The Mitophagy-Ferroptosis-Neuroinflammation Triad in Parkinson’s Disease: Pathogenic Crosstalk and Targeted Interventions

Abstract

Parkinson’s disease (PD) is now understood as a protein aggregation-related disease and a systemic disease related to impaired organelle quality control. Previous reviews often discussed individual cell death pathways separately. This review focuses on the mitophagy-ferroptosis-neuroinflammation axis by organizing the pathologic links involved in dopaminergic neuronal degeneration. We focus on mitochondrial quality control impairment and compare the classical ubiquitin-dependent pathway mediated by PINK1-Parkin-USP30 with adaptive recognition mechanisms involving PHB2 receptors and lipid dynamics. This review considers mitophagy impairment as an early convergent hub and pathologic amplifier within the PD pathologic network, rather than the only initiating cause. Evidence from PD models suggests that this defect usually occurs together with other pathologic changes and may contribute to a self-reinforcing pathologic cascade. In fact, damaged mitochondria accumulate intracellularly and disrupt cellular iron homeostasis. This process triggers ferroptosis induced by lipid peroxidation and releases danger signals. These signals activate a response driven by cGAS-STING-dependent neuroinflammation. This review categorizes novel therapeutic approaches into metabolic reprogramming agents (e.g., AMPK/SIRT1 activators) and precision-targeted drugs (e.g., USP30 and c-Abl inhibitors) based on this working mechanism. Electroacupuncture therapy is also discussed as a non-pharmacologic strategy. Current evidence suggests that electroacupuncture therapy may regulate axonal transport and immune checkpoints. We further propose a combined strategy that restores mitochondrial clearance capacity, while blocking downstream ferroptosis and inflammatory signaling. This integrated approach may help overcome the limitations of current single-target therapies and provide direction for future translational research.