Hepatotropic AAV8 encoding shRNAs targeting S100A10 or S100A11 were used to downregulate these proteins specifically in the liver of mice fed a diet inducing hepatic steatosis, inflammation, and fibrosis and in a genetic mouse model of MASLD bearing hepatocyte-specific deletion of PTEN (LPTENKO). The gene discussed is S100A10; the disease is metabolic dysfunction-associated steatotic liver disease.