Macrophage pyroptosis in inflammatory bowel disease: mechanistic insights, pathological roles and treatment strategies.

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the intestinal tract. Imbalanced intestinal immune homeostasis, particularly macrophage pyroptosis, plays a central role in the pathogenesis of IBD. Pyroptosis is a pro-inflammatory form of programmed cell death mediated by the gasdermin protein family. It is characterized by cellular swelling, membrane rupture, and the massive release of inflammatory mediators. Under physiological conditions, moderate pyroptosis contributes to the maintenance of intestinal immune homeostasis by eliminating intracellular pathogens and releasing immunomodulatory signals. However, aberrant activation of pyroptosis triggers the excessive release of inflammatory mediators and damage signals that drive the initiation and progression of intestinal inflammation. Recent studies have shown that macrophage pyroptosis is profoundly involved in the pathological evolution of IBD. Upon stimulation by danger signals, macrophages undergo pyroptosis and release a high amount of inflammatory mediators that remodel the local immune network. Macrophage pyroptosis can also directly impair the intestinal mucosal barrier, thereby driving the pathological progression of IBD. This article systematically reviews the molecular mechanisms involved in pyroptosis, summarizes the pathological mechanisms through which macrophage pyroptosis drives IBD progression, and introduces various therapeutic strategies targeting macrophage pyroptosis to alleviate IBD. Finally, this review provides novel perspectives for the mechanistic research and precision treatment of IBD and facilitates the clinical translation of strategies targeting macrophage pyroptosis.