UPLC-Q-TOF/MS-Based Metabolomics and 16S rRNA Profiling Reveal that Corosolic Acid Ameliorates High-Fat Diet-Induced MASLD by Modulating the Gut-Liver Axis to Inhibit the cGAS-STING Pathway.

Metabolic-associated steatohepatitis liver disease (MASLD) is characterized by abnormal hepatic fat accumulation and liver injury. Corosolic acid (CA) has proven lipid-lowering and hepatoprotective effects, yet the underlying mechanism by which CA mitigates MASLD remains unclear. In this study, mice were fed a high-fat diet for 8 weeks to induce MASLD, followed by 8 weeks of CA intervention. We found that CA significantly suppressed weight gain, reduced serum lipid levels, and improved liver function in the HFD-fed mice. Fecal metabolomic analysis showed that CA regulated multiple metabolic pathways including histidine metabolism and altered 10 shared metabolites between feces and serum, such as HAD-Car. 16S rRNA sequencing and fecal microbiota transplantation confirmed that CA reshaped gut microbiota, upregulating beneficial bacteria (e.g., Lachnospiraceae_NK4A136_group) and downregulating harmful strains (e.g., Blautia ). Mechanistically, HAD-Car alleviated MASLD by inhibiting the cGAS-STING pathway. Collectively, CA exerts anti-MASLD effects via regulating gut microbiota and metabolites, offering new insights into MASLD treatment.