Inhibition of Lipid peroxidation by ALR protects the kidney from ischemia-reperfusion injury

Abstract Background Ferroptosis, characterized by lipid accumulation in intracellular compartments, is related to acute kidney injury (AKI), but the mechanism remains obscure. In our previous study, we reported important roles for augmenter of liver regeneration (ALR) in antioxidant mechanisms. However, the roles of ALR in ferroptosis, especially the morphological changes in mitochondria induced by this type of regulated cell death, remain unclear and warrant further investigation. Methods We subjected Kidney-specific deletion of the ALR gene (ALR-K-KO), as well as HK-2 cells, to ischemia-reperfusion (I/R) induced AKI models. We assessed the kidney function and ferroptosis of proximal tubular epithelial cells. We also examined the level of lipid peroxidation by MS/MS. ALR and Long chain acyl-CoA synthetase 4 (ACSL4) were colocalized and interacting regions were detected by protein docking-analyses. Results Here, we hypothesize that ALR regulates oxylipin accumulation in proximal tubular cells and attenuates ferroptosis induced by ischemia-reperfusion (I/R) injury in AKI. Kidney-specific deletion of the ALR gene (ALR-K-KO) aggravated ferroptosis, accompanied by increased ROS production and mitochondrial damage, whereas overexpression of the ALR gene attenuated lipid accumulation. Moreover, acsl4 loss reduced mostly polyunsaturated fatty acids. In addition, ALR and ACSL4 colocalize in the mitochondria of HK-2 cells and protein docking analysis found the interacting regions. Conclusion We showed for the first time that ALR binds to ACSL4 and regulates ferroptosis in proximal tubular cells by attenuating oxylipin accumulation.