Pregnane X receptor activation attenuates intestinal inflammation: The role of pyroptosis and necroptosis inhibition

This is the authors' abstract. We don't add key points for this paper.

Intestinal inflammation compromises epithelial barrier integrity and disrupts immunological homeostasis, escalating the risk of severe gastrointestinal disorders. The Pregnane X Receptor (PXR), a xenobiotic-sensing nuclear receptor, is critical for maintaining intestinal structural integrity and suppressing inflammation, although its mechanistic underpinnings remain poorly characterized. In this study, we explored the therapeutic potential of PCN, a PXR agonist, in mitigating intestinal inflammation using two models: enterohaemorrhagic Escherichia coli O157:H7 (EHEC)-infected mice and lipopolysaccharide (LPS)-stimulated intestinal epithelial cells. PCN administration significantly improved survival rates in EHEC-challenged mice, alleviated intestinal mucosal damage, and restored tight junction protein (ZO-1 and occludin) expression. Concurrently, PCN attenuated Paneth cell dysfunction, macrophage hyperactivation, and pro-inflammatory mediator release (e.g., TNF-α, IL-6). In vitro, PCN counteracted LPS-induced barrier disruption and inflammation by suppressing the TLR4/NF-κB/MAPK axis and downstream pyroptotic (NLRP3/caspase-1/GSDMD), and necroptotic (RIPK1/RIPK3/MLKL) signaling cascades. Interestingly, both EHEC infection and LPS stimulation impaired PCN-driven PXR activation. While PCN rescued EHEC-induced mortality, histological damage, and barrier dysfunction in wild-type mice, its protective effects were markedly diminished in PXR-knockout ( PXR −/− ) mice. Furthermore, PXR silencing in cultured cells abolished PCN-mediated inhibition of NF-κB, NLRP3 inflammasome, and necroptosis pathways. These results demonstrate that PXR activation coordinately blocks pyroptosis and necroptosis by modulating the TLR4/NF-κB/MAPK-NLRP3/caspase-1/GSDMD-RIPK1/RIPK3/MLKL axis, thereby preserving intestinal homeostasis. This dual-pathway targeting positions PXR as a promising therapeutic candidate for inflammatory bowel diseases.