MALAT1 mitigates cardiac ischemia-reperfusion injury by regulating ER stress and mitophagy

Background Myocardial ischemia-reperfusion injury (MI/RI) involves endoplasmic reticulum stress (ERS) and mitochondrial impairment, but the role of LncRNA MALAT1 in this context is unclear. Method H9c2 cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) following MALAT1 knockdown via siRNA. Mitochondrial morphology was assessed by Transmission Electron Microscopy (TEM). Oxidative damage was evaluated by measuring reactive oxygen species (ROS), mitochondrial membrane potential (TMRE), ATP, and ferrous iron (Fe 2+ ). Apoptosis was analyzed by flow cytometry and TUNEL. ERS and mitophagy proteins were detected by Western blot. In vivo, a murine MI/RI model was established by left anterior descending coronary artery occlusion, with MALAT1 siRNA administered intravenously 24 h pre-surgery. Result MALAT1 deficiency exacerbated mitochondrial dysfunction in the H/R model, evidenced by cristae damage, vacuolization, increased Cytochrome c release, and reduced PGC-1α. ERS markers (ATF6, BiP), ROS, and Fe 2+ accumulation were elevated, leading to apoptosis. Conversely, MALAT1 mitigated these effects. In the murine MI/RI model, MALAT1 was upregulated in damaged myocardium, and its knockdown reversed the pathological state, reducing ERS and mitochondrial dysfunction. Mechanistically, MALAT1 suppressed the PERK/IRE1α/ATF6 cascade while promoting PGC-1α-mediated mitochondrial stabilization. Conclusion These findings suggest that MALAT1 may protect against MI/RI by attenuating ER stress and preserving mitochondrial homeostasis, at least in part through modulation of the PERK/IRE1α/ATF6 pathway and PGC-1α-associated mitochondrial stabilization. Further mechanistic studies are warranted to establish direct causality.