The irony of Parkinson's disease: Converging mechanisms of redox imbalance and ferroptosis

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and its prevalence will increase with population aging. PD is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), leading to severe motor and debilitating non-motor symptoms. Current therapies provide symptomatic relief without preventing the progressive nigrostriatal neurodegeneration. Unfortunately, clinical trials investigating single-target drugs and antioxidant supplementation have not provided robust clinical responses. Since PD is a multifactorial disease involving mitochondrial dysfunction, oxidative stress, α-synuclein aggregation, and neuroinflammation, the classical "one-drug-one-target" philosophy may be ineffective in preventing progression of the disease, while "one-drug-multiple-targets" approaches may offer greater neuroprotection. This review summarizes PD-related pathogenic events and potential disease-modifying strategies, with a particular focus on ferroptosis, a regulated iron-dependent cell death mechanism that has recently emerged as a key driver of dopaminergic degeneration. By synthesizing recent iron chelators- and antioxidant-based clinical trials, repurposed drugs and emerging preclinical pleiotropic strategies, we advocate for an integrated, multi-targeted approach to effectively halt the progression of PD.