炎症性肠病（IBD）是一种慢性复发性胃肠道疾病，目前治疗效果不佳。近年来，大量研究表明，坏死磺胺 (NSA) 通过阻断混合谱系激酶结构域样蛋白 (MLK​​L) 的聚合，在许多炎症性疾病中发挥保护作用。然而，NSA 对葡聚糖硫酸钠 (DSS) 诱导的结肠炎的保护作用尚未见报道。在本研究中，我们使用 DSS 建立急性结肠炎小鼠模型，以探索 NSA 的积极作用。我们的研究表明，NSA 通过减少体重减轻和疾病活动指数 (DAI) 评分来减轻 DSS 诱发的结肠炎的症状。此外，NSA 抑制巨噬细胞和 CD4+/CD8 + T-由DSS引起的结肠组织中的细胞聚集。此外，我们发现NSA对DSS诱导的结肠炎有治疗作用。从机制上讲，我们检测了磷酸化 MLKL 的表达水平、LDH、细胞因子和N -gasdermin D ( N -GSDMD)的释放，以检查细胞坏死和细胞焦亡途径。我们发现 NSA 通过抑制体内磷酸化 MLKL 和N -GSDMD的表达来减轻 DSS 诱导的结肠炎的严重程度。在体外实验中，我们发现 NSA 抑制炎症因子和 LDH 的释放以及N-骨髓来源的巨噬细胞中的 GSDMD。此外，我们通过蛋白质印迹和流式细胞仪发现 NSA 抑制磷酸化 MLKL 的表达和 NCM460 细胞的坏死性凋亡。总的来说，这项研究揭示了 NSA 抑制细胞焦亡和坏死性凋亡途径，最终减轻肠道炎症，这可能成为 IBD 治疗的潜在候选者。

"点击查看英文标题和摘要"

Necrosulfonamide ameliorates intestinal inflammation via inhibiting GSDMD-medicated pyroptosis and MLKL-mediated necroptosis

Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the gastrointestinal tract, while the present therapeutic efficacy is insufficient. In recent years, numerous studies have shown that necrosulfonamide (NSA) played a protective role in many inflammatory diseases by blocking mixed lineage kinase domain-like protein (MLKL) polymerization. However, the protective effect of NSA in dextran sodium sulfate (DSS)-induced colitis has not been reported. In the present study, we used DSS to establish mouse models of acute colitis to explore the proactive effect of NSA. Our study showed that NSA alleviated symptoms of DSS-induced colitis through reducing weight loss and disease activity index (DAI) score. Furthermore, NSA inhibited macrophages and CD4+/CD8 + T-cell accumulation in colon tissue caused by DSS. In addition, we found that NSA had the therapeutic effects on DSS-induced colitis. Mechanistically, we detected the expression level of phosphorylated MLKL, the release of LDH, cytokines, and N-gasdermin D (N-GSDMD) to examine necroptosis and pyroptosis pathways. We found NSA alleviated the severity of DSS-induced colitis by inhibiting the expressions of phosphorylated MLKL and N-GSDMD in vivo. In vitro experiments, we found NSA inhibited the release of inflammatory factors and LDH and the expressions of N-GSDMD in bone marrow-derived macrophages. Furthermore, we found NSA inhibited the expression of phosphorylated MLKL and necroptosis of NCM460 cell through western blot and flow cytometer. In general, this study reveals that NSA inhibits pyroptosis and necroptosis pathways to eventually alleviate intestinal inflammation, which may serve as a potential candidate for IBD therapy.