ZAKα Induces Pyroptosis of Colonic Epithelium Via the Caspase-11/GSDMD Pathway to Aggravate Colitis

• DOI: 10.1007/s10753-025-02262-z
• Publication Date: 2025-02-24T12:23:10Z
• Authors: Song Li; Mingfei Chen; Sizhe Zheng; Waresi Abudourexiti; Feng Zhu; Zhongyuan Wang; Yanzhe Guo; Zeqian Yu; Zirui Yang; Liang Zhang; Chao Ding; Jianfeng Gong
• Keywords: Pyroptosis

ZAKα-driven ribotoxic stress response (RSR) has been shown to trigger diverse biological effects. Nevertheless, its role in the pathogenesis of ulcerative colitis (UC) remained unclear. This study aimed determine ZAKα development UC. Our found that expression was significantly increased colonic epithelium UC patients and DSS-colitis mouse models. Moreover, level mRNA showed a positive correlation with disease activity. In model, Vemurafenib, inhibitor, treatment reduced inflammation ameliorated intestinal mucosal barrier damage, while Anisomycin, RSR agonist, opposite effect. vitro experiments demonstrated Anisomycin induced pyroptosis instead apoptosis C26 cell line. Western blot analysis revealed triggered via Caspase-11/GSDMD pathway. Further animal studies confirmed Vemurafenib downregulated this pathway, reducing epithelial pyroptosis. Finally, blocking Caspase-11 severity DSS-induced Anisomycin-treated mice. all, seems play crucial colitis, as it promotes cells exacerbates part by upregulating axis. ZAKα, key kinase driving (RSR), is highly expressed patients, activation can upregulate pathway induce cells.