Hepatology International最新文献

Background: Biliary atresia (BA) is a rare but severe neonatal cholangiopathy characterized by progressive fibro-inflammatory obstruction of the bile ducts, ultimately leading to liver failure and the need for liver transplants. Despite intensive researches, the etiology of BA remains poorly understood. Recent discoveries implicate primary cilia-solitary, microtubule-based organelles that regulate developmental signaling pathways-as central to the pathogenesis of both syndromic and non-syndromic BA.

Methods: We systematically reviewed genetic, histological, organoid-based, and animal model studies that investigate the role of primary cilia in BA. Evidence was synthesized across genome-wide association studies, sequencing analyses, tissue-level ciliary assessments, and functional perturbation experiments in model organisms to integrate current understanding of ciliary defects and their mechanistic contribution to BA.

Results: Genetic analyses identified both common and rare variants in cilia-related genes-polycystin 1 like 1 (PKD1L1), kinesin family member 3B (KIF3B), tetratricopeptide repeat domain 17 (TTC17), and ciliogenesis and planar polarity effector (CPLANE) complex members-particularly in BA patients with laterality defects. Histological evaluation of BA liver tissues consistently demonstrated shortened, misoriented, or absent cholangiocyte cilia, while patient-derived organoids reproduced these structural abnormalities alongside disrupted epithelial polarity. Functional studies in zebrafish and mouse models showed that loss of ciliary genes impaired bile duct morphogenesis, delayed biliary drainage, and induced progressive cholangiopathy, closely mirroring human BA. Perturbation of cilia-dependent signaling pathways, including Hedgehog (Hh), further exacerbated disease phenotypes, underscoring the causal role of ciliary dysfunction.

Conclusions: Taken together, these findings support the emerging view of BA as a cilia-related developmental disorder. This review offers new insights into disease mechanisms and provides a basis for advancing early diagnosis, risk stratification, and targeted therapeutic strategies of BA.

Background: The treatment of hepatocellular carcinoma (HCC) remains thorny, due to that just few molecules have been defined as pathogenic drivers. Ribosome biogenesis and alternative splicing (AS) are dysregulated during the development of HCC, but how both processes coordinate remains unexplored.

Methods: Pan-cancer analyses and tissue microarray were used to assess the clinical relevance of BRIX1. Functional studies employed CCK-8 assays, colony formation assays, Transwell migration/invasion assays, flow cytometry analysis, and animal studies. Splicing networks were analyzed by RNA-seq and validated through isoform-specific qRT-PCR. Molecular mechanisms were dissected via ChIP-PCR, Co-IP/MS, immunofluorescence, EU RNA Synthesis, and puromycin incorporation assay.

Results: BRIX1 is upregulated in HCC, involved in the mTORC1-SP1 signaling, correlated with a poor prognosis, suggesting it as a critical oncogene. BRIX1 depletion suppresses the proliferation, migration and invasion, and induces the apoptosis of HCC cells. Mechanically, BRIX1 localizes to the nucleolus to interact with UBTF and POLR1A, thus promoting rDNA transcription and ribosomal biogenesis. BRIX1 depletion triggers ribosomal stress, disturbs pre-rRNA synthesis, and inhibits global protein translation. Furthermore, BRIX1 knockdown suppresses SRSF1-mediated oncogenic AS, reduces the production of carcinogenic isoforms MKNK2 and S6K1, and silences mTORC1-4EBP1 signaling. SRSF1 overexpression reverses the phenotypic and molecular changes induced by BRIX1 knockdown.

Conclusion: BRIX1 activated by mTORC1-SP1 signaling regulates ribosome biogenesis and AS to promote HCC progression. Our findings establish BRIX1 as a governor on both ribosome biogenesis and AS in HCC, and a possible prognostic or therapeutic biomarker.

Background: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by immune-mediated hepatocellular injury. Regulatory T cells (Tregs) are crucial for maintaining immune tolerance, but their role in AIH remains unclear. This study aimed to evaluate the phenotype, function, and tissue distribution of Tregs in AIH and examine their potential association with immune dysregulation.

Methods: Peripheral blood and liver samples were collected from 57 biopsy-confirmed AIH patients. Single-cell RNA sequencing was performed on peripheral blood mononuclear cells (PBMCs) from one individual per group (healthy control, before treatment, and flare after steroid discontinuation). Flow cytometry (PBMCs n = 45; livers n = 37) and immunohistochemistry (IHC, n = 33) assessed Treg frequency and phenotype. Treg suppressive function was evaluated using co-culture assays with effector T cells (Teffs) isolated from PBMCs (n = 25).

Results: IHC revealed marked immune cell infiltration in AIH liver tissues, and FOXP3 + cell counts correlated positively with serum AST levels (p = 0.0096) and portal-peripheral activity severity (p < 0.05). Single-cell RNA sequencing showed expansion of distinct Tregs and transcriptional changes, including IL-7R upregulation suggesting functional instability. Flow cytometry confirmed significantly increased total and activated Tregs in AIH liver samples (both p < 0.0001). However, co-culture assays demonstrated that Tregs from AIH patients had markedly reduced suppressive capacity compared to healthy controls (p < 0.0001).

Conclusions: Despite their expansion in liver tissue, Tregs in AIH exhibit impaired suppressive function, indicating functional instability contributes to immune dysregulation in AIH.

Background and aim: Functional cure is considered the advanced treatment goal for patients with chronic hepatitis B (CHB). We aimed to evaluate hepatitis B surface antigen (HBsAg) loss rates after combination treatment of entecavir (ETV) and peginterferon alfa-2b (Peg-IFN) with or without granulocyte-macrophage colony-stimulating factor (GM-CSF).

Methods: In this randomized controlled trial, virally suppressed patients undergoing nucleos(t)ide analogs with HBsAg < 3000 IU/mL were randomized 1:1:1 to receive either ETV for 96 weeks (E group), or 48 weeks of Peg-IFN + ETV, followed by 48-week Peg-IFN alone (EP group), or 48 weeks of Peg-IFN + ETV + GM-CSF, followed by 48-week Peg-IFN alone (EPG group). The primary outcome is HBsAg loss at week 96.

Results: Among 249 patients (81 in E group, 83 in EP group and 85 in EPG group), EP group (30.12%, 25.30%) and EPG group (22.35%, 20.00%) achieved significantly higher HBsAg loss and HBsAg seroconversion rates than E group (0.00%, 0.00%; p < .0001, p < .0001) at week 96. At week 120, HBsAg loss was maintained in 22 of 25 patients (88.00%) in EP group and 15 of 19 (78.95%) in EPG group. During the 24-week off-treatment follow-up, late HBsAg loss occurred in one EP and three EPG patients. Multivariate analysis showed that age, baseline HBsAg level, and 24-week HBsAg decline correlated with HBsAg loss and HBsAg seroconversion at week 96. 24-week HBV RNA decline correlated with HBsAg loss. The HBsAg dynamics during therapy could predict HBsAg loss with an area under the curve of 0.944. More patients in EP group and EPG group experienced adverse events than E group.

Conclusion: In virally suppressed patients with HBsAg level < 3000 IU/mL, ETV plus Peg-IFN significantly increased HBsAg loss and HBsAg seroconversion, whereas adding GM-CSF conferred no additional efficacy benefit. Age, early on-treatment HBsAg level and 24-week HBV RNA decline correlated with HBsAg loss. This trial is registered at ClinicalTrials.gov, NCT02327416.