Docosahexaenoic acid-acylated astaxanthin esters alleviate cisplatin-induced acute kidney injury by modulating the ferroptosis-related GPX4/xCT signaling pathway and reducing oxidative stress

Abstract Acute kidney injury (AKI) can be caused by various factors, such as renal ischemia and hypoxia, drug toxicity, and malnutrition, leading to a rapid decline in renal function, abnormal nitrogen metabolism, or reduced urine output. Previous studies have reported that astaxanthin (AST) has positive effects on the kidneys, and the main form of docosahexaenoic acid-acylated astaxanthin esters (AST-DHAs) widely found in seafood is astaxanthin monoesters acylated with docosahexaenoic acid (AST-DHA) and astaxanthin diesters acylated with docosahexaenoic acid (AST-2DHA). In this study, we successfully prepared AST-DHAs through enzymatic/chemical methods and constructed a mouse model of cisplatin-induced AKI to explore the impact of AST-DHAs on AKI. The experimental results are interesting: compared with the model group, AST-DHA treatment showed strong efficacy. It not only significantly enhanced the renal function of mice and significantly reduced urea nitrogen and creatinine levels but also significantly reduced pathological damage and oxidative stress. Moreover, AST-DHA treatment significantly upregulated the expression of the ferroptosis core protein, glutathione peroxidase 4, and the cystine/glutamate transporter. Further metabolomic analysis revealed that AST-DHAs can regulate the related changes in mice caused by AKI and effectively improve the AKI status of mice by inhibiting ferroptosis. These results strongly indicate that AST-DHAs are potential therapeutic adjuvants for alleviating AKI, providing a new direction and hope for the treatment of AKI.