Front Biosci (Landmark Ed). 2026 Apr 20;31(4):50047. doi: 10.31083/FBL50047.
ABSTRACT
BACKGROUND: Luteolin, a natural flavonoid, is an active ingredient in traditional herbs used to treat cardiovascular diseases. However, little is known about the effects of luteolin on oxidative damage in cardiomyocytes, and the underlying mechanisms remain poorly understood. Therefore, this study aimed to investigate the protective effects of luteolin against hydrogen peroxide (HO)-induced mitophagy and apoptosis in cardiomyocytes.
METHODS: H9c2 cells were exposed to HO for 4 h, which caused severe cellular damage accompanied by apoptosis. The protein expression of β-actin, FK506 binding protein 12, mammalian target of rapamycin (mTOR), acetyl-coenzyme A carboxylase alpha (ACC), sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae) (SIRT1), peroxisome proliferator-activated receptor gamma, coactivator 1-alpha (PGC-1α), autophagy-related 5 homolog (S. cerevisiae) (ATG5), microtubule-associated protein 1 light chain 3 beta (LC3B), B-cell lymphoma 2 (BCL2)-associated X protein (Bax), B-cell leukemia/lymphoma 2 (Bcl-2), PTEN-induced putative kinase 1 (PINK1), and peroxisome proliferator-activated receptor gamma (PPARγ) was analyzed by Western blotting. Intracellular reactive oxygen species (ROS) levels were assessed using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining (DCFH) oxidation staining. The expressions of phosphorylated AMP-activated protein kinase alpha (p-AMPKα), SIRT1, and caspase 8 were evaluated by immunofluorescence. Mitochondrial membrane potential and mitochondrial permeability transition pore (MPTP) opening were assessed using 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide (JC-1) staining and an MPTP assay kit, respectively.
RESULTS: HO treatment significantly reduced the viability of H9c2 cardiomyocytes and induced mitochondrial apoptosis. Furthermore, HO upregulated the expression of p-AMPK, SIRT1, mTOR, ACC, and PGC-1α, while downregulating PPARγ expression. Concurrently, HO activated mitophagy, suggesting involvement of the AMPK/mTOR signaling pathway. Notably, pretreatment with luteolin effectively reversed these HO-induced alterations by attenuating excessive ROS production, inhibiting MPTP opening, and normalizing the Bcl-2/Bax ratio and caspase 8 expression. Additionally, luteolin suppressed the HO-induced upregulation of proteins associated with the AMPK/mTOR signaling axis, mitophagy, and apoptosis.
CONCLUSIONS: These findings suggest that luteolin protects H9c2 cells from mitochondria-mediated apoptosis by modulating the AMPK/mTOR signaling pathway and inhibiting excessive mitophagy. Moreover, these results suggest that luteolin has potential as a therapeutic agent for preventing and treating cardiovascular diseases.
PMID:42052839 | DOI:10.31083/FBL50047