3,3′,4,5′‐Tetramethoxy‐trans‐stilbene Alleviates Metabolic Dysfunction‐Associated Steatotic Liver Disease

ABSTRACT Prolonged high‐fat diet causes insulin resistance and metabolic dysfunction‐associated steatotic liver disease (MASLD). 3,3′,4,5′‐Tetramethoxy‐trans‐stilbene (3,3′,4,5′‐TMS), a methoxy derivative of resveratrol, has been demonstrated to ameliorate oxidative stress and insulin resistance in vitro. However, it remains unclear whether 3,3′,4,5′‐TMS exhibits protective effects on insulin resistance‐related MASLD, which is investigated in the current study. Male C56BL/6 J mice were fed a high‐fat diet (60 kcal% fat) for 12 weeks to establish a model of diet‐induced obesity (DIO) with insulin resistance and associated MASLD. 3,3′,4,5′‐TMS (10 mg/kg/d) was intragastrically administered for 4 weeks. Hematoxylin and eosin, Oil‐red O, and periodic acid‐Schiff staining were performed to observe pathological changes of the liver. Protein markers for antioxidant and insulin signaling pathways were assessed by Western blot. 3,3′,4,5′‐TMS treatment ameliorated hyperglycemia, hyperlipidemia, and fatty liver in insulin‐resistant and MASLD mice. 3,3′,4,5′‐TMS regulated blood glucose through the activation of the insulin signaling pathway: increasing phosphorylation of IRS1 (Ser307), Akt (Ser473), and GSK3β (Ser9), upregulating protein expression of IRS2 and PI3K, and decreasing phosphorylation of GS (Ser641) in DIO mouse liver. Furthermore, 3,3′,4,5′‐TMS reduced oxidative stress in livers by upregulating Nrf2/HO‐1 signaling pathway. These findings indicate that 3,3′,4,5′‐TMS ameliorates insulin resistance and MASLD, possibly through the activation of IRS/PI3K/Akt/GSK3β/GS and Nrf2/HO‐1 pathways.