The Role of cGAS-STING-Driven PANoptosis in Neurodegenerative Diseases and Therapeutic Prospects
TL;DR
A review of neurodegenerative diseases highlights the cGAS-STING-PANoptotic cascade as a shared pathogenic mechanism and discusses the current evidence and remaining challenges in confirming this hypothesis.
Abstract
Highlights What are the main findings? The cGAS-STING pathway may be associated with panoptosis, potentially regulating cell death. The theoretical basis for the cGAS-STING-PANoptosis axis in neurodegenerative diseases. What are the implications of the main findings? This cellular regulatory mechanism hypothesis holds promise as a novel therapeutic approach for diseases. Neurodegenerative diseases face numerous safety challenges, necessitating focused attention on clinical translation and biomarkers. Abstract Neurodegenerative diseases share features of neuronal loss, neuroinflammation, and protein aggregation. The cGAS-STING pathway, a key DNA sensor, mediates neuroinflammation via TBK1-IRF3 and IKK-NF-κB axes, inducing type I interferons and pro-inflammatory cytokines. This pathway upregulates ZBP1, promotes PANoptosome assembly, and triggers PANoptosis, releasing DAMPs and creating a self-amplifying “inflammation–death” cycle. In Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis, pathological proteins (Aβ, Tau, α-synuclein, TDP-43) or genetic defects (e.g., C9orf72 repeats) cause mitochondrial DNA leakage or genomic instability, activating this axis. This review highlights the cGAS-STING-PANoptotic cascade as a shared pathogenic mechanism and discusses the current evidence and remaining challenges in confirming this hypothesis.