Dual-Pathway Astrocyte Failure in Parkinson’s Disease: Therapeutic Targeting of Nrf2/TFEB Suppression and cGAS-STING/Ferroptosis Activation

Parkinson's disease (PD) is increasingly recognized as a disorder of glial dysfunction, wherein astrocytes transition from homeostatic supporters to active drivers of neurodegeneration. This review synthesizes recent evidence to propose a novel dual-pathway failure model in which internalized alpha-synuclein orchestrates a self-amplifying cycle of astrocytic toxicity. Pathological alpha-synuclein simultaneously suppresses key cytoprotective systems, the Nrf2-mediated antioxidant response and TFEB-regulated autophagy-lysosomal degradation, while hyperactivating neuroinflammatory signaling via NF-κB/MAPK and the recently implicated cGAS-STING axis, triggered by mitochondrial DNA release. This imbalance fosters chronic oxidative stress, proteostatic collapse, and sustained neuroinflammation. Ferroptosis, a form of necrotic cell death characterized by iron dependency and lipid peroxidation, may represent a likely downstream consequence of astrocytic death when protective failure (Nrf2/TFEB suppression) overlaps with toxic activation (cGAS-STING/NF-κB signaling) and disturbances in iron and lipid homeostasis. The concurrent failure of antioxidant defenses and the buildup of labile iron and peroxidizable lipids could establish a conducive environment for ferroptotic membrane rupture, potentially resulting in secondary neuronal damage. This gliocentric model reframes PD pathogenesis as a feed-forward loop of neurotoxicity originating in astrocytic reprogramming. Therapeutically, breaking this cycle via STING inhibition, Nrf2/TFEB activation, and anti-ferroptotic agents represents a promising but still experimental avenue for intervention aimed at restoring astrocyte homeostasis and potentially halting neurodegeneration. However, it is critical to note that the evidence supporting these approaches is derived almost exclusively from preclinical models, with no approved therapies targeting these astrocytic pathways currently available for PD patients.