PANoptosis, a collective form of programmed cell death that includes apoptosis, necroptosis, and pyroptosis, is turning out to be a key player in the neuroimmune activation and sustaining chronic neuroinflammation in the nervous system. PANoptosis, in contrast to single cell death mechanisms, is a web of events coordinating neuronal death, glial cell changes, and inflammatory signals, being implicated in the initiation and progression of neurodegenerative and neuroinflammatory diseases. This review compiles current knowledge of the molecular pathways of PANoptotic signaling, its interaction with autophagy and immune pathways, and the in vivo models utilized for its pathogenic role in the central nervous system. We also tackle translational hurdles such as biomarker identification, therapeutic safety, disease, stage precision, and patient heterogeneity, which all point to the necessity of highly accurate interventions. Moreover, novel techniques combining systems biology, AI-based target identification, and personalized neuroimmunomodulation may effectively harness PANoptosis regulation to be both controlled and disease-specific. Through bridging the gap between the mechanistic insights and the translational perspectives, this review points out that PANoptosis provides a comprehensive basis for neuroimmune-associated pathology and represents a viable target for novel therapeutic approaches to counteract both chronic neuroinflammation and neurodegeneration.
