed the most robust predictive performance (optimism-corrected coefficient 1.76, 95% CI 1.48-4.36; p<0.001) after bootstrap validation, outperforming all established prognostic scores. CONCLUSIONS:In cACLD, hepatic decompensation is an early, biologically active, and prognostically dominant event, whereas PVT is a late, biologically restricted complication. The VAIL score (VEGF-D, Angiopoietin-1, I-FABP, IL-6) provides superior mechanism-based risk stratification for predicting clinical deterioration.
Fibrolamellar hepatocellular carcinoma (FLC) and combined hepatocellular-cholangiocarcinoma (cHCC-CCA) are rare primary liver cancers for which limited evidence is available to guide clinical management. cHCC-CCA could arises in the context of chronic liver disease and shares epidemiological and molecular features with both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), reflecting its intermediate biological and clinical position between these two entities. Its diagnosis remains challenging particularly when based on tumor biopsy specimens. Surgical resection remains the standard of care when feasible. Liver transplantation, trans-arterial chemoembolization, ablation, or selective internal radiation therapy have been used in selected cases. For advanced disease, systemic treatments commonly used for HCC or CCA have been applied in real-world practice, including platinum-based chemotherapy, tyrosine kinase inhibitors, and more recently immunotherapy. In addition, molecularly guided therapies have been explored, as targetable genetic alterations can be identified in a subset of cHCC-CCA. In contrast, FLC typically arises in non-cirrhotic livers of young patients and is frequently associated with metastatic disease, including lymph node involvement. At the molecular level, FLC is characterized by the presence of the DNAJB1-PRKACA fusion and by elevated serum procalcitonin secreted by the tumor. Surgical resection remains the cornerstone of treatment when feasible, but data guiding systemic therapy in unresectable cases are limited. Several regimens, including gemcitabine-oxaliplatin, lenvatinib, and immunotherapy, have been evaluated. More recently, clinical trials have reported antitumor activity with combinations of immunotherapy and vaccines targeting the DNAJB1-PRKACA fusion. To improve patient care, since cHCC-CCA and FLC are rare subtypes of liver cancer, we need to compile prospective samples and clinical data from the patients, including their response to any type of treatment at the national and international levels.
BACKGROUND & AIMS:Liver cirrhosis and chronic liver diseases remain major causes of premature mortality globally, with a disproportionate burden in sub-Saharan Africa (SSA). We aimed to quantify temporal trends and future projections of cirrhosis burden in SSA and assess the potential impact of hepatitis B vaccination scale-up. METHODS:We analysed Global Burden of Disease 2023 data from 1990 to 2023. Age-standardised death rates (ASDRs) and disability-adjusted life years (DALYs) were examined by sex, geography, aetiology, and socio-demographic index (SDI). Bayesian hierarchical models were used to project burden to 2040, including a scenario-based hepatitis B vaccination intervention. RESULTS:In 2023, cirrhosis accounted for 179,329 deaths in SSA, despite a 31% decline in ASDR since 1990. Absolute deaths increased by 72%, and DALYs rose by 68%, reflecting demographic change. Hepatitis B (37%), hepatitis C (29%), and alcohol-related cirrhosis (14%) were the leading causes. Marked geographic and sex disparities persisted, with the highest burden in Central and Western SSA and among males. Low-SDI countries were disproportionately affected, driven by hepatitis B, whereas MASLD contributed more prominently in higher-SDI settings. By 2040, ASDRs for viral and alcohol-related cirrhosis are projected to decline by approximately 6-32% across subregions, while MASLD-related burden remains relatively stable. Under model assumptions, vaccination scale-up was associated with reductions in HBV-related cirrhosis burden. CONCLUSIONS:Despite declining age-standardised rates, the absolute burden of cirrhosis continues to rise across SSA owing to demographic change. Viral hepatitis remains the dominant driver, alcohol-related liver disease continues to contribute substantially, and metabolic liver disease is emerging in higher-SDI settings, highlighting an increasingly layered liver disease burden requiring integrated prevention strategies. IMPACT AND IMPLICATIONS:This study addresses the under-characterised burden of cirrhosis in sub-Saharan Africa by integrating long-term trends with scenario-based projections. The findings reveal a divergence between declining age-standardised rates and rising absolute burden, alongside persistent geographic and socio-demographic inequities. These results are directly relevant to clinicians, researchers, and policymakers prioritising liver disease control in resource-limited settings. They support strategies to sustain viral hepatitis elimination efforts while strengthening preparedness for alcohol-related and emerging metabolic liver disease in higher-SDI settings.
BACKGROUND & AIMS:Radiotherapy confers clinical benefits to hepatocellular carcinoma (HCC) patients across all stages, yet its clinical efficacy is limited by radioresistance. This study aimed to identify key regulators of HCC radiosensitivity through genome-wide functional screening. METHODS:A genome-wide CRISPR-Cas9 screen in Huh7 cells identified radiosensitivity regulators, with SRSF6 validated by siRNA knockdown and γ-H2AX assessment. Stable shRNA-mediated SRSF6 knockdown was established in Huh7 and HepG2 cells, followed by clonogenic, EdU incorporation, apoptosis, micronucleus, and comet assays. Mechanistically, RNA-seq, western blotting, mRNA stability assays, RIP-qPCR, and RAD51 overexpression rescue assays were performed. The therapeutic potential of the SRSF6 inhibitor indacaterol was evaluated using MTS assays, HCC xenograft mouse models (BALB/c-nu/nu, N=28), and HCC patient-derived organoids (PDOs) (N=3). In addition, SRSF6 expression and its correlation with patient survival were analyzed using data from The Cancer Genome Atlas and a tissue microarray (N=14 HCC and 14 paired adjacent non-tumorous liver samples). RESULTS:We identified the RNA-binding protein SRSF6 as a driver of HCC radioresistance. SRSF6 depletion enhanced the radiosensitivity of HCC cells (p<0.05-0.0001) by post-transcriptionally destabilizing the mRNAs of critical DNA repair genes (p<0.05-0.0001), thereby impairing radiation-induced DNA damage repair. The radiosensitizing effect of SRSF6 depletion was partially abrogated by ectopic overexpression of the core DNA repair protein RAD51 (p<0.05-0.001). Indacaterol exhibited cytotoxic effects on HCC cells (p<0.05-0.0001) and enhanced the antitumor efficacy of radiation in vivo (p<0.05-0.0001), as further validated across multiple HCC patient-derived organoids (p<0.05-0.0001). CONCLUSIONS:SRSF6 is a key regulator of HCC radioresistance through its post-transcriptional control of DNA repair capacity, and represents a novel therapeutic target to sensitize HCC to radiotherapy. IMPACT AND IMPLICATIONS:In this study, we performed a genome-wide CRISPR-Cas9 knockout library screen to dissect the molecular determinants governing HCC radiosensitivity, and identified RNA-binding protein SRSF6 as a driver of HCC radioresistance. We demonstrate that SRSF6 depletion disrupts the post-transcriptional stability of key DNA repair gene mRNAs and enhances HCC radiosensitivity. These findings are important for radiation oncologists and translational researchers, as they identify SRSF6-dependent RNA regulation as a critical determinant of radiotherapy response in HCC. Practically, we show that the clinically approved bronchodilator indacaterol suppresses SRSF6 function and enhances the antitumor efficacy of radiotherapy, offering a readily repurposable pharmacological strategy to overcome radioresistance. These implications are based on preclinical evidence across multiple models; however, future clinical trials are needed to validate the safety and efficacy of indacaterol-based radiosensitization in patients with HCC.
Background & Aims Fibroblast growth factor receptor 2 gene (FGFR2) rearrangements are among the most common oncogenic drivers in intrahepatic cholangiocarcinoma (iCCA). While FGFR inhibitors are clinically approved, primary and secondary resistance remain major limitations. Preclinical investigation of resistance mechanisms, including cancer cell-extrinsic crosstalk, is hampered by current models that rely on human FGFR2-fusion transgenes in immunodeficient hosts. We therefore aimed to generate an entirely murine FGFR2-fusion driven iCCA (Ff-iCCA) model to study immunomodulatory mechanisms in the tumor microenvironment (TME). Methods A syngeneic cholangiocyte organoid-based iCCA mouse model was engineered via endogenous chromosomal rearrangement of the Fgfr2 gene combined with Trp53 deletion (PFf) and other co-occurring genetic alterations. KrasG12D-mutated lines (PK) served as comparison. TME characterization was performed using 30-plex spatial proteomics on ∼250,000 cells. Bulk RNA-sequencing was conducted on FGFR inhibitor-treated PFf and PK organoids. Pharmacodynamics of FGFR inhibition on Ff-iCCA were assessed by immunostaining and quantitative RT-PCR. Results Intrahepatic implantation produced well-differentiated Ff-iCCA with morphologic features resembling human small duct type iCCA. In immunocompetent hosts, additional co-alterations were required for tumor penetrance, with Pten deletion being most robust with 75%. Compared to KRAS-driven iCCA, Ff-iCCA showed a significantly increased infiltration by Ly-6C/G+ neutrophils (19-fold, p=0.004) and CD8+ T cells (8-fold, p<0.001). Transcriptome analysis revealed increased chemokine expression in PFf versus PK organoids, which was not reversed by FGFR inhibition. Ff-iCCA responded to FGFR inhibition with a 6.5-fold reduced proliferation in vivo (p=0.029), without observation of significant TME remodeling. Conclusions Our syngeneic murine Ff-iCCA model recapitulates hallmarks of human FGFR2-fusion iCCA, providing a platform for functional investigation of cancer cell-TME crosstalk in this molecular subtype. Impact and Implications This study introduces the first fully syngeneic, endogenously engineered murine model of FGFR2-fusion driven iCCA, overcoming the key limitation of prior models relying on human transgenes in immunodeficient hosts. The model faithfully recapitulates hallmarks of human FGFR2-fusion iCCA, including a small duct type morphology and a distinct neutrophil-enriched tumor immune microenvironment, validating its translational relevance. The finding that an upregulated chemotaxis signature in FGFR2-fusion persists despite FGFR inhibition, alongside upregulation of interferon-stimulated genes upon treatment, points to compensatory immunomodulatory mechanisms that remain to be mechanistically resolved. Overall, this work provides a physiologically relevant platform to interrogate cancer cell–tumor microenvironment crosstalk in FGFR2-fusion driven iCCA.
BACKGROUND & AIMS:Systemic therapy for hepatocellular carcinoma (HCC) has evolved rapidly with the introduction of tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICIs), anti-vascular endothelial growth factor (anti-VEGF) antibodies, and their combinations. This multicenter study aimed to characterize real-world systemic treatment patterns and clinical outcomes in treatment-naïve patients with HCC in China. METHODS:Patients initiating systemic therapy for HCC between 2017 and 2023 across five centers were retrospectively enrolled. Four systemic treatment categories were analyzed: TKI monotherapy, ICIs monotherapy, TKI plus ICIs, and anti-VEGF plus ICIs. Baseline clinical characteristics, treatment patterns across lines, survival outcomes, tumor response, and adverse events (AEs) were analyzed. RESULTS:A total of 4,250 patients were included (median age, 53 years), predominantly male (88.7%) with hepatitis B virus infection (86.3%); 81.3% had Barcelona Clinic Liver Cancer stage C disease. In the first-line setting, 92.3% of patients received systemic therapy combined with transarterial therapy. Median overall survival (OS) was 20.7 months (95% CI, 19.1-22.3), and median progression-free survival (PFS) was 9.7 months (95% CI, 8.2-11.2). Baseline characteristics differed across systemic treatment groups, including demographic and disease characteristics and treatment patterns involving transarterial therapy, and were accounted for using inverse probability of treatment weighting and multivariable Cox regression. Median OS was 17.0, 21.4, 21.6, and 22.4 months in the TKI monotherapy, ICIs monotherapy, TKI plus ICIs, and anti-VEGF plus ICIs groups, respectively. Grade ≥3 AEs occurred in 28.3% of patients. CONCLUSIONS:In this multicenter cohort, ICIs-based systemic regimens combined with transarterial therapy were frequently applied in patients with HCC and associated with favorable survival outcomes and acceptable safety profiles. These findings provide contemporary real-world insights into systemic treatment patterns and outcomes. IMPACT AND IMPLICATIONS:The therapeutic landscape of hepatocellular carcinoma (HCC) has evolved rapidly, whereas treatment patterns in routine clinical practice may differ substantially from those represented in randomized clinical trials, particularly in regions with a high burden of hepatitis B-related disease. This large multicenter real-world study delineates contemporary systemic treatment strategies in China and describes clinical outcomes associated with the use of immune checkpoint inhibitor-containing regimens, particularly when integrated with transarterial therapy, in routine clinical practice. These findings provide additional real-world context regarding multidisciplinary treatment approaches for HCC and may help inform future prospective evaluation of systemic and locoregional treatment integration. Although limited by its observational design, this study generates hypotheses for future prospective studies evaluating multimodal treatment strategies and patient selection for immunotherapy-based approaches in HCC.
BACKGROUND & AIMS:Atezolizumab plus bevacizumab (Atezo/Bev) is considered standard first-line therapy for unresectable hepatocellular carcinoma (HCC), yet reasons for treatment discontinuation vary, and conventional survival endpoints do not capture the time-varying probability of each cause. This multicentre retrospective study aimed to quantify the cause-specific discontinuation and its predictors. METHODS:We analysed 685 consecutive patients treated with Atezo/Bev (10 excluded). Time to discontinuation was defined from treatment initiation to cessation and right-censored at last follow-up if ongoing. Discontinuation reasons were categorized as progressive disease (PD), adverse event (AE)-driven discontinuation (treatment-related AEs without hepatic decompensation), hepatic dysfunction-driven discontinuation (decompensation irrespective of mechanism), response/strategy change, and other causes. Cumulative incidence functions (CIFs) were estimated, and cause-specific Cox models were fitted with multiple imputation. RESULTS:Discontinuation causes included PD (n=334), AE (n=125), hepatic dysfunction (n=48), response/strategy change (n=44), and other causes (n=35); 99 were censored. One-year CIFs were 0.394, 0.153, 0.056, 0.042, and 0.041, respectively. Baseline AFP predicted PD-driven discontinuation (HR 1.18 per log10[AFP+1]; p=3.95×10-5). AE-driven discontinuation was independently associated with age (HR 1.03/year), ECOG performance status ≥1 (HR 1.82), and ALBI (HR 1.07 per 0.1 increase; p=7.43×10-4). Hepatic dysfunction-driven discontinuation was strongly associated with age (HR 1.07/year; p=4.28×10-4) and ALBI (HR 1.29 per 0.1 increase; p=8.65×10-13). AFP (<400 vs ≥400 ng/mL) × mALBI (1/2a vs 2b/3) defined four strata. Low AFP/poor mALBI showed the highest 1-year toxicity-related discontinuation (CIF 0.339), whereas high AFP/good mALBI showed predominantly PD-driven discontinuation (CIF 0.520). CONCLUSIONS:Four clinically defined risk strata based on AFP and mALBI differentiated distinct patterns of treatment discontinuation, capturing both PD and toxicity-pathways. This framework may support risk-adapted monitoring and early treatment optimisation, but external validation is warranted. IMPACT AND IMPLICATIONS:Atezolizumab plus bevacizumab is a standard first-line regimen for unresectable HCC, yet discontinuation occurs for multiple reasons that are not captured by conventional survival summaries. Analysis of a large multicentre cohort revealed distinct patterns of treatment discontinuation along with clinical predictors. Baseline AFP primarily forecasted PD-driven discontinuation, whereas baseline liver function (ALBI) and older age dominated the risk of AE and hepatic decompensation. An AFP×mALBI matrix separated patients into distinct discontinuation pathways, identifying a low-AFP/poor-mALBI subgroup with high early toxicity-related discontinuation and a high-AFP/preserved-mALBI subgroup with predominantly PD-driven discontinuation. Since this framework has not yet been externally validated, it should be regarded as hypothesis-generating. Nevertheless, it may help clinicians consider risk-adapted monitoring, toxicity preparedness, and supportive care according to the dominant discontinuation risk.
BACKGROUND & AIMS:Metabolic dysfunction-associated steatohepatitis (MASH) is the progressive form of metabolic dysfunction-associated steatotic liver. It is highly prevalent, particularly among individuals with overweight or obesity, and substantially impairs health-related quality of life. Semaglutide 2.4 mg received accelerated approval from the US Food and Drug Administration in August 2025 for adults with noncirrhotic MASH and fibrosis stages F2-F3 based on results from the ESSENCE trial. This study aimed to estimate the impact of semaglutide on health utility in this population. METHODS:This exploratory analysis used Week 72 data from ESSENCE Part 1, a phase 3, randomized, double-blind, placebo-controlled trial. Adults with biopsy-confirmed MASH and fibrosis stage F2 or F3 were randomized 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo plus standard of care. EuroQol 5-Dimension (EQ-5D) utilities were mapped from Short Form-36 (SF-36) scores using the Rowen et al. (2009) algorithm. Change from baseline was analyzed with treatment, baseline diabetes status, fibrosis stages as covariates. RESULTS:A total of 800 participants were included in this analysis (semaglutide 2.4 mg n=534; placebo n=266). Mean age was 56.0 years; 57.1% were female; mean body mass index was 34.6 kg/m2 and 55.9% had type 2 diabetes. Baseline mapped EQ-5D utility was approximately 0.78 in both groups. At Week 72, semaglutide significantly improved mapped EQ-5D utility versus placebo (estimated treatment difference 0.03; 95% confidence interval [CI]: 0.01, 0.06; nominal p=0.0015), with consistent effects across fibrosis stages. CONCLUSIONS:In adults with MASH and F2 or F3 fibrosis, once-weekly semaglutide 2.4 mg was associated with statistically significant improvements in mapped EQ-5D health utility versus placebo. These exploratory findings provide utility estimates that may help to inform cost-effectiveness evaluations and health technology assessments. IMPACT AND IMPLICATIONS:This study provides the first estimation of EuroQol 5-Dimension (EQ-5D) health utility gains associated with once-weekly semaglutide 2.4 mg in people with metabolic dysfunction-associated steatohepatitis (MASH) and F2/F3 fibrosis. The findings are important for payers and clinicians because they demonstrate a statistically significant improvement in mapped EQ-5D health utility with semaglutide 2.4 mg over 72 weeks. These results can directly inform cost-effectiveness models and support healthcare decision-making by quantifying the health-related quality of life benefits of semaglutide using a widely accepted preference-based metric. Given the use of mapped rather than directly measured utilities and the UK-specific tariff, the results should be interpreted with appropriate caution.
BACKGROUND & AIMS:The circadian clock dictates time-of-day dependent gene, protein expression, and metabolite levels to ensure liver homeostasis. Circadian misalignment is implicated in the development of various metabolic disorders, but its contribution to the progression of Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) toward Metabolic dysfunction-Associated Steatohepatitis (MASH) remains poorly understood. Here, we aimed to dissect the role of the circadian clock in MASH development. METHODS:Using an environmental model of chronic circadian misalignment (n=6-12/group), combined with metabolic and immune phenotyping, single nuclei transcriptomics and lipidomic profiling, we investigated the role of the clock in MASLD development and hepatic inflammation. To dissect the specific contribution of the immune clock, we used a genetic model overexpressing the clock component Rev-erbα in myeloid cells (n=3-5/group). RESULTS:Chronic circadian misalignment combined with a high-fat, high-sucrose, cholesterol-enriched (HFHSC) diet markedly amplified hepatic inflammation, characterized by the upregulation of pro-inflammatory genes (p<0.01) and increased immune cell infiltration, including the expansion of hepatic lipid-associated macrophages (hLAMs) (p<0.0001). This heightened inflammatory response promoted fibrotic deposition (p<0.0001). Although circadian misalignment did not worsen glucose intolerance or hepatic steatosis, it altered hepatic metabolic gene expression profile, indicating a broad reprogramming of immune and metabolic pathways. Conversely, myeloid-specific Rev-erbα overexpression attenuated hepatic inflammation in HFHSC-fed mice (p<0.05). CONCLUSIONS:The circadian clock controls both hepatic fatty acid profile and inflammatory process, and its misalignment aggravates MASLD by increasing liver inflammation and fibrosis. Targeting circadian regulators such as Rev-erbα in myeloid cells may offer a promising therapeutic avenue for controlling liver inflammation in MASLD. IMPACT AND IMPLICATIONS:By combining environmental and genetic approaches, this study highlights the central role of the circadian clock in regulating hepatic inflammation during MASLD progression. These findings underscore the importance of considering biological rhythms in the prevention of chronic metabolic diseases and support the potential of circadian clock-targeted strategies as a novel therapeutic avenue.
