Microglial Nrf2 Activation Orchestrates Ferroptosis Inhibition and α-Synuclein Clearance in Parkinson's Disease

Parkinson's disease (PD) is pathologically characterized by the abnormal aggregation of α-synuclein and the progressive loss of dopaminergic neurons, with microglia-mediated neuroinflammation acting as a pivotal driver of pathogenesis. Ferroptosis, an iron-dependent form of regulated cell death, significantly contributes to PD progression. However, the precise mechanisms governing microglial ferroptosis under α-synuclein pathology, particularly the regulatory role of the master antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), remain elusive. Here, we employed an in vitro BV2 microglial model and an in vivo A53T transgenic mouse model to elucidate the regulatory effects and underlying mechanisms of Nrf2 on ferroptosis-associated phenotypes induced by α-synuclein pre-formed fibrils (PFFs). In vitro, PFF treatment significantly downregulated microglial Nrf2 expression, triggering ferroptosis-associated phenotypes characterized by reactive oxygen species (ROS) accumulation, ferrous iron (Fe²⁺) overload, and elevated lipid peroxidation. Genetic knockdown of Nrf2 exacerbated these ferroptosis-associated phenotypes and accelerated α-synuclein aggregation. Conversely, Nrf2 overexpression or pharmacological activation via dimethyl fumarate (DMF) profoundly suppressed α-synuclein pathology and mitigated ferroptosis-associated signatures. In vivo, microglial activation in the substantia nigra of PD mice was accompanied by marked Nrf2 downregulation. Strikingly, microglia-specific Nrf2 overexpression significantly reversed motor and non-motor deficits (including olfactory and locomotor impairments), demonstrating the sufficiency of microglial protection. Furthermore, systemic administration of the Nrf2 activator DMF not only ameliorated motor dysfunction but also concurrently rescued nigral dopaminergic neurons and reduced striatal α-synuclein aggregation. Taken together, our findings identify Nrf2 downregulation-driven microglial ferroptosis-associated phenotypes as a critical pathogenic mechanism, and demonstrate that targeting this pathway in vivo ameliorates motor and non-motor deficits while preserving dopaminergic neurons in PD mice. These findings support further research on Nrf2 activation and DMF as potential therapeutic strategies for PD.