PANoptosis: potential new targets and therapeutic prospects in digestive diseases

PANoptosis, a newly defined, multifaceted programmed cell death (PCD) pathway, integrates key features of pyroptosis, apoptosis, and necroptosis. It is orchestrated by multiprotein complexes called PANoptosomes (ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosomes), which assemble via domain interactions in response to specific pathogen- or damage-associated signals. This integrated pathway plays crucial roles in maintaining tissue homeostasis by eliminating infected and damaged cells and provides potent innate immune defence through the coordinated release of inflammatory cytokines and damage-associated molecular patterns (DAMPs), offering superior pathogen clearance compared with single PCD modes. Increasing evidence underscores the significant involvement of PANoptosis in digestive diseases. In gastric cancer, it modulates tumour progression, the immune microenvironment and chemoresistance. PANoptosis drives epithelial cell death in ulcerative colitis and Crohn's disease, contributing to mucosal barrier disruption and inflammation. It influences immune infiltration, metabolic reprogramming, and therapeutic response in colorectal cancer. PANoptosis also contributes to the pathogenesis of diverse liver conditions, including failure, fibrosis, metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma, and mediates pancreatic injury in acute pancreatitis. While research on oesophageal and pancreatic malignancies is nascent, PANoptosis-based molecular subtyping and therapeutic targeting demonstrate translational potential. This review synthesizes current evidence, highlighting PANoptosis as a critical regulator in digestive pathologies and as a promising target for intervention.