α-Tocopherol Alleviates Lipotoxicity in Hepatocytes by Rejuvenating Mitochondrial Quality, Underlying the Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)-Counteracting Efficacy of Moringa oleifera Leaves in Mice

Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a leading liver disease and lacks effective drugs or therapies. Moringa oleifera leaves (MOL) offer metabolic benefits, but their active components and precise mechanisms against MASLD are unclear. Phytochemical isolation of MOL extract (MOLE) identified α-tocopherol (TCP) as a key constituent. TCP dose-dependently ameliorated PA-induced lipotoxicity in hepatocytes, mirroring the protective effects of MOLE against MASLD in HFC diet-fed mice. Mechanistically, TCP mitigated PA-induced mitochondrial fragmentation and oxidative stress. These effects were accompanied by improvements in the levels of mitochondrial dynamics and mitophagy regulators in PA-treated hepatocytes or the livers of MOLE-treated HFC mice, including DRP1, MFN2, OPA1, PINK1, and Parkin. This restoration of mitochondrial quality emerged as a central mechanism involving the lipotoxicity-ameliorating effects of TCP, underlying the anti-MASLD action of M. oleifera in mice. These findings provide a mechanistic basis for using MOL and TCP in managing metabolic disorders, including MASLD.