Aldometanib attenuates OGD/R-induced cardiomyocyte injury via mitigation of mitochondrial dysfunction

Myocardial ischemia-reperfusion injury (MIRI) is a secondary condition following the reestablishment of blood flow to the heart, resulting in myocardial damage such as cardiomyocyte death, ferroptosis, fibrosis, and hypertrophy. However, there is still a lack of targeted therapeutic drugs to date.Aldometanib is a newly developed activator of AMP-activated protein kinase (AMPK) located on the lysosomal membrane, which exhibits significant pharmacological potential. Nevertheless, its role in MIRI remains incompletely understood.

This study assessed aldometanib's impact on myocardial ischemia-reperfusion injury using H9c2 and AC16 cardiomyocyte lines as in vitro models.

Experimental data demonstrated that aldometanib promoted cardiomyocyte proliferation, reduced oxidative stress, and alleviated inflammatory responses. Furthermore, we identified that aldometanib could inhibit ferroptosis in cardiomyocytes. Mechanistically, our investigations revealed that aldometanib exerted a cardioprotective effect by alleviating cardiomyocyte damage through the regulation of mitochondrial function. Specifically, aldometanib enhanced mitophagy by activating lysosomal AMPK. Additionally, we found that aldometanib exerted an antioxidant effect via Nrf2, thereby mitigating ferroptosis. In animal models, we preliminarily confirmed that aldometanib treatment attenuated tissue damage and functional impairment following myocardial ischemia-reperfusion, further supporting its therapeutic potential.

This study uncovers the protective effect of aldometanib against MIRI and its underlying mechanism, providing experimental evidence and a potential candidate drug for targeting MIRI.