Sesamin Ameliorates High-Sugar, High-Fat Diet-Induced Hepatic Dysfunction via CYP1A2-Mediated Regulation of Lipid Metabolism and Oxidative Stress.

BackgroundHigh-sugar, high-fat diets (HSDFD) can lead to hepatic dysfunction, but the molecular mechanisms underlying protective compounds like sesamin remain unclear MethodsWe employed a multi-faceted approach combining in silico and in vivo techniques. Utilizing the AlphaFold database, we screened multi-species proteomes to identify potential sesamin targets. Molecular dynamics simulations and MM-PBSA analysis were used to characterize sesamin-protein interactions. In vivo studies included single-cell RNA sequencing of hepatocytes from HSDFD-fed mice. We validated our findings using cellular thermal shift assays (CETSA), drug affinity responsive target stability (DARTS) assays, Western blotting, and qPCR. ResultsHSDFD induced significant redistribution of hepatocyte subpopulations with high CYP1A2 abundance. Computational analysis identified CYP1A2 as a direct target of sesamin, with species-specific interaction patterns. Sesamin exhibited stable binding to CYP1A2, modulating its activity through subtle conformational changes. Key residues F451 and I386 were crucial for sesamin's regulation of CYP1A2-mediated ROS production. Sesamin supplementation ameliorated HSDFD-induced hepatic dysfunction by modulating fatty acid metabolism and oxidative stress responses. ConclusionOur study unveils CYP1A2 as a key molecular target of sesamin in HSDFD-induced hepatic dysfunction, providing new insights into potential therapeutic strategies for metabolic liver disorders.