Biliary atresia-related liver fibrosis

Biliary atresia (BA) is a devastating cholestatic disease of infancy characterized by progressive fibro-obliterative cholangiopathy, which, without timely intervention, inexorably leads to end-stage liver disease and the need for liver transplantation. Hepatic fibrosis constitutes not only the histopathological cornerstone of BA but also the principal determinant of disease trajectory, native liver survival, and long-term outcomes. This review provides a comprehensive synthesis of the current understanding and unmet clinical needs in BA-associated liver fibrosis, systematically addressing three interconnected domains: pathogenesis, diagnostic modalities, and therapeutic strategies. In the pathogenic realm, we dissect the multilayered molecular architecture-from genetic susceptibility loci (including ciliopathy-related PKD1L1, developmental regulators ADD3,GPC1, and immune-modulating polymorphisms) through aberrant cellular activation (biliary epithelial cells undergoing ductular reaction and epithelial-mesenchymal transition, hepatic stellate cells and portal fibroblasts transdifferentiating into myofibroblasts, and immune cells polarizing toward pro-fibrotic phenotypes), to the integrated signaling network of TGF-β/Smad, Wnt/β-catenin, Hippo/YAP, and Notch pathways, further sustained by epigenetic modifications involving DNA methylation, histone remodeling, and non-coding RNAs. In diagnostics, we evaluate conventional ultrasound, emerging shear wave elastography, serum matrix metalloproteinase-7 as a promising biomarker, and risk-stratification algorithms, while critically comparing their strengths and limitations. In therapeutics, we assess the enduring role of Kasai portoenterostomy (KPE), the limitations of current adjunctive therapies, and the evolving landscape of pharmacological interventions-including ileal bile acid transporter inhibitors (odevixibat), farnesoid X receptor agonists (obeticholic acid), eicosapentaenoic acid, and N-acetylcysteine-alongside ongoing clinical trials. We further highlight how single-cell and spatial transcriptomic technologies are revolutionizing our comprehension of cellular heterogeneity and intercellular crosstalk within the fibrotic niche, offering unprecedented opportunities for molecular subtyping and precision medicine. By bridging mechanistic insights with clinical translation, this review provides a conceptual framework to guide future research, improve diagnostic precision, and develop rationally targeted combination therapies for BA-associated liver fibrosis.