Role of IFI204 in Modulating NF-ΚB Pathway and Myocardial Protection in Ischemia-Reperfusion Injury

Ischemia-reperfusion (I/R) injury remains a major contributor to myocardial damage, significantly impacting cardiovascular morbidity and mortality. This study identifies key genes and pathways involved in I/R-induced myocardial injury through differential gene expression analysis and weighted gene co-expression network analysis. Functional enrichment analyses, including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Disease Ontology, highlight the involvement of immune response and oxidative stress pathways in I/R injury. Machine learning approaches, such as LASSO, Support Vector Machine Recursive Feature Elimination, and Random Forest, were employed to identify feature genes predictive of I/R progression, with Ifi204 emerging as a critical factor. The role of interferon-induced protein 204 (Ifi204) in myocardial protection during I/R injury was further explored using a heart-specific Ifi204 knockout mouse model. The effects of Ifi204 deficiency on myocardial injury, inflammation, and oxidative stress were assessed. Notably, heart-specific Ifi204 knockout mice demonstrated reduced myocardial infarct size, improved heart function, and lower serum markers of myocardial injury, including creatine kinase, lactate dehydrogenase, and cardiac troponin T. These mice also exhibited attenuated oxidative stress and suppressed NF-κB signaling, as evidenced by reduced malondialdehyde levels and increased superoxide dismutase activity. Furthermore, overexpression of Ifi204 in primary cardiomyocytes enhanced the inflammatory response via NF-κB activation, leading to increased secretion of proinflammatory cytokines, such as TNF-α and IL-6. These effects were mitigated by NF-κB inhibition, suggesting that Ifi204 modulates inflammation through NF-κB signaling. This study provides new insights into the molecular mechanisms underlying myocardial I/R injury and positions Ifi204 as a potential therapeutic target for cardiovascular diseases.