Abstract: Objective: To investigate the protective effect and mechanism of docosahexaenoic acid-enriched phosphatidylserine (DHA-PS) against cyclophosphamide (CTX)-induced renal injury in mice. Methods: Thirty-two male institute of cancer research (ICR) mice were randomly divided into four groups: control (CON), model (MOD), 50 mg/kg mb DHA-PS (50 DHA-PS), and 100 mg/kg mb DHA-PS (100 DHA-PS), with eight mice in each group. The renal injury model was established by intraperitoneal injection of 80 mg/kg mb CTX. Five days later, the mice in the MOD and DHA-PS groups were gavaged for 7 days with an equal volume of physiological saline and DHA-PS, respectively and then sacrificed. Kidney indexes, serum biochemical indicators, the levels of renal oxidative stress and inflammatory factors, histopathological changes, and non-targeted metabolomics of renal tissues were evaluated. Results: Compared with the MOD group, DHA-PS significantly decreased kidney indexes, creatinine, blood urea nitrogen, cystatin C, and kidney injury molecule-1 levels (P < 0.05), increased the activities of antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) (P < 0.05), reduced the content of malondialdehyde (MDA) (P < 0.05), downregulated the expression of pro-inflammatory cytokines including interleukin (IL)-6, IL-1β, tumor necrosis factor-α (P < 0.05), and upregulated the level of the anti-inflammatory cytokine IL-10 (P < 0.05). Staining results showed a significant restoration of kidney tissue structure in the DHA-PS group. Additionally, the results of renal tissue metabolomics indicated that DHA-PS mitigated CTX-induced metabolic disorders in mouse kidneys mainly by affecting glycerophospholipid metabolism, purine metabolism, and their metabolites. Conclusion: DHA-PS can alleviate CTX-induced renal injury in mice through reducing oxidative stress and inflammatory response, and regulating the glycerophospholipid and purine metabolism pathways.

Key words: cyclophosphamide; docosahexaenoic acid-enriched phosphatidylserine; kidney injury; metabolomics; ameliorative effect