南京大学徐强研究团队探明了小化合物PEITC直接抑制TXNIP-NLRP3-GSDMD通路可减少小鼠结肠细胞的焦亡并减轻溃疡性结肠炎。2025年4月7日出版的《中国药理学报》发表了这项成果。

课题组之前的研究表明，从十字花科蔬菜中提取的异硫氰酸苯乙基异硫氰酸酯（PEITC）通过抑制肝细胞焦亡来减轻小鼠急性肝损伤。在这项研究中，小组评估了PEITC治疗UC的治疗潜力及其潜在机制。采用2.5% （w/v）葡聚糖硫酸钠（DSS）每日给药，连续7 d建立UC motheme模型。PEITC（5、10或20 mg·kg^-1d^-1,专营)。在造模前2天给药，共给药10天。

小组发现，在dss诱导UC的发展过程中，焦亡途径被激活，同时硫氧还蛋白相互作用蛋白（TXNIP）和nod样受体热蛋白结构域相关蛋白3 （NLRP3）的表达水平升高，以及caspase-1、gasdermin D （GSDMD）和白介素-1β (IL-1β)的激活。PEITC剂量依赖性地降低了TXNIP和NLRP3的表达，同时抑制了与焦亡途径相关的蛋白如caspase-1、GSDMD和IL-1β的裂解。在HT29细胞体外模型中，该课题组证实了PEITC（0.2、1、5 μM）对结缔组织细胞焦亡的抑制作用，PEITC（0.2、1、5 μM）剂量依赖性地抑制了TXNIP和NLRP3的表达以及前caspase-1、GSDMD和前il -1β的激活。

该课题组人员发现PEITC直接与TXNIP结合，并破坏TXNIP与NLRP3之间的相互作用，导致细胞炎症和氧化应激水平降低。综上所述，本研究表明，PEITC通过与TXNIP结合，破坏TXNIP与NLRP3的相互作用，抑制NLRP3的激活和结肠菌焦亡，有效缓解小鼠UC症状。该研究为UC的临床预防和治疗提供了新的药物靶点和潜在的治疗候选药物。

研究人员表示，溃疡性结肠炎是一种慢性炎症性肠病。UC的病因是多方面的，其潜在的发病机制仍不完全清楚。焦亡是由气真皮介导的程序性细胞死亡，由于其在上皮屏障破坏和炎症扩增中的双重作用，是UC病理的关键驱动因素。

附：英文原文

Title: Direct inhibition of the TXNIP-NLRP3-GSDMD pathway reduces pyroptosis in colonocytes and alleviates ulcerative colitis in mice by the small compound PEITC

Author: Wang, Jie, Zhang, Cui, Qin, Jia, An, Ning, Bai, Mei, Du, Rong-hui, Shen, Yan, Wu, Xu-dong, Cheng, Jing-cai, Wu, Xue-feng, Xu, Qiang

Issue&Volume: 2025-04-07

Abstract: Ulcerative colitis (UC) is a chronic inflammatory bowel disease. The etiology of UC is multifaceted, and the underlying pathogenesis remains incompletely understood. Pyroptosis, programmed cell death mediated by the gasdermins, is a pivotal driver of UC pathology due to its dual role in epithelial barrier disruption and inflammatory amplification. We previously showed that phenethyl isothiocyanate (PEITC), an isothiocyanate derived from cruciferous vegetables, alleviated acute liver injury in mice by suppressing hepatocyte pyroptosis. In this study we evaluated the therapeutic potential of PEITC in the treatment of UC and the underlying mechanisms. UC mouse models were established by administration of 2.5% (w/v) dextran sulfate sodium (DSS) daily for 7 days. PEITC (5, 10, or 20mg·kg1·d1, i.g.) was given 2 days before the start of modeling, and the dosing lasted for a total of 10 days. We showed that during the progression of DSS-induced UC, the pyroptosis pathway was activated accompanied by elevated expression levels of thioredoxin-interacting protein (TXNIP) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3), as well as the activation of caspase-1, gasdermin D (GSDMD) and interleukin-1β (IL-1β). Treatment with PEITC dose-dependently reduced TXNIP and NLRP3 expression while inhibiting the cleavage of proteins associated with the pyroptosis pathway such as caspase-1, GSDMD, and IL-1β. We confirmed the inhibitory effect of PEITC on colonocyte pyroptosis in an in vitro model established in HT29 cells, where PEITC (0.2, 1, 5μM) dose-dependently inhibited TXNIP and NLRP3 expression and the activation of pro-caspase-1, GSDMD and pro-IL-1β. We revealed that PEITC is directly bound to TXNIP and disrupted the interaction between TXNIP and NLRP3, leading to diminished cellular inflammation and oxidative stress levels. In conclusion, this study demonstrates that PEITC disrupts the interaction of TXNIP and NLRP3 by binding to TXNIP, inhibits NLRP3 activation and colonocyte pyroptosis, and thus effectively alleviates UC symptoms in mice. This study offers novel drug targets along with potential therapeutic candidates for the clinical prevention and treatment of UC.

DOI: 10.1038/s41401-025-01549-z

Source: https://www.nature.com/articles/s41401-025-01549-z