Integrated Multi-Omics Analysis Reveals the Regulatory Mechanism of Peanut Skin Procyanidins on Lipid Metabolism in High-Fat-Diet-Induced Obese Mice

<b>Background</b>: Obesity-associated metabolic disorders represent a critical global health challenge, which necessitates innovative strategies targeting lipid metabolism. Peanut skin procyanidins (PSPs), abundant bioactive compounds derived from agricultural by-products, show potential in lipid regulation, but molecular mechanisms remain unclear. <b>Methods</b>: This study integrated hepatic metabolomics, network pharmacology, and gut microbiota analysis to systematically decipher the mechanisms for PSP to ameliorate high-fat diet (HFD)-induced lipid metabolism disorders. <b>Results</b>: PSP intervention significantly attenuated HFD-induced increases in LDL-C, TG, and TC levels and effectively mitigated hepatic lipid accumulation. Metabolomics revealed that PSP reshaped hepatic lipid dynamics by modulating glycerophospholipid, linoleic acid, arachidonic acid, tryptophan, and nitrogen metabolism. Subsequent network pharmacology identified <i>PLA2G10</i>, <i>PLA2G5</i>, <i>PLA2G2A</i>, and <i>CYP1B1</i> as the core targets, and PSP could markedly suppress their HFD-induced overexpression. Furthermore, PSP selectively reshaped the gut microbiota, enriching beneficial genera such as <i>Akkermansia</i> and <i>Bacteroides</i> while reducing the abundance of harmful bacteria within Firmicutes. PICRUSt-based functional prediction indicated that PSP alters gut microbial glutamine synthetase activity. <b>Conclusions</b>: Mechanistically, PSP regulates lipid metabolism by downregulating <i>PLA2G10</i>, <i>PLA2G5</i>, <i>PLA2G2A</i>, and <i>CYP1B1</i> expression, remodeling gut microbiota structure, and increasing hepatic glutamine level. These findings provide novel insights into value-added utilization of agricultural byproducts and development of targeted intervention strategies for metabolic diseases.