Sepsis, a syndromic response to infection, contributes to nearly 20 % of all deaths in 2017 and imposes significant burden on global medical system (Rudd et al., 2020). Sepsis-associated encephalopathy (SAE) is common in critically ill patients in intensive care units and occurs up to 70 % in those with severe systemic infection (Gofton and Young, 2012). The underlying mechanism is that sepsis triggers the disruption of the blood-brain barrier (BBB) and results in neuroinflammation (Sekino et al., 2022).

Microglia drive central nervous system inflammation during SAE (Heming et al., 2017). Microglia during sepsis are activated to pro-inflammatory M1 type (Li et al., 2020). M1 microglia can be identified by specific markers such as CD86 and cause neuroinflammation via cytokine release. In contrast, M2 anti-inflammatory microglia labeled by CD206 promote tissue repair and neuronal regeneration (Castro et al., 2022). Therefore, targeting microglial M1/M2 polarization is expected to reduce neuroinflammation and attenuate SAE (Michels et al., 2017).

Enhancer of Zeste Homolog 2 (EZH2) is a critical determinant in immune regulation and has become a promising therapeutic target for sepsis (Yang et al., 2021, Liu et al., 2019, Li et al., 2023). MS177 was found to inhibit not only the classical EZH2 pathway but also the non-classical EZH2 pathway (Wang et al., 2022a, Yu et al., 2023). Our previous studies have demonstrated that MS177 could reduce acute lung injury in sepsis by promoting the polarization of lung macrophages towards M2 type through AKTIP-AKT2 pathway (Wang et al., 2024).Since AKTIP and AKT2 could express in brain tissues, we hypothesized that a degradation agent of EZH2 could also alleviate SAE. MS177, as a novel small molecule PROTAC, has the potential to cross the blood-brain barrier (Tashima, 2023, Wang et al., 2021).

Compared with traditional synthetic small molecules, natural products usually have fewer nitrogen and halogen atoms, more hydrogen bond acceptors and donors, and higher hydrophilicity and molecular rigidity. These differences were confirmed to be potentially advantageous (Atanasov et al., 2021). In terms of clinical application, we employed a high-throughput screening (HTS) system using the Traditional Chinese Medicine database (YaTCM) to identify potential EZH2 degrader agents (Ru et al., 2014). Based on the structure of MS177 (, Appendix A Supplementary material), Sigmoidin B, a natural compound, was screened. This study was designed to confirm that Sigmoidin B can ameliorate SAE through in vivo and in vitro tests.