Bazedoxifene attenuates intestinal injury in sepsis by suppressing the NF-κB/NLRP3 signaling pathways

Acute inflammatory injury is the primary cause of sepsis, leading to various organ failures. Bazedoxifene (BAZ) has been proven to have anti-inflammatory effects. However, its effects on sepsis-induced intestinal injury are unclear. Here, we demonstrated the beneficial effects of BAZ on intestinal injury and explored the underlying mechanisms using cecal ligation and perforation (CLP)-mediated sepsis mouse model and in vitro cultured intestinal epithelial MODE-K cells. We found that BAZ elevated the survival rate of septic mice and attenuated CLP-triggered intestinal damage. BAZ inhibited intestinal inflammation and restored the impaired intestinal barriers in CLP mice. The mechanistic study in lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-stimulated MODE-K cells showed that BAZ significantly downregulated the expression of NOD-like receptor protein 3 (NLRP3), interleukin-1β (IL-1β), Caspase-1, and gasdermin D (GSDMD), and markedly reduced the phosphorylation of molecules in the nuclear factor kappa B (NF-κB) pathway. Moreover, BAZ prominently rescued the decreased viability of MODE-K cells and reduced Lactate Dehydrogenase (LDH) release upon LPS/ATP challenge. However, BAZ did not affect the inflammasome assembly, as evidenced by the lack of changes in ASC (Apoptosis speck-like protein containing a CARD) speck formation. Our results suggest that BAZ relieves inflammation and intestinal barrier function disruption by suppressing the NF-κB/NLRP3 signaling pathways. Therefore, BAZ is a potential therapeutic candidate for treating intestinal injury in sepsis.

Bazedoxifene; Inflammation; Intestinal injury; NF-κB; NLRP3 inflammasome; Sepsis.