Cordycepin attenuated cyclophosphamide (CTX)-induced immunosuppression in mice via EGFR/Nrf2 antioxidant signaling pathway

Immunosuppression causing the host more vulnerable to pathogen invasion, increases the risk of malignant tumors and inflammatory diseases. Cordycepin possesses diverse pharmacological activities, including anti-inflammatory, antioxidant, and antitumor effects. However, the immunomodulatory mechanisms of cordycepin remain poorly understood. This study aimed to explore the immunoregulatory effect of cordycepin and elucidate its underlying mechanisms. In our study, cordycepin restored body weight, organ indices and ameliorated splenic damage in cyclophosphamide (CTX)-induced immunosuppressed mice. Cordycepin enhanced the proliferation of T and B lymphocytes stimulated by ConA and LPS. Cordycepin normalized the counts of white blood cells (WBC), lymphocytes (LYM), neutrophils (NEU) and eosinophils (EOS), and increased the levels of immunoglobulins (immunoglobulin A (IgA), IgM, IgG). Cordycepin also increased the production of pro-inflammatory cytokines IL-2 and IFN-γ, but decreased the level of inhibitory cytokines IL-10. Additionally, cordycepin reduced serum level of malondialdehyde (MDA), enhanced content of glutathione (GSH) and the enzymatic activities of superoxide dismutase (SOD) and catalase (CAT). Moreover, metabolomic analysis of spleen and serum revealed that cordycepin counteracted the metabolic disturbance induced by CTX, particularly regulating pyruvate metabolism pathway. Network pharmacology approaches suggested that cordycepin modulated metabolic and immune pathways by targeting EGFR. Furthermore, cordycepin reduced the protein level of phosphorylated EGFR and upregulated the protein expression of Nrf2, NQO1 and HO-1 in the spleens of immunosuppression mice. In conclusion, this study demonstrated that cordycepin ameliorated CTX-induced immunosuppression of mice by reversing metabolic dysfunction and activating Nrf2 pathway through regulating EGFR, indicating its potential as a therapeutic agent for immunosuppression.