Silencing of HAVCR2 Attenuates Skeletal Muscle Ischemia-Reperfusion Injury by Inhibiting Oxidative Stress.

Skeletal muscle ischemia-reperfusion (IR) injury is a common clinical condition associated with oxidative stress and inflammation that leads to muscle damage and multi-organ failure. However, the molecular mechanisms underlying its pathogenesis remain incompletely understood. R software and the limma package were used to analyze mRNA expression profiles from the GSE275811 dataset. Hub genes were identified using the protein-protein interaction (PPI) network, support vector machine-recursive feature elimination (SVM-RFE), and least absolute shrinkage and selection operator (LASSO) regression analysis, and their diagnostic performances were assessed using receiver operating characteristic (ROC) curves. The roles of hepatitis A virus cellular receptor 2 (HAVCR2) were explored in IR-induced Sprague-Dawley rat models and in vitro hypoxia-reoxygenation (HR)-treated human umbilical vein endothelial cells (HUVECs). A total of 188 differentially expressed genes (DEGs) were screened, primarily enriched in pathways associated with immune responses and inflammation regulation. CX3CR1, HAVCR2, IL1B, LYZ2, and PTPRC were identified as key genes with potential to distinguish between normal and IR samples. HAVCR2 silencing alleviated rat muscle fiber disruption, inflammatory infiltration, and oxidative stress, with reduced levels of ROS, MDA, IL-6, and TNF-α and elevated levels of GSH, SOD, MnSOD, and CAT. Similarly, HAVCR2 knockdown conferred protective effects in HUVECs subjected to HR injury, improving cell viability, enhancing migratory ability, and restoring antioxidant defenses. HAVCR2 knockdown inhibited oxidative stress in the skeletal muscle IR, suggesting that targeting HAVCR2 represents a promising therapeutic strategy for skeletal muscle IR injury.