Targeting Nrf2 Signaling in Parkinson's Disease: Mechanisms, Strategies, and Therapeutic Perspectives.
TL;DR
This review summarizes the regulatory mechanisms of the Keap1-Nrf2 pathway and evaluates how its activation counteracts core PD pathologies, and highlights the extensive crosstalk between Nrf2 and other major signaling networks that collectively determine dopaminergic neuronal survival.
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons and the accumulation of α-synuclein. Disease progression is driven by a complex interplay of chronic oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired proteostasis. As a central regulator of the cellular antioxidant response, nuclear factor erythroid 2-related factor 2 (Nrf2) protects against these cellular insults by driving the expression of various cytoprotective genes. In this review, we summarize the regulatory mechanisms of the Keap1-Nrf2 pathway and evaluate how its activation counteracts core PD pathologies. We also highlight the extensive crosstalk between Nrf2 and other major signaling networks that collectively determine dopaminergic neuronal survival. Finally, we examine the therapeutic potential of current Nrf2 modulators, including natural phytochemicals, clinical-stage candidates, and repurposed drugs, and critically discuss the pharmacokinetic barriers, electrophilic off-target toxicities, and the Nrf2 paradox that must be overcome to successfully translate these compounds into disease-modifying therapies for PD, highlighting the transition toward non-covalent PPI inhibitors.