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

Abstract

Context Drug-induced liver injury remains a major clinical challenge due to the lack of effective therapeutic options. Polygonatum odoratum extract (PO), derived from the traditional medicinal and edible plant Polygonatum odoratum (Mill.) Druce, has long been used in folk practices in forms such as herbal soups and tea infusions. However, its protective effect against acetaminophen (APAP)-induced liver injury has not yet been investigated. 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. In vitro, PO demonstrated anti-ferroptotic effects in APAP- or RSL3-treated AML12 cells. Discussion and Conclusion PO confers hepatoprotection via the gut–liver axis, which is associated with changes in ceramide metabolism and ferroptosis-related markers.