Cajanolactone A alleviates high-fat diet-induced MAFLD by modulating liver de novo lipogenesis, inflammatory signaling, and bile acid composition in the gut-liver axis.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common chronic liver disease worldwide, affecting more than a quarter of the adult population. Cajanolactone A (CLA), a stilbenoid derived from Cajanus cajan, has been shown to significantly reduce hepatic lipid accumulation. However, its molecular mechanisms in MAFLD remain unclear. In this high-fat diet (HFD)-induced mice model of MAFLD, CLA significantly improved dyslipidemia, suppressed liver de novo lipogenesis by downregulating the expression of core genes and proteins involved in glycolysis and the tricarboxylic acid (TCA) cycle, and regulated SREBP-1c/ChREBP signaling to improve lipid metabolism and maintain lipid homeostasis. Furthermore, CLA markedly ameliorated the TLR4/NF-κB p65 signaling-mediated inflammatory microenvironment induced by HFD-stimulated intestinal endotoxins, increased the expression of intestinal tight junction (TJ) biomarkers Claudin-1 and ZO-1, protected intestinal barrier permeability, and enhanced intestinal immune function homeostasis, inhibited NF-κB p65/NLRP3-mediated inflammatory cascades in the liver by suppressing gut-liver axis signaling, activated liver FXR to regulate bile acid (BA) composition, thereby alleviating MAFLD. Overall, these findings suggest that CLA reduces HFD-induced MAFLD by regulating de novo lipogenesis, lipolysis, inflammatory signaling, and BA composition in the gut-liver axis, laying a scientific foundation for clinical prevention and treatment of MAFLD.