Mechanisms and reversal strategies of liver fibrosis: from regulation of cell fate to clinical translation

BACKGROUND: Liver fibrosis is a dynamic and reversible pathological process underlying chronic liver diseases, characterized by excessive extracellular matrix deposition and progressive hepatic architectural distortion. It acts as a critical precursor to cirrhosis, hepatic decompensation, and hepatocellular carcinoma, imposing a substantial global disease burden. MAIN BODY: Accumulating evidence indicates that liver fibrosis is a highly plastic process governed by multicellular crosstalk, immune microenvironment remodeling, epigenetic-metabolic coupling, and mechanotransduction. This review outlines core cellular effectors and their heterogeneity revealed by single-cell omics, and highlights key regulatory layers including circadian rhythm, epigenetic imprinting, metabolic reprogramming, and the gut-liver axis, as well as etiology-specific differences in fibrosis progression, reversibility, and therapeutic response. We also summarize advances in non-invasive diagnosis and clinical translation of anti-fibrotic therapies, and discuss key bottlenecks leading to clinical trial failures. CONCLUSION: A deeper understanding of cell fate regulation and multicellular ecosystem remodeling will facilitate the development of precise strategies to achieve meaningful fibrosis regression and improve long-term clinical outcomes in chronic liver diseases.