Capsaicinoid Glucoside Attenuates Lipid Accumulation in HepG2 Cells Through TRPV1/AMPK‐Dependent Signaling Pathway

Metabolic disorders associated with excessive lipid accumulation pose a significant global health challenge. Capsaicinoid glucoside (CG), a novel water-soluble derivative of capsaicin, offers improved bioavailability and reduced pungency. In this study, we evaluated the lipid-lowering effects of CG and its underlying mechanisms in oleic acid (OA)-induced HepG2 cells. Treatment with 100 μg/mL CG significantly reduced triglyceride (TG) levels by 60.7% and total cholesterol (TC) levels by 34.4%, compared to the OA group. CG also markedly decreased intracellular reactive oxygen species (ROS) and reduced lipid droplet accumulation, as confirmed by Oil Red O staining. At the molecular level, CG significantly upregulated TRPV1 and AMPK gene and protein expression, while downregulating lipogenic markers such as SREBP-1c and FASN. It also increased the expression of lipid oxidation-related genes, including PPARδ. Molecular docking revealed stable interactions of CG with both TRPV1 and AMPK, supporting their roles in the observed metabolic effects. These findings suggest that CG exerts its lipid-lowering and antioxidant effects via the TRPV1/AMPK signaling pathway and highlight its potential application as a functional food component or therapeutic supplement for improving hepatic lipid metabolism.