Programmed cell death in autoimmune diseases

Autoimmune diseases (AIDs) are chronic inflammatory disorders in which loss of self-tolerance intersects with tissue stress and damage. Increasing evidence indicates that regulated cell death (RCD) can act as an upstream amplifier in selected autoimmune settings, while in other settings it may mainly report downstream collateral injury caused by cytotoxic lymphocytes, immune complexes, complement activation, or tissue hypoxia. Accordingly, this review distinguishes causal death execution from associative pathway signatures and highlights the types of longitudinal, cell-type-resolved, and perturbational evidence needed to make that distinction. We summarize how apoptosis, necroptosis, pyroptosis, and ferroptosis operate as an interlocking network in autoimmune microenvironments, frequently co-existing as context-dependent mixed-death states driven by shared triggers such as cytokines, PRR ligands, and oxidative stress, and governed by decision hubs including RIPK1 and caspase-8. We highlight integrated concepts such as PANoptosis to explain pathway convergence and compensatory switching into parallel lytic branches when a single node is constrained. The review further connects mechanistic insights to translational priorities, emphasizing biomarker strategies that report pathway engagement, targeted modulation of executors or upstream sensing and cytokine circuits, and lesion-localized delivery approaches to improve the therapeutic window. Finally, we outline key gaps that must be addressed to enable precision interventions, including spatial and cell-type resolved validation of death programs, longitudinal profiling across flare-remission trajectories, and harmonized composite panels capable of capturing mixed-death dynamics in heterogeneous AIDs.