ATF5 reduces LPS-induced cardiac injury by modulating pyroptosis via mitophagy

Myocarditis, often triggered by infections such as sepsis, involves complex mechanisms including mitochondrial dysfunction, oxidative stress and inflammation. The role of activating transcription factor 5 (ATF5) in myocarditis remains unclear. This study aimed to investigate the role of ATF5 in LPS-induced cardiac injury and its potential mechanism involving mitophagy and pyroptosis. An LPS-induced septic cardiomyopathy model was established in H9c2 cardiomyocytes and rats. ATF5 was overexpressed via plasmid transfection in vitro and in vivo. Cell viability, apoptosis, inflammatory cytokine levels, oxidative stress markers, mitophagy-related proteins (LC3-II, Parkin, PINK1, p62), and pyroptosis-related proteins (NLRP3, Caspase-1, GSDMD) were assessed using CCK-8, flow cytometry, ELISA, Western blot, and biochemical assays. Autophagy inhibitor chloroquine (CQ) and GSDMD-targeted siRNA were applied to explore mechanistic interactions. The results showed that ATF5 overexpression alleviated LPS-induced cardiomyocyte injury by enhancing cell viability, reducing apoptosis, and suppressing inflammatory cytokine release (IL-1β, IL-6 and IL-18) and myocardial injury markers (CK-MB and cTn-I). ATF5 promoted mitophagy, reduced oxidative stress (ROS, LDH, GSH-Px and SOD), and inhibited pyroptosis. Mechanistically, CQ abolished the ATF5-mediated protection against cardiomyocyte injury, which was then restored by si-GSDMD. In vivo, ATF5 overexpression improved cardiac function, attenuated fibrosis and decreased serum injury markers in LPS-treated rats. In conclusion, ATF5 enhanced mitophagy, effectively cleared damaged mitochondria, reduced ROS generation, and subsequently inhibited the pyroptosis pathway, ultimately alleviating myocardial injury.