Apigenin Enhances Hepatic Lipophagy through Regulating Lipid Droplet Size via the AKT-FHL2/PPARγ-CIDEC Pathway

Large lipid droplets (LDs) resist lipophagy-mediated degradation due to steric hindrance, contributing to hepatic lipid accumulation in nonalcoholic fatty liver disease (NAFLD). Apigenin (API), a flavonoid abundant in fruits and vegetables, improves NAFLD, but its mechanism remains unclear. In this study, we found that API notably reduced LD size, thereby facilitating subsequent lipophagy. Transcriptomic analysis and validation revealed that API downregulated cell death-inducing DFF45-like effector C (CIDEC), a key promoter of LD fusion. Mechanistically, API suppressed CIDEC transcription by inhibiting four and a half LIM domains protein 2 (FHL2)-dependent nuclear translocation of peroxisome proliferator-activated receptor γ (PPARγ). Network pharmacology identified the Phosphatidylinositol 3-Kinase-Protein Kinase B (PI3K-AKT) pathway as a potential regulatory pathway. SC79-mediated AKT activation reversed API-induced LD size reduction and lipophagy enhancement. Collectively, API suppressed CIDEC expression through the AKT-FHL2/PPARγ pathway, thereby limiting LD fusion and creating better conditions for lipophagy, providing novel dietary intervention strategies for NAFLD.