Drug-induced liver injury (DILI) is a leading cause of acute liver failure, posing a significant public health burden. Emerging evidence underscores the gut microbiota as a critical environmental factor that profoundly influences liver function and DILI progression, yet the underlying mechanisms remain poorly understood. Here, we identify hepatic long non-coding RNA SNHG9 as a key mediator linking the gut microbiota to acetaminophen (APAP)-induced liver injury. Upregulation of hepatic SNHG9 protects against hepatotoxicity by activating MAS, a G protein-coupled receptor that facilitates the clearance of cellular damage via enhanced autophagy. Mechanistically, SNHG9 binds to insulin-like growth factor 2 mRNA-binding protein 2 (IMP2), enhancing its interaction with MYC mRNA and suppressing MYC translation. Since MYC acts as a transcriptional repressor of the MAS1 gene, this suppression leads to upregulated MAS expression. Notably, hepatic SNHG9 expression is modulated by the gut microbiota, particularly through the metabolite 2-hydroxy 2-methylbutyric acid (HMB). Supplementation with HMB or HMB-producing microbes robustly induces hepatic SNHG9 expression and attenuates APAP-induced liver injury. Our findings unveil a previously unrecognized gut-liver axis and provide mechanistic insight into how gut microbiota regulate hepatic stress responses, suggesting potential avenues for modulating this pathway in drug-induced liver injury.
© 2026. The Author(s).