Fxyd5 downregulation protects the heart from ischemia/reperfusion injury by suppressing myocardial inflammation

Background Myocardial ischemia/reperfusion (I/R) injury is a common cause of death. FXYD domain-containing ion transport regulator-5 (Fxyd5) is a type I membrane protein that plays a significant role in mediating cellular functions. However, the expression and function of Fxyd5 in myocardial I/R injury remain unclear. Methods Male C57BL/6 mice (8–10 weeks) were subjected to myocardial I/R by ligating the left anterior descending coronary artery. Preventive intervention was performed using adeno-associated virus 9 (AAV9)-mediated Fxyd5 knockdown. An in vitro hypoxia/reoxygenation (H/R) in H9c2 cardiomyoblasts was used for validation. Results Myocardial I/R injury significantly upregulated Fxyd5 expression ( p  < 0.01). Silencing Fxyd5 markedly improved cardiac function, as evidenced by a 58.0 % increase in EF ( p  < 0.01) and a 54.5 % reduction in infarct size ( p  < 0.01). Fxyd5 knockdown also attenuated myocardial apoptosis and inflammation, demonstrated by decreased cleaved caspase-3 expression and reduced levels of IL-6 (−44.2 %) and TNF-α (−42.7 %) ( p  < 0.01). Mechanistically, Fxyd5 silencing suppressed NF-κB activation, and these protective effects were confirmed in vitro in H/R-treated cardiomyocytes. Conclusion Fxyd5 silencing significantly attenuated I/R-induced myocardial injury, reduced infarct size, and improved cardiac function, while also decreasing apoptosis and inflammatory cytokine expression ( p  < 0.01). These findings indicate that Fxyd5 contributes to the pathogenesis of myocardial I/R injury and that its inhibition confers cardioprotective effects, partly through suppression of the NF-κB pathway.