Targeting ferroptosis in rotenone-induced Parkinson’s disease: from mechanistic insights to pharmacological interventions

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, leading to disabling motor and non-motor symptoms. Ferroptosis, an iron-dependent oxidative cell death driven by lethal lipid peroxidation, has emerged in preclinical models as a candidate pathogenic mechanism in PD, although its causal centrality in human PD remains to be established. Rotenone, a mitochondrial complex I inhibitor widely used to model PD, recapitulates key clinical and pathological features of the disease. Accumulating evidence demonstrates that rotenone induces ferroptosis through a coordinated network of iron dyshomeostasis, inactivation of the System Xc − –GPX4 antioxidant axis, dysregulated lipid metabolism, mitochondrial dysfunction, ferritinophagy-mediated iron release, neuroinflammation, and SIRT1–Nrf2 pathway suppression. Importantly, pharmacological targeting of these ferroptotic nodes—with agents such as Fer-1, iron chelators, Nrf2 activators, and modulators of ferritinophagy—effectively attenuates rotenone-induced neurodegeneration and restores motor function in preclinical models. This review systematically dissects the molecular circuitry of ferroptosis in rotenone -based PD models and evaluates the therapeutic potential of ferroptosis inhibitors, aiming to inform the development of disease-modifying strategies for PD.