Perilla Seed Oil Alleviates High-Fat-Diet-Induced Hyperlipidemia by Regulating Fatty Acid Metabolism via the PI3K/Akt/NOS3 Pathway

Perilla seed oil (PSO), rich in alpha-linolenic acid (ALA), has been traditionally used to relieve exterior syndrome and promote digestion, with modern studies confirming its anti-hyperlipidemic and anti-atherosclerotic properties. This study investigated the lipid-lowering effects of PSO and its underlying mechanisms in high-fat-diet-induced hyperlipidemic rats. Chemical standardization by UPLC-MS and GC-MS identified 591 compounds in PSO, with ALA accounting for 57.5% of its composition. The PSO administration significantly improved the general condition of hyperlipidemic rats, reduced body weight, lowered serum total cholesterol and LDL-C levels, and alleviated liver tissue injury and lipid accumulation. Serum metabolomics analysis revealed that PSO upregulated ALA and eicosapentaenoic acid while downregulating pro-inflammatory metabolites, including arachidonic acid, prostaglandin H2, and prostaglandin E2. Integrated network pharmacology and molecular docking studies identified the PI3K/Akt/NOS3 pathway as the primary signaling mechanism, which was further confirmed by Western blot analysis showing that PSO upregulated expression of p-PI3K, p-Akt, and NOS3 proteins. These results demonstrated that PSO-ameliorated hyperlipidemia, through PI3K/Akt/NOS3 pathway activation, coordinately modulated fatty acid metabolism and endogenous inflammatory responses. Our findings provided scientific evidence supporting PSO as a dietary intervention for managing hyperlipidemia and related metabolic disorders.