Targeting pyroptosis in intestinal and systemic inflammatory diseases: mechanisms and therapeutic opportunities.

Pyroptosis is a lytic form of programmed cell death driven by gasdermin cleavage and subsequent plasma membrane pore formation, which triggers cell swelling, lysis, and the release of inflammatory cytokines that amplify tissue injury. Once viewed as an innate antimicrobial defense mechanism, pyroptosis is now recognized as a central pathogenic pathway in both acute and chronic inflammatory diseases, including inflammatory bowel disease (IBD). Its execution proceeds through a cascade of druggable events-inflammasome assembly, caspase activation, and gasdermin pore formation-and it operates within an interconnected cell death network, engaging apoptosis, necroptosis, and ferroptosis under the emerging PANoptosis framework. In the intestine, this network displays striking cell type- and context-dependent duality: gasdermin-mediated death can disrupt the epithelial barrier and exacerbate mucosal inflammation, yet the same effectors support barrier integrity, epithelial repair, and controlled cytokine release. This duality may explain why pyroptosis inhibition, although robustly protective in preclinical colitis models, has so far shown limited clinical efficacy. In this review, we summarize the molecular mechanisms of pyroptotic signaling, its crosstalk with other death pathways, and its roles in intestinal and systemic inflammatory diseases. We then critically evaluate the therapeutic landscape, covering NLRP3 inflammasome inhibitors, regulators of gasdermin post-translational modifications, natural compounds, and nanotechnology-based delivery systems, with emphasis on multi-indication clinical progress and the lessons from recent trial failures. Finally, we highlight priorities for translation-human disease models, tissue-restricted delivery, and biomarker-guided patient stratification-that may convert mechanistic insight into clinical benefit for patients with IBD and related inflammatory disorders.