Review on the Mechanism of and Therapies Targeting PANoptosis in Ulcerative Colitis.

Ulcerative colitis (UC) is a complex chronic inflammatory bowel disease, and its pathogenesis is closely related to immune imbalance, intestinal flora disorder and intestinal barrier damage. In recent years, a novel form of programmed cell death, PANoptosis, has been confirmed to play a core role in the pathological process of UC. PANoptosis is driven by the PANoptosome complex, which is assembled by key molecules such as ZBP1, NLRP3, and RIPK1, which can simultaneously activate pyroptosis, apoptosis, and necroptosis. This not only leads to damage to the intestinal epithelial barrier, but it also aggravates the dysfunction of immune cells by releasing a large amount of pro-inflammatory cytokines and damage-associated molecular patterns (DAMPs), thus forming a vicious cycle of "cell death and inflammation". Given the complexity of the PANoptosis signaling network, the efficacy of single-target inhibitors is limited. This review systematically expounds the mechanism of action of PANoptosis in UC and focuses on discussing multi-target combination treatment strategies represented by smart hydrogels loaded with multiple inhibitors (such as MCC950, GSK772, VX-765, disulfiram, etc.). This strategy achieves synergy through "vertical blocking" and "horizontal coverage", and in combination with targeted delivery to the lesion, provides a highly promising innovative direction for fundamentally breaking the pathological cycle of UC. Future research should focus on the development of new inhibitors, the optimization of delivery systems, and in-depth clinical translation to promote this strategy as a breakthrough therapy for refractory UC.