KI-696

Myocardial ischemia/reperfusion (MI/R) injury is a major cause of adverse outcomes after acute myocardial infarction. Ferroptosis is an iron-dependent and lipid-peroxidation-driven form of cell death implicated in this injury. However, the regulatory role of long non-coding RNAs (lncRNAs) in this process remains unclear. Here, we investigated whether the lncRNA OIP5 antisense RNA 1 (Oip5-as1) modulates ferroptosis during MI/R. A cardiomyocyte-specific Oip5-as1 knockout mouse was generated using CRISPR/Cas9 technology combined with the Cre-LoxP system. Isolated hearts were then exposed to MI/R in a Langendorff perfusion apparatus. Compared with floxed controls, Oip5-as1-deficient hearts exhibited impaired hemodynamic parameters, larger infarcts, more severe histopathological damage, and marked mitochondrial disruption, as determined by Langendorff system analysis, triphenyltetrazolium chloride staining, hematoxylin-eosin staining, and transmission electron microscopy, respectively. These structural and functional deficits were accompanied by elevated ferrous iron levels, increased lipid peroxidation, reduced antioxidant capacity, upregulation of the ferroptosis driver ACSL4, and downregulation of the ferroptosis suppressors FTH1, SLC7A11, and GPX4. Administration of the selective ferroptosis inhibitor Ferrostatin-1 restored antioxidant capacity, normalized the expression of ferroptosis-related proteins, and significantly reduced infarct size and cardiac functional impairment in Oip5-as1-deficient hearts. Mechanistic analyses revealed that Oip5-as1 deletion suppressed the p62/KEAP1/NRF2 signaling pathway, whereas disruption of KEAP1-NRF2 binding with KI696 reactivated NRF2 signaling and reinstated resistance to ferroptosis. Collectively, these findings demonstrate that Oip5-as1 limits MI/R injury by sustaining p62/KEAP1/NRF2-mediated suppression of ferroptosis. Furthermore, Oip5-as1 is identified as a promising therapeutic target for cardioprotection.