Ferulic acid ameliorates metabolic dysfunction associated with fatty liver disease by regulating macrophage polarization through spermidine derived from gut microbiota

Objectives This study aimed to investigate the efficacy and mechanism of Ferulic acid (FA) in a high-fat diet (HFD)-induced murine model of Metabolic dysfunction-associated steatotic liver disease (MASLD), focusing on the gut microbiota-polyamine-macrophage polarization axis. Methods A murine MASLD model was induced with an HFD and treated with FA. We evaluated its efficacy through serological and histopathological analyses. Key mechanisms, including macrophage polarization and gut microbiota, were investigated using molecular analyses and 16S rRNA gene sequencing. The direct effect of spermidine on Kupffer cell (KC) polarization was confirmed in vitro. Key findings FA administration attenuated HFD-induced increases in body and liver weight and improved liver pathology. Mechanistically, FA treatment ameliorated gut dysbiosis, increasing beneficial genera like Akkermansia, Enterorhabdus, and Eubacterium xylanophilum, which was associated with elevated serum spermidine. Critically, FA suppressed hepatic KC M1 polarization and enhanced M2 polarization. In vitro experiments confirmed that spermidine directly mediated these immunomodulatory effects. Conclusions FA alleviates MASLD by modulating a novel gut microbiota-spermidine-macrophage axis. These findings suggest a new hepatoprotective mechanism for FA and highlight this axis as a potential therapeutic target for MASLD.