Molecular mechanism of PANoptosis and programmed cell death in neurological diseases

Abstract

PANoptosis represents a highly coordinated inflammatory programmed cell death governed by the assembly and activation of PANoptosome, which strategically integrate core molecular elements from pyroptosis, apoptosis, and necroptosis. The triple-component cell death pathways set themselves apart from alternative regulated cell death mechanisms through their unique capacity to concurrently integrate and process molecular signals derived from multiple death-signaling modalities, thereby coordinating a multifaceted cellular defense system against diverse pathological insults. Pathogen-associated molecular patterns synergistically interact with cytokine storms, and oncogenic stress to active PANoptosis, establishing this programmed cell death pathway as a critical nexus in inflammatory pathogenesis and tumor immunomodulation. This molecular crosstalk highlights PANoptosis as a promising therapeutic target for managing immune-related disorders and malignant transformation. Emerging evidence links PANoptosis to neuroinflammatory disorders through dysregulated crosstalk between programmed death pathways (apoptosis, necroptosis, pyroptosis) and accidental necrosis, driving neuronal loss and neural damage. Single-cell transcriptomics reveals spatially resolved PANoptosis signatures in Alzheimer's hippocampal microenvironments and multiple sclerosis demyelinating plaques, with distinct molecular clusters correlating to quantifiable neuroinflammatory metrics. Emerging PANoptosis-targeted therapies show preclinical promise in alleviating neurovascular dysfunction while preserving physiological microglial surveillance functions. Accumulating evidence linking dysregulated cell death pathways (particularly PANoptosis) to neurological disorders underscores the urgency of deciphering its molecular mechanisms and developing precision modulators as next-generation therapies. This review systematically deciphers PANoptosome assembly mechanisms and associated cell death cascades, evaluates their pathological roles in neurological disorders through multiscale regulatory networks, and proposes PANoptosis-targeted therapeutic frameworks to advance precision neurology.