Although pyroptosis was first viewed as an innate antimicrobial defense mechanism, the review describes it as a pathway whose effects vary according to cell type and biological context. The therapeutic interest in this pathway comes from the availability of several potentially druggable steps. Interventions discussed in the review include NLRP3 inflammasome inhibitors, regulators of gasdermin post-translational modifications, natural compounds and nanotechnology-based delivery systems.

Pyroptosis also operates within an interconnected cell-death network involving apoptosis, necroptosis and ferroptosis, all of which are considered together within the emerging PANoptosis framework. The review examines these mechanisms alongside the role of pyroptosis in intestinal and systemic inflammatory diseases. In the intestine, the pathway has a notable dual role.

Gasdermin-mediated death can disrupt the epithelial barrier and intensify mucosal inflammation, while the same effectors can also support barrier integrity, epithelial repair and controlled cytokine release. This context dependence helps explain why inhibiting pyroptosis has produced robust protection in preclinical colitis models but has so far shown limited clinical efficacy. The review’s interpretation is not that gasdermin activity is uniformly harmful, but that blocking it may remove protective functions as well as disease-associated effects.

Its therapeutic assessment is therefore based on preclinical findings, mechanistic analysis and lessons from clinical trials rather than evidence that the reviewed interventions are established treatments for inflammatory bowel disease or related inflammatory disorders. For translation, the authors identify three central priorities: human disease models that better reproduce relevant disease biology, delivery restricted to affected tissues and biomarker-guided stratification of patients. The review also emphasizes the need to distinguish patients in whom pyroptotic signaling contributes to disease from those in whom inhibition could interfere with repair or other protective processes.

Its coverage of multi-indication clinical progress and recent trial failures provides the basis for those priorities, while the abstract available here does not provide detailed trial-specific outcomes or establish a proven therapeutic approach. Overall, the review presents pyroptosis as a mechanistic target whose value depends on where, in whom and under what conditions it is inhibited. By integrating inflammasome biology, gasdermin function, competing cell-death pathways and the protective roles of epithelial responses, the authors argue that translation requires selective intervention and more informative human models rather than treating pyroptosis as a uniform inflammatory mechanism.

The scope of the review is the molecular basis and therapeutic landscape of pyroptosis in intestinal and systemic inflammatory diseases, with particular attention to inflammatory bowel disease.

Subject of Research: Molecular mechanisms and therapeutic targeting of pyroptosis in intestinal and systemic inflammatory diseases

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

Article References: Li, J., Chen, Y., Yu, Q., Fu, X., Sun, J., & Zhu, L. (2026). Targeting pyroptosis in intestinal and systemic inflammatory diseases: mechanisms and therapeutic opportunities. Molecular Biology Reports, 53(1), Article 1766. https://doi.org/10.1007/s11033-026-12920-6

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12920-6

Keywords: pyroptosis, gasdermin pores, NLRP3 inflammasome, inflammatory bowel disease, colitis models, PANoptosis, cell death, inflammation, molecular therapeutics, biomarker-guided stratification, Targeting, intestinal