Apigenin Reverses Cardiomyocyte Lipotoxic Injury by Regulating Autophagy Through the JNK/Beclin-1 Pathway

Background As the predominant contributor to global mortality, cardiovascular diseases (CVDs) are fundamentally driven by cardiomyocyte lipotoxicity. Purpose This study investigates the cardioprotective mechanism of apigenin through c-Jun N-terminal kinase (JNK)/Beclin-1 pathway-mediated autophagy regulation, aiming to establish novel therapeutic strategies for metabolic cardiovascular disorders. Methods Utilizing an H9c2 rat cardiomyocyte model, experimental groups were categorized as: control, apigenin (graded concentrations), palmitic acid (PA)-induced lipotoxic model, SP600125 (JNK inhibitor), RAP (mammalian target of rapamycin (mTOR) inhibitor), apigenin+3-MA (autophagy inhibitor), and apigenin+SP600125+3-MA groups. Comprehensive assessments included cell viability, apoptosis, oxidative stress markers, and immunoblotting of AMP-activated protein kinase (AMPK)/mTOR signaling components (AMPK, p-AMPK, mTOR, p-mTOR) along with apoptosis/autophagy regulators (Beclin-1, Bcl-2, Bax, cleaved caspase-3). Results PA administration induced dose-dependent cardiomyocyte damage, evidenced by suppressed viability. After 24 h of PA treatment, intracellular reactive oxygen species levels increased significantly, malondialdehyde content increased, and superoxide dismutase activity decreased accordingly. Apigenin treatment (50 µM) effectively attenuated these abnormalities by activating the JNK/Beclin-1 pathway, and the validation experiment confirmed that apigenin activated this pathway to mediate autophagy. Conclusion Our findings elucidate that apigenin mitigates lipid-overload cardiomyocyte injury by potentiating JNK/Beclin-1-mediated autophagic clearance, providing the first evidence of apigenin’s dual regulatory capacity in harmonizing lipid homeostasis and autophagic flux, advancing phytochemical-based therapeutics for metabolic CVDs. However, future studies are required to evaluate whether it plays similar roles in cardiomyocyte injury in patients with CVDs.