Inhibition of STING alleviates lipotoxicity in viral-infected primary mouse hepatocytes and viral hepatitis-associated liver damage.

INTRODUCTION

RNA virus infections often cause liver steatosis and lipid deposition, which significantly exacerbate liver damage. However, the underlying mechanisms linking viral-induced lipid accumulation to hepatocellular death remain incompletely understood.

METHODS

We employed a primary mouse hepatocyte model of vesicular stomatitis virus (VSV) infection and an in vivo mouse model of virus-induced acute liver failure. The role of STING was investigated through genetic knockdown and pharmacological inhibition using H-151. Furthermore, clinical relevance was assessed using data from the National Health and Nutrition Examination Survey (NHANES, 2007-2010) to analyze correlations between hepatic steatosis and injury biomarkers.

RESULTS

Viral exposure induced time-dependent upregulation and activation of STING, which driven the pathological accumulation of lipid droplets and subsequent ferroptotic cell death. Genetic knockdown or pharmacological inhibition of STING (H-151) effectively mitigated metabolic stress and preserved cell viability. These protective effects were recapitulated in vivo, where H-151 administration significantly improved survival and reduced tissue damage in a mouse model of virus-induced acute liver failure. Analysis of NHANES data corroborated these findings, showing that in patients with concurrent viral hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD), the fatty liver index (FLI) and triglyceride levels correlate linearly with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels.

CONCLUSION

Collectively, our study identifies the STING-lipotoxicity axis as a key driver of viral hepatotoxicity, highlighting its potential as a therapeutic target for liver injury.