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Icariin rescues immune dysfunction in sepsis through RSK2-driven YAP-cGAS-IFN-β signaling activation.

Yuran Huang,Fupeng Wu,Tianle Zhan,Xinyue Cao,Weilian Bao,Guize Feng,Jiahui Ni,Yirui Wang,Haidong Li,Tongqing Chen,Keyuan You,Dong Wang,Xiao Shen,Keyu Sun

Published 2025 in Phytomedicine

ABSTRACT

BACKGROUND Sepsis frequently leads to an immunosuppressive phase with high risk of secondary infection and mortality. Icariin (ICA) exhibits various bioactivities, yet its role in sepsis-induced immunosuppression is unclear. PURPOSE This study aimed to investigate the therapeutic potential of ICA against sepsis-induced immunosuppression and its molecular mechanism. STUDY DESIGN Combined experimental approach using both a septic mouse model with secondary infection and an endotoxin-tolerant macrophage model. METHODS Sepsis was induced by cecal ligation and puncture (CLP), followed by secondary Pseudomonas aeruginosa (PA) challenge. ICA was administered at doses of 45, 90, and 180 mg/kg once daily for 8 consecutive days (i.g.), starting at 4 days after CLP surgery. Survival, organ injury, bacterial load, and macrophage polarization were assessed. In vitro, bone marrow-derived macrophages (BMDMs) were rendered endotoxin-tolerant via LPS stimulation. Phagocytosis, bacterial killing, and molecular pathways were examined via qPCR, Western blot, co-IP, and docking. RESULTS ICA significantly improved survival, reduced organ damage and bacterial load, and increased M1/M2 ratio in mice. In vitro, ICA enhanced phagocytosis and bactericidal function. Mechanistic studies have identified RSK2 as a target of ICA. Specifically, ICA binds to its target RSK2, which in turn promotes the phosphorylation and degradation of YAP. Consequently, the inhibitory effect of YAP on cGAS is attenuated, thereby upregulating the expression of IFN-β through the TBK1-IRF3 pathway and activating Stat1/2 signaling. CONCLUSION ICA alleviates sepsis-induced immunosuppression and enhances antibacterial immunity via the RSK2-YAP-cGAS-IFN-β pathway, indicating its therapeutic potential for secondary infections.

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