The present study represents the first attempt to demonstrate that 1) the SIRT1/HMGB1 pathway is a pivotal therapeutic target for preventing NAFLD progression, 2) SalB confers protection against HFD- and PA-induced hepatic steatosis and inflammation, and 3) the protective effect of SalB may be associated with the SIRT1/HMGB1 pathway. Here, SIRT1 is linked to fatty liver disease.