Programmed cell death in inflammation: interactions and holistic perspective

Programmed cell death (PCD) is a major regulatory mechanism that maintains tissue homeostasis and immune balance and strongly influences the initiation, progression and resolution of inflammation. Although apoptosis, pyroptosis, necroptosis and ferroptosis are individual PCD modes that are regulated by different molecular mechanisms, they are not mutually exclusive in inflammatory microenvironments. Instead, these pathways are linked via common signaling mediators and regulatory nodes that enable crosstalk, compensatory activation and context-dependent fine-tuning. It is evident that apoptosis, pyroptosis and necroptosis can be coordinated within defined inflammatory platforms, as exemplified by concepts such as PANoptosis. Pathway-specific modeling is inadequate for inflammatory diseases involving multiple PCD modalities, metabolic and organelle stress, immune-cell interactions and tissue-level changes that molecular models cannot capture. Here, an integrated cell death network (ICDN) paradigm is presented as an organizational schema describing how various types of PCD are coregulated through common regulatory pathways in inflamed tissues. This framework does not identify a new mode of cell death per se but rather integrates pathway compensation following extracellular perturbations, disease-specific inflammatory responses, and susceptibility to therapeutic intervention at common network nodes. This review defines the molecular mechanisms and crosstalk of inflammatory pyroptosis, apoptosis, and necroptosis pathways; links recent advances in death modality applications for specific diseases to the ICDN framework; and highlights important current limitations that require further examination, including the need for stronger evidence of dynamic switching across cell death modalities, spatial architecture during inflammation, and reconfiguration at both the multiprotein complex and network levels, such as inflammasome networks.