Atractylenolide III Alleviates Cisplatin-Induced Acute Liver Injury by Regulating Gut-Liver Axis Through Inhibiting ACT1/TRAF6/NF-κB-Mediated IL-17 Pathway

Introduction: Cisplatin (DDP) is a highly effective and broad-spectrum chemotherapeutic agent. However, its clinical application is limited by severe hepatotoxicity. Currently available hepatoprotective agents are often associated with insufficient efficacy or side effects. Therefore, developing new hepatoprotective agents that are highly efficient and low in toxicity is urgent. Objectives: Atractylodes macrocephala Koidz. is a well-known traditional Chinese medicine for strengthening the spleen function. According to the theory of traditional Chinese medicine, “When liver disease occurred, the spleen should be strengthened first” suggests that A. macrocephala Koidz. might possess hepatoprotective properties. Therefore, this study focuses on the molecular mechanism by which the active factors of A. macrocephala Koidz. exert their liver-protective effects. Methods: Animal experiments were adopted to screen the active factors of A. macrocephala Koidz. Multi-omics integrated analysis, including gut microbial diversity, transcriptomics, and metabolomics, combined with fecal microbiota transplantation (FMT) experiments were performed to clarify the mechanism of liver-protective effects of atractylenolide III (AT-III). Results: We found that AT-III-derived from A. macrocephala Koidz. significant decreased ALT, AST levels and hepatic pathological symptoms in DDP-induced acute liver injury (ALI). AT-III alleviated DDP-induced ALI via the “gut-liver axis” by inhibiting the ACT1/TRAF6/NF-κB-mediated IL-17 signaling pathway. Eight distinct microbial species, including Parabacteroides and Alloprevotella, were identified with significant differences. Besides, metabolite N6-(1,2-dicarboxyethyl)-AMP was identified as a novel biomarker for hepatotoxicity. Meanwhile, the FMT results indicated that the intestinal microbiota has a better alleviating effect on ALI than the metabolites of the intestinal microbiota.