Sesaminol Ameliorates Metabolic and Alcohol‐Related Liver Injury by Activating the PPARα/Slc27a5 Axis‐Driven Hepatic Fatty Acid β‐Oxidation

Hepatic diseases pose a major and life-threatening global health challenge. Sesaminol, a sesame-seed lignan with antioxidant and anti-inflammatory properties, was investigated for its ability to combat metabolic dysfunction-associated fatty liver disease (MAFLD) and alcohol-related liver injury. Mice fed a high-fat diet (HFD) or subjected to binge alcohol injury received oral sesaminol to evaluate its protective effects against hepatic dysfunction. Complementary in vitro studies used HepG2 cells to delineate the potential mechanism. Sesaminol reduced body-weight gain, enhanced glucose tolerance and insulin signaling, lowered hepatic and serum lipid accumulation, and attenuated the inflammatory response in mice. Moreover, sesaminol dose-dependently reduced triglyceride (TG) accumulation and suppressed pro-inflammatory cytokines in vitro. Transcriptomic and docking analyses identified peroxisome proliferator-activated receptor alpha (PPARα) as a direct sesaminol target and revealed solute carrier family 27 member 5 (Slc27a5) as a novel downstream gene. Sesaminol enhanced PPARα occupancy on the Slc27a5 promoter, increased fatty acid uptake, and restored mitochondrial β-oxidation flux. Therefore, sesaminol may function as a natural PPARα agonist that links fatty acid import to mitochondrial oxidation via Slc27a5, thereby ameliorating hepatic steatosis and inflammation in both metabolic and alcohol-related liver dysfunction.