Kaji-ichigoside F1 prevents acetaminophen-induced acute liver injury by modulating microbial metabolism

Introduction: Acetaminophen overuse is the leading cause of acute liver injury (ALI) in developed countries. Unfortunately, effective treatment strategies remain limited. Kaji-ichigoside F1 (KF1), the primary active compound in Rosa roxburghii Tratt, exhibits excellent anti-inflammatory properties. However, the protective effects of KF1 against drug-induced liver injury and its potential mechanisms are not yet understood.Objectives: We aimed to investigate the effects of KF1 on ALI and explore its underlying mechanisms, particularly its role in modulating the gut microbiota to inhibit ALI development.Methods: Mouse models of ALI were established using acetaminophen (350 mg/kg) treatment, with or without KF1 (5 and 10 mg/kg). 16S rRNA gene sequencing, metabolomics, and transcriptomics ap-proaches were employed to explore the inhibitory effect of KF1 on ALI. Additionally, the role of the gut microbiota was investigated through antibiotic treatment and fecal microbiota transplantation (FMT) experiments. Finally, we elucidated the critical roles of key functional bacteria and metabolites mod-ulated by KF1 in the context of ALI.Results: KF1 inhibited the development of ALI in mice in a dose-dependent manner. Treatment with KF1 significantly altered the gut microbiota composition, notably increasing the abundance of the probiotic Akkermansia muciniphila (A. muciniphila). Furthermore, A. muciniphila enhanced the levels of beneficial metabolites, including Inosine. Notably, Inosine significantly suppressed inflammatory factors and improved acetaminophen-induced ALI. Transcriptomic analysis revealed that Inosine in-hibited, key signaling pathways, including MAPK, PI3K-Akt, JAK-Stat3, IL-17, TNF, and cyto-kine-chemokine interactions. Importantly, the preventive effect of KF1 is dependent on microbial mechanisms. FMT from KF1-treated mice to germ-free mice partially recapitulated the protective effects of KF1.Conclusion: KF1 protects against ALI by modulating the gut microbiota and associated metabolites, thereby promoting a more favorable state and inhibiting pro-inflammatory pathways.