Polygonatum odoratum extract ameliorates acetaminophen-induced acute liver injury by modulating the gut-liver axis and remodeling microbial and ceramide metabolism to suppress hepatic ferroptosis: insights from multi-omics.

Context: Drug-induced liver injury remains a major clinical challenge due to the lack of effective therapeutic options. Objective: This study evaluated the preventive effects of PO against APAP-induced acute liver injury in mice. Materials and Methods: An APAP-induced acute liver injury model was established in C57BL/6 mice. The hepatoprotective effects of PO were validated via histopathological analysis, oxidative stress assays,and serum biomarkers Multi-omics approaches, including 16 S rDNA sequencing, transcriptomics, and network pharmacology, were integrated with molecular biology techniques and pseudo-germ-free (PGF) mouse models to elucidate the underlying mechanisms. Results: PO significantly alleviated hepatic histopathological damage, oxidative stress, and reduced serum ALT, AST, and LDH. PO remodeling gut microbiota, mitigated colonic inflammation and oxidative stress, and improved intestinal morphology, effects abolished by microbiota depletion. Mechanistically, PO maybe inhibited hepatic ferroptosis via the gut microbiota-ceramide axis, evidenced by upregulation of GPX4 and FSP1, NRF2/KEAP1 pathway activation, downregulation of ACSL4, TFRC/TFR2, and DUOX2, restored iron homeostasis, and decreased lipid peroxidation and ROS. Discussion and Conclusion: PO confers hepatoprotection via the gut-liver axis, which is associated with changes in ceramide metabolism and ferroptosis-related markers.