PANoptosis in rheumatological and immunological diseases: Redefining cell death beyond classical pathways

Dysregulated programmed cell death (PCD) is a core pathogenic mechanism in rheumatological and immunological disorders, directly causing chronic inflammation, disrupting immune self-tolerance, and leading to irreversible tissue destruction. Classical biological concepts have conventionally characterized PCD modalities as autonomous, linear signaling cascades. However, inflamed tissues from affected patients frequently show activation of multiple cell death markers, and pharmacological interventions that selectively target single PCD pathways have repeatedly yielded disappointing clinical outcomes. These observations indicate extensive molecular crosstalk across the initiation, regulatory integration, and induction of cell death signaling. In this regard, PANoptosis has emerged as a single, synchronized form of inflammatory cell death that combines features of apoptotic, necroptotic, and pyroptotic processes. PANoptosis is not only a coincidental overlap of individual death modalities; it is triggered through a multiprotein signaling complex, the PANoptosome. Through synergistic signaling, the PANoptotic process initiates a cytotoxic cascade that transcends the constraints of conventional linear cell death. Despite its relevance to immune-mediated pathology, a comprehensive, disease-oriented mechanistic pathway for PANoptosis remains underdeveloped in rheumatology and immunology. This review consolidates recent advances to examine the assembly and activation dynamics of representative PANoptosomes across diverse inflammatory microenvironments. In this review, the translational implications of this combined model is examined, highlighting therapeutic strategies that prioritize upstream sensors and regulatory hubs over terminal induction effectors. This review establishes PANoptosis as a pivotal regulatory nexus of inflammatory cell death. It provides a mechanistically unified, translationally oriented pathway to inform next-generation therapeutic development in rheumatic and immune-mediated diseases.