Role of PANoptosis in intestinal diseases and its therapeutic implications.

PANoptosis is a novel programmed inflammatory cell death pathway. It integrates pyroptosis, apoptosis, and necroptosis components via a unified molecular platform termed PANoptosome. Unlike single classical cell death pathway, PANoptosis is tightly regulated by key regulators such as ZBP1, RIPK3, caspase-8, and ASC, resulting in a highly inflammatory and immunogenic form of cell death. While its pathological relevance has been widely investigated in cancer, microbial infections, and systemic inflammatory syndromes, its role in intestinal diseases has not been comprehensively explored. In this review, we summarize emerging evidence highlighting its key role in intestinal diseases, including Crohn's disease, ulcerative colitis, colorectal cancer, intestinal ischemia/reperfusion injury, necrotizing enterocolitis, celiac disease, and immune checkpoint inhibitors-induced colitis. We further summarize recent advances in PANoptosis mechanisms and immunological regulation in intestinal diseases, highlight its intricate interplay with gut microbiota, and discuss the therapeutic potential of targeting PANoptosis to restore intestinal homeostasis and mitigate disease progression.