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Background Hepatolithiasis is a chronic hepatobiliary disease that can lead to intrahepatic bile stone formation and thereby increase liver fibrosis progression. There is a growing body of evidence supporting the role of dysbiosis of intestinal microbiota in the pathogenesis of liver fibrosis through the gut-liver axis. However, its role in mediating ferroptosis and apoptosis, two regulated forms of cell death integral in driving hepatic injury, remains unclear. In this study, we explore how gut microbiota alteration affects ferroptotic and apoptotic mechanisms in hepatolithiasis-mediated liver fibrosis.Methods A prospective case-control study was performed on 60 hepatolithiasis patients and 30 healthy controls (patients with no history of hepatobiliary stones, no history of cirrhosis, however, need surgical partial liver resection due to benign non-infectious liver diseases). Microbial diversity and composition were assessed by gut microbiota profiling (16S rRNA sequencing). The liver biopsy samples were subjected to analyses for the ferroptosis markers (GPX4, ACSL4, TFRC) and the apoptosis markers (Cleaved Caspase-3, BAX/BCL-2 ratio) using immunohistochemistry (IHC), qRT-PCR (quantitative real-time polymerase chain reaction) and Western blotting. Microbial metabolites (SCFAs, LPS, bile acids) were measured and correlated with markers of oxidative stress (serum levels of MDA, GSH) and lipoperoxidation. Statistics used were Spearman correlation and ANOVA, regression modeling.Results Hepatolithiasis patients showed clinically significant gut dysbiosis, with reduced microbial diversity (Shannon Index: 3.2 vs 4.5, p<0.001) ( IDDF2026-ABS-0204 Figure 1) and increased pathogenic genera (Enterococcus, Escherichia/Shigella). The low expression of GPX4 (0.45 vs. 1.2, p<0.001) and high ACSL4 (2.1 vs. 0.8, p<0.001) (IDDF2026-ABS-0204 Figure 2) confirmed ferroptotic hepatocyte injury. Elevated apoptotic markers indicated excessive cell death. LPS correlated negatively with markers of ferroptosis and apoptosis (r = -0.52, p<0.01) (IDDF2026-ABS-0204 Figure 3), implicating microbiota in hepatic injury modulation.Conclusions Changes of gut microbiota trigger ferroptosis and apoptosis that aggravate hepatolithiasis-induced fibrosis. Addressing microbiota composition and ferroptosis regulators represent potential novel therapeutic strategies for curtailing hepatic fibrosis progression.Abstract IDDF2026-ABS-0204 Figure 1Abstract IDDF2026-ABS-0204 Figure 2Abstract IDDF2026-ABS-0204 Figure 3