Sigma-1 receptor protects against renal ischemia-reperfusion injury by enhancing mitophagy via Rac1 regulation

Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury, associated with mitochondrial dysfunction, excessive reactive oxygen species (ROS) production, and tubular cell apoptosis. The Sigma-1 receptor (Sigma1R), an intracellular chaperone, plays a crucial role in maintaining mitochondrial homeostasis and promoting cellular survival. In this study, we found that Sigma1R expression was significantly downregulated in renal IRI. Overexpression of Sigma1R alleviated renal dysfunction, reduced apoptosis, stabilized mitochondrial membrane potential, and attenuated ROS accumulation. Mechanistically, Sigma1R modulated Rac1 activity and enhanced PINK1/Parkin-mediated mitophagy, which facilitated the removal of damaged mitochondria and the restoration of mitochondrial quality control. In vitro, similar protective effects were observed in HK-2 cells subjected to hypoxia/reoxygenation (H/R) injury. These findings demonstrate that Sigma1R exerts its renoprotective effects by regulating Rac1-mediated mitophagy and improving mitochondrial function, thereby highlighting Sigma1R as a promising therapeutic target for preventing and treating renal IRI.