Dihydrotanshinone I Attenuates Diet‐Induced Nonalcoholic Fatty Liver Disease via Up‐Regulation of IRG1

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, but effective therapeutic drugs are still lacking. Dihydrotanshinone I (DHTS), a natural product isolated from Salvia miltiorrhiza , has been shown to have ameliorative effects on NAFLD. The aim of this study was to investigate the hepatoprotective effect of DHTS on NAFLD and its mechanism. A model of NAFLD and DHTS treatment was established using a Western diet to observe the effect of DHTS on NAFLD, which were detected by immunohistochemical, immunofluorescence, and other experiments. The mechanism was further explored by constructing immune responsive gene 1 (IRG1) knockout mice, RNA sequence, and molecular docking. The results revealed that DHTS significantly improved diet‐induced metabolic disorders in mice, notably alleviating liver inflammation, oxidative stress, and fibrosis. Further analysis revealed that the intervention of DHTS was associated with the activation of IRG1. Subsequent experiments confirmed that IRG1 gene deletion reversed the above protective effects of DHTS in NAFLD. Mechanistically, DHTS enhanced the antioxidant nuclear factor–erythroid 2‐related factor 2 (Nrf2) pathway through IRG1/itaconate and blocked the oxidative stress response in the liver. In addition, DHTS also inhibited the activation of NACHT‐, leucine‐rich repeat (LRR)–, and pyrin domain (PYD)–containing protein 3 (NLRP3) inflammasome via IRG1/itaconate, blocking the inflammatory amplification effect in the liver. The study suggests that DHTS may be a potential drug for the treatment of NAFLD, which exerts protective regulatory effects mainly through the IRG1/itaconate molecular pathway.