Eur J Pharmacol. 2026 Mar 31:178832. doi: 10.1016/j.ejphar.2026.178832. Online ahead of print.
ABSTRACT
Krüppel-like factor 5 (KLF5) plays a critical role in various cardiovascular diseases. Previous studies have shown that KLF5 promotes oxidative stress and apoptosis, thereby exacerbating myocardial remodeling. However, its specific role in myocardial ischemia/reperfusion (I/R) injury remains poorly understood. In this study, we investigated the effects of KLF5 in cardiomyocytes using both in vivo and in vitro models of myocardial I/R injury. Mice were subjected to myocardial I/R, and neonatal rat cardiomyocytes (NRCs) were treated with hypoxia/reoxygenation (H/R). We observed that KLF5 expression was significantly upregulated in the hearts of I/R mice and in H/R-treated cardiomyocytes during the early phase. Cardiac-specific knockdown of KLF5 attenuated myocardial injury in I/R mice, reduced apoptosis, and decreased reactive oxygen species (ROS) production in H/R-treated cardiomyocytes. Similar protective effects were observed following administration of a KLF5 inhibitor ML264. Notably, autophagic flux was impaired during I/R, whereas cardiac-specific KLF5 downregulation restored autophagic flux in I/R mice. Mechanistically, KLF5 knockdown reduced myocardial infarct size and improved cardiac function in vivo by restoring autophagic flux, and these effects were abolished by treatment with Bafilomycin A1 (Baf). Furthermore, cardiac-specific KLF5 downregulation alleviated mitochondrial damage, inhibited cardiomyocyte apoptosis in I/R mice, and reduced ROS accumulation in NRCs exposed to H/R through restoration of autophagic flux. In conclusion, our findings demonstrate that cardiac-specific downregulation of KLF5 protects against myocardial I/R injury by restoring autophagic flux, thereby suppressing apoptosis and facilitating the clearance of damaged mitochondria. These results highlight KLF5 as a potential therapeutic target for mitigating myocardial ischemia/reperfusion injury.
PMID:41933871 | DOI:10.1016/j.ejphar.2026.178832