Cajanstilbenoid A from Pigeon Pea: A Functional Food Component for Managing High-Fat Diet-Induced Hepatic Steatosis via PPARα Activation

Pigeon pea ( Cajanus cajan (L.) Millsp.), a plant with documented safety and dual use in food and traditional medicine, holds promise for developing hepatoprotective agents. This study aimed to evaluate its potential to mitigate high-fat diet (HFD)-induced hepatic steatosis. We investigated a stilbene-enriched extract (EX) from pigeon pea leaves and its major constituent, cajanstilbenoid A (CSA). In HFD-fed mice, both EX and CSA significantly reduced body weight, liver index, lipid accumulation and serum cholesterol/triglyceride levels. CSA also ameliorated oxidative stress and improved liver function markers. Mechanistic studies revealed that CSA acted as a selective agonist of peroxisome proliferator-activated receptor alpha (PPARα): Network pharmacology, transcriptomics, and molecular docking predicted PPARα as a target; this was confirmed by cellular thermal shift assay (CETSA), drug affinity responsive target stability assays (DARTS) and surface plasmon resonance (SPR), which demonstrated direct binding. Crucially, siRNA-mediated knockdown of PPARα in HepG2 cells abolished the lipid-lowering effects of CSA. Our findings demonstrated that CSA alleviated HFD-induced hepatic steatosis primarily by activating the PPARα pathway, reducing oxidative stress and promoting lipid metabolism. This study highlighted the therapeutic potential of CSA for non-alcoholic fatty liver disease and underscored pigeon pea as a valuable medicinal and edible resource.