Helicobacter pylori infection aggravates hepatic steatosis by lactylation-driven WTAP-mediated m(6)A modification.

Helicobacter pylori (H. pylori) infection has been investigated as a potential risk factor for extragastric diseases, including metabolic dysfunction-associated fatty liver disease (MASLD). However, details of the underlying mechanisms remain inadequately understood. In this study, we elucidate that H. pylori infection exacerbates hepatic metabolic disorders both in vitro and in vivo, manifesting as increased lipid deposition and insulin resistance. Mechanistically, H. pylori infection upregulates hepatic m(6)A content, particularly increasing the expression of WTAP. Overexpression of hepatic WTAP promotes liver steatosis characteristics, including increased lipogenesis and decreased fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). Conversely, knockdown of hepatic WTAP mitigated hepato-steatosis and insulin resistance in high-fat diet (HFD) mice and hepatic cells. After H. pylori infection, lactate accumulates in the liver, which potently induces WTAP upregulation in HepG2 cells via H3K18 lactylation. Notably, we identified two lactylation modification sites, K99 and K134, on WTAP, which are essential for WTAP to regulate GLUT3 mRNA stability in an m(6)A-YTHDF1-dependent manner. The upregulation of GLUT3 subsequently enhanced glycolysis, establishing a feedback loop that resulted in increased lactate accumulation. In conclusion, our findings highlight the significance of lactylation-driven WTAP-mediated RNA m(6)A modification in the aggravation of hepatic steatosis due to H. pylori infection. Therefore, the status of H. pylori should be taken into account in MASLD treatment strategies. Furthermore, the WTAP-YTHDF1-GLUT3 axis may be a potentially promising therapeutic target for MASLD progression.