Sepsis is a lethal syndrome featured by a strong inflammatory response coinciding with multiple-organ functional impairments (Taeb et al., 2017). Despite increased progress in treating sepsis, it remains the most common cause of death in intensive care units (ICUs) (Chen et al., 2020b; Rudd et al., 2020). Thus, it is essential to further investigate its potential mechanisms, which can lead to the development of novel therapeutics and elevate the survival rate of patients with sepsis.

The intestine has customarily been regarded as an essential character in the pathological process of sepsis. It has been identified as the “motor” of systemic inflammatory response syndrome (SIRS) (Adelman et al., 2020). Impairment of the intestinal barrier during sepsis increases gut permeability, permits luminal microbes and endotoxins into the bloodstream, causes the release of a variety of inflammatory mediators (Haussner et al., 2019), and subsequently exacerbates multiorgan failure and lethal sepsis (Hu et al., 2019; Zhou and Verne, 2018). Based on prior studies, restraining sepsis-induced intestinal injury increases survival rates in sepsis (Coopersmith et al., 2002; Fu et al., 2019). Hence, conserving the intestinal barrier is vital for septic defense and cure.

NOD-like receptor protein 3 (NLRP3) inflammasome, a multi-protein complex that boosts inflammatory reactions, is one of the most extensively studied inflammasomes (He et al., 2016). Our previous studies have found that inhibiting the NLRP3 inflammasome can ameliorate multiorgan dysfunction in septic mice through anti-inflammation mechanisms (Zhang et al., 2020). Other studies have also reported similar results, showing that inhibition of the NLRP3 inflammasome signaling pathway ameliorates sepsis-related brain, liver, and lung damage (Chen et al., 2020a; Cornelius et al., 2020). Thus, restraining the activation of NLRP3 inflammasomes provides treatment strategies for sepsis (Zhao et al., 2020).

Bazedoxifene (BAZ), a new IL-6/GP130 inhibitor, has been acknowledged by the Food and Drug Administration (FDA) as a reliable estrogen receptor regulator for the therapy of osteoporosis in postmenopausal women (Yavropoulou et al., 2019). Our recent investigations have indicated that BAZ acts as a protective character against inflammatory impairment of endothelial cells by targeting CD40 (Song et al., 2020). BAZ was also reported to influence the signal transducer and activator of transcription 3 (STAT3) and inhibit cardiac inflammation failure (Wang et al., 2020). These reports demonstrate that BAZ has anti-inflammatory effects. However, the study on the role of BAZ in sepsis is scarce, and the mechanism by which BAZ exerts its anti-inflammatory effects is still elusive.

In this study, we aimed to determine whether the therapy with BAZ can improve the intestinal disorder of sepsis. Through the cecal ligation and puncture (CLP)-mediated sepsis mouse model and lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-induced in vitro intestinal epithelial cell damage model, we demonstrated the beneficial roles of BAZ in attenuating sepsis and intestinal epithelial cell damage both in vivo and in vitro. For the first time, we revealed that BAZ restrained the priming and activation of NLRP3 inflammasome signaling by inhibiting nuclear factor kappa B (NF-κB) signaling rather than interrupting its assembly. Our work suggests that BAZ is a novel promising therapeutic for treating sepsis.