[Costunolide improves sorafenib-induced cardiomyocyte injury by inhibiting mitophagy]

This study focused on the protective effect of costunolide(COS) against sorafenib(SOR)-induced cardiomyocyte injury and its association with mitophagy. Cell viability was assessed using the CCK-8 assay. H9c2 cells were divided into six groups: control(ctrl) group, SOR group, SOR + low-dose COS(SOR+low-COS) group, SOR + high-dose COS(SOR+high-COS) group, SOR + high-COS + rapamycin group, and SOR + high-COS + adenosine monophosphate-activated protein kinase(AMPK) activator(AICAR) group, with each group receiving the respective treatments for 24 hours. Concurrently, male C57BL/6J mice were randomly assigned to six groups(10 per group): ctrl group, SOR group, SOR + low-COS group, SOR + high-COS group, SOR + high-COS + rapamycin group, and SOR + high-COS + AICAR group. Following the respective interventions, cardiac function and myocardial pathological changes were evaluated. The autophagosome formation labelled by microtubule-associated protein 1A/1B light chain 3(LC3) and the overall autophagic status, as well as the expression levels of proteins related to the AMPK/UNC-51-like autophagy activating kinase 1(ULK1)/FUN14 domain containing 1(FUNDC1) signaling pathway, were examined in both cellular and murine samples. The results demonstrated that 0-20 μmol·L~(-1) SOR significantly reduced H9c2 cell viability in a dose-dependent manner(P<0.05). Conversely, 2.5-10 μmol·L~(-1) COS dose-dependently and significantly increased the viability of SOR-treated H9c2 cells(P<0.05). Compared with the ctrl group, the SOR group exhibited notable changes in multiple indicators, including a significant increase in lactate dehydrogenase(LDH) leakage rate, LC3-related indices, and the expression levels of various autophagy-related proteins, as well as a significant decrease in mitochondrial membrane potential and p62 protein(p62) expression(P<0.05). Following COS administration, these indices were significantly reversed in the SOR+low-COS and SOR+high-COS groups(P<0.05). Further addition of rapamycin and AICAR resulted in changes opposite to those observed in the SOR+high-COS groups(P<0.05). Animal experiments exhibited a similar trend: the SOR group showed significant differences in multiple cardiac functional parameters and protein expression levels compared with the ctrl group, which were ameliorated by COS treatment. Upon further addition of rapamycin and AICAR, both cardiac functional indices and protein expression levels displayed trends opposite to those in the SOR+high-COS group(P<0.05). In conclusion, COS inhibits excessive mitophagy in cardiomyocytes and exerts a protective effect against SOR-induced cardiomyocyte injury, a mechanism potentially mediated through suppression of the AMPK/ULK1/FUNDC1 signaling pathway.