Enhancer of zeste homolog (EZH2) is a potential target in treatment of sepsis. The current study is aimed to screen a novel EZH2 degrader agent based on the Traditional Chinese Medicine Database YaTCM. This may provide an important clue for development of new drugs to treat sepsis-associated encephalopathy (SAE).Macrophage-specific EZH2 knockout mice were used to observe the effects of EZH2 on the survival rate, levels of inflammatory cytokines, S100B, CD86, and CD206 in sepsis mice. Sigmoidin B was screened as the novel EZH2 degrader based on the structure of MS177 using large-scale virtual high-throughput screening. Molecular dynamics simulations and MMGBSA analysis were used to assess the stability and binding characteristics of Sigmoidin B. The protective effect of MS177 and the novel EZH2 degrader were verified using in vivo and vitro experiments.Macrophage-specific knockout of EZH2 had been shown to enhance the survival rate in mice with sepsis, reduce levels of CD86 and TNF-α, promote the expression of IL-10 and CD206, and mitigate the extent of brain injury. Sigmoidin B exhibited strong binding affinity to EZH2 and featured a flavonoid core structure along with an olefin side chain. Molecular validation experiments confirmed that Sigmoidin B could ameliorate cognitive dysfunction and modulate microglial polarization via the EZH2-AKT2 pathway. Notably, Sigmoidin B demonstrated superior efficacy compared to MS177 in alleviating inflammation.Natural compound Sigmoidin B was successfully screened and confirmed as a novel EZH2 degrader, which was a potential target for the development of new therapeutic for SAE.Copyright © 2025 Elsevier Ltd. All rights reserved.