Here, we demonstrated that administration of oroxylin A during the middle or late stages of sepsis induces the transcription of the E3 ligase fbxo15, which remains at a extremely low level in the absence of oroxylin A. Activated FBXO15 binds to CHOP and further induces CHOP degradation through the proteasome pathway, and further resuming the production of pro-inflammatory factors, eventually alleviating the immunoparalysis of CLP mice. The gene discussed is DDIT3; the disease is Sepsis.