Cordycepin alleviates oxaliplatin-induced fatty liver disease

Abstract

Aim: Oxaliplatin (OXA), a cornerstone chemotherapeutic agent for malignant tumors, can induce hepatic steatosis, inflammation, and fibrosis, meeting the criteria for drug-induced fatty liver disease (DIFLD). However, OXA-induced DIFLD lacks a clear definition and effective interventions. Therefore, our study aimed to verify the OXA-DIFLD link and explore cordycepin’s protective role in DIFLD.

Methods: (1) A retrospective analysis was conducted to compare the degrees of hepatic inflammation, fibrosis, and steatosis among 161 patients with colorectal cancer liver metastasis in the OXA chemotherapy (OCG) and non-chemotherapy (NCG) groups; (2) Fifteen mice were randomly allocated into Control, OXA, and OCordy (OXA + cordycepin) groups. The OXA and OCordy groups received OXA (8 mg/kg, 3 days) injections to induce acute DIFLD; the OCordy group additionally received oral cordycepin (100 mg/kg, 6 days). Liver injury across the three groups was assessed via hepatic pathology, serum biochemical indicators, and oxidative stress markers; (3) Untargeted metabolomics and Data-Independent Acquisition (DIA) proteomics were conducted across the three groups to clarify OXA-induced liver injury mechanisms and pinpoint targets for cordycepin intervention.

Results: (1) Clinical investigations demonstrated markedly elevated hepatic inflammation, fibrosis, and steatosis in the OCG group compared with the NCG group; (2) Animal experiments showed that OXA induced hepatic dysfunction, lipid accumulation, and oxidative stress, which were mitigated by cordycepin; (3) Multi-omics analyses revealed that OXA disrupted lipid metabolism and oxidative stress pathways, whereas cordycepin restored homeostasis by modulating arginine biosynthesis and bile secretion and suppressing α-ketoglutarate levels.

Conclusion: This study characterized OXA-induced DIFLD and validated cordycepin’s protective effects via the α-ketoglutarate-arginine/bile acid axis, offering a foundation for treating OXA-induced liver injury.

Keywords

Oxaliplatin / drug-induced fatty liver disease / cordycepin / malignant neoplasm / liver injury

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