Wiring and rewiring PANoptosis: Molecular vulnerabilities for targeting inflammatory cell death in human disease

PANoptosis represents a unified inflammatory cell death program that mechanistically integrates pyroptosis, apoptosis, and necroptosis through multiprotein complexes known as PANoptosomes. While prior models treated these death pathways as distinct, emerging evidence reveals their convergence through shared sensors, signaling adaptors, and executioners-allowing cells to bypass immune evasion strategies by pathogens or tumors. Despite its biological importance, a cohesive mechanistic framework for PANoptosis has remained elusive. In this review, we present a novel, sensor-specific dissection of PANoptosome architecture, detailing how distinct innate immune sensors-ZBP1, RIPK1, AIM2, and NLRP12 serve as organizing hubs for context-dependent activation of inflammatory cell death. We integrate this with a cross-pathway analysis of caspase-8, RIP kinases, and gasdermins, revealing PANoptosis as a highly adaptable logic circuit governing immune activation and cell fate. We further chart the dual roles of PANoptosis across disease contexts-highlighting its protective functions in infection and tumor suppression, as well as its detrimental consequences in cytokine storms, neurodegeneration, and multi-organ failure. By comparing sensor-driven outcomes across organs and disease states, we propose new therapeutic entry points for modulating PANoptotic signaling with precision. This review offers a mechanistically integrated and translationally focused roadmap to PANoptosis, establishing it as a master regulator of inflammatory cell death and a frontier for next-generation immune interventions.