Nrf2 Activators in Parkinson's Disease: Modulating Mitophagy and Regulating Cuproptosis

Parkinson's disease (PD), one of the most prevalent age-related neurodegenerative disorders, is neuropathologically defined by the progressive degeneration and massive loss of dopaminergic neurons within the substantia nigra pars compacta of the midbrain. Multiple pathological cascades, which include excessive oxidative stress, persistent neuroinflammation, aberrant cuproptosis, and mitochondrial dysfunction, converge to drive PD pathogenesis and aggravate its progression. Nuclear factor erythroid 2-related factor 2 (Nrf2), a pivotal transcription factor governing antioxidant defense and cellular stress responses, is markedly downregulated and functionally compromised within the pathological microenvironment of PD-affected brain tissue. A growing body of evidence has demonstrated that Nrf2 activators represent promising and innovative therapeutic candidates for the treatment of PD. These compounds effectively trigger the activation of the downstream Nrf2 signaling cascade, thereby promoting the initiation and execution of mitophagy to eliminate dysfunctional and damaged mitochondria and restore intracellular metabolism homeostasis. Meanwhile, activation of the Nrf2 signaling pathway suppresses aberrant intracellular copper accumulation and prevents excessive lipid peroxidation, thereby exerting a robust inhibitory effect on neuronal cuproptosis. This review systematically delineates the regulatory mechanisms by which Nrf2 activators modulate pivotal molecular-level biological processes. It further synthesizes and critically appraises the most recent preclinical findings as well as emerging early-stage clinical data regarding Nrf2-targeted therapeutic strategies for PD, while also delineating prevailing challenges and outlining prospective avenues for future investigation in this domain. Collectively, targeting the Nrf2 signaling pathway constitutes a promising integrative therapeutic strategy for the management of PD.