Baicalein attenuates metabolic dysfunction-associated steatohepatitis by regulating macrophage ferroptosis through nuclear factor (erythroid-derived 2)-like 2 pathway

Ferroptosis, an iron-dependent cell death form, has recently been implicated in the development of metabolic dysfunction-associated steatohepatitis (MASH). Baicalein has demonstrated potential benefits in the prevention and treatment of liver diseases. However, the mechanisms by which baicalein ameliorates hepatic ferroptosis in MASH remain inadequately understood. In this study, we established a mouse model of MASH induced by Western diet (WD) feeding. Our findings indicate that baicalein treatment ameliorated metabolic abnormalities and inhibited the progression of MASH in mice. Most importantly, baicalein supplementation significantly restored iron homeostasis in the liver, mitigating disorders such as iron overload and ferritin transport Additionally, baicalein reduced WD-induced hepatic lipid peroxidation. The protective effects of exogenous baicalein on ferroptosis were also observed in free fatty acid (FFA)-treated Raw264.7 cells. Mechanistically, macrophage, rather than hepatocyte, were implicated in the effect of baicalein. Furthermore, baicalein treatment inhibited WD or FFA-induced M1 polarization while activating the nuclear factor (erythroid-derived 2)-like 2/ferroptosis suppressor protein 1 (Nrf2/FSP1) signaling pathway. Collectively, these findings suggest that exogenous baicalein inhibits hepatic ferroptosis in MASH by promoting M2 polarization of macrophage through the Nrf2/FSP1 pathway, establishing that baicalein as a promising candidate drug for the treatment of hepatic ferroptosis in MASH.