Autophagy Regulates Ferroptosis‐Mediated Diabetic Liver Injury by Modulating the Degradation of ACSL4

Abstract

Background: Diabetic liver injury is a serious complication due to the lack of effective treatments and the unclear pathogenesis. Ferroptosis, a form of cell death involving reactive oxygen species (ROS)‐dependent lipid peroxidation (LPO), is closely linked to autophagy and diabetic complications. Therefore, this study is aimed at investigating the role of autophagy in regulating ferroptosis by modulating the degradation of acyl‐CoA synthetase long‐chain family member 4 (ACSL4) in diabetic hepatocytes and its potential impact on diabetic liver injury.Methods: Initially, ferroptosis and autophagy were assessed in liver tissues from streptozotocin‐induced diabetic rats and in palmitic acid (PA)–treated LO2 cells. Subsequently, the study focused on elucidating the regulatory role of autophagy in mediating ferroptosis through the modulation of ACSL4 expression in PA‐treated LO2 cells.Results: The results demonstrated that ACSL4‐mediated ferroptosis and inhibition of autophagy were observed in diabetic hepatocytes in vivo and in PA‐treated LO2 cells. Additionally, the ferroptosis inhibitor was able to mitigate the PA‐induced cell death in LO2 cells. Mechanistically, the stability and expression level of the ACSL4 protein were upregulated and primarily degraded via the autophagy‐lysosome pathway in PA‐treated LO2 cells. The use of the autophagy inhibitor 3‐methyladenine (3‐MA) and the inducer rapamycin further demonstrated that autophagy regulated ferroptosis by mediating ACSL4 degradation, highlighting its critical role in diabetic liver injury.Conclusions: These results elucidate the roles of ferroptosis, autophagy, and their interactions in the pathogenesis of diabetic liver injury, offering potential therapeutic targets. Furthermore, they shed light on the pathogenesis of ferroptosis and other diabetic complications.