Protective effects of sinensetin on intestinal barrier damage induced by lipopolysaccharide in mice through TLR4/NLRP3/GSDMD pathway

Recent studies have increasingly indicated that sinensetin, a dietary-derived natural compound and key component of orange peel, can alleviate intestinal damage induced by cisplatin. In this study, we established a mouse model and utilized a Caco-2 cell system to investigate the effects of sinensetin, known for its wide-ranging physiological properties, on intestinal damage induced by lipopolysaccharide (LPS). Our findings demonstrate that oral administration of sinensetin significantly alleviated LPS-induced intestinal barrier damage in mice. This protective effect was reflected by improved intestinal permeability and tissue morphology, along with a reduction in goblet cell depletion. Furthermore, sinensetin markedly suppressed LPS-induced pyroptotic cell death in the intestinal epithelium and reversed the downregulation of key tight junction (TJ) proteins, such as occludin and zonula occludens-1 (ZO-1), in both colonic tissues and Caco-2 monolayers. Additionally, sinensetin inhibited the recruitment of immune cells (macrophages and neutrophils) to the gut mucosa and reduced levels of key pro-inflammatory mediators, including tumor necrosis factor-alpha (TNF-α), interleukin 1β (IL-1β), and IL-18. Potential mechanisms likely include inhibited Toll-like receptor 4 (TLR4) activation and suppressed NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling. Based on these results, sinensetin may alleviate LPS-induced pyroptosis and colon injury by regulating the TLR4/NLRP3/gasdermin D (GSDMD) signaling pathway in Caco-2 cells and mice. Overall, our study indicates that sinensetin may be developed as a potential dietary supplement to prevent intestinal barrier injury. It provides a scientific basis for exploring a potential colon injury treatment strategy derived from natural products and acting through novel mechanisms, as well as for the high-value utilization of agricultural by-products. • Sinensetin prevents against LPS-provoked intestine injury in mice • Sinensetin alleviates LPS-induced pyroptosis in mice and Caco-2 cells • Sinensetin regulates the LPS-induced TLR4/NLRP3/GSDMD pathway in mice and Caco-2 cells • The TLR4/NLRP3/GSDMD pathway is tightly associated with intestinal injury and pyroptosis