Ferroptosis in Parkinson's disease: a review of molecular mechanisms and emerging therapeutic strategies.

Research overview

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Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra and the presence of Lewy bodies containing aggregated α-synuclein (α-syn). While these pathological hallmarks are well-established, the mechanisms underlying neuronal death remain incompletely understood. Emerging evidence highlights ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, as a critical pathway in PD pathogenesis. This review synthesizes recent advances elucidating the synergistic interplay between α-syn aggregation and ferroptosis. We detail how α-syn aggregation not only directly induces ferroptosis but also disrupts iron homeostasis, while iron accumulation in turn accelerates α-syn fibrillation and oxidative stress, forming a vicious cycle that propagates neurodegeneration. Furthermore, we explore the amplifying role of glial cells-microglia and astrocytes-in this process through the promotion of neuroinflammation, oxidative damage, and dysregulation of iron metabolism. Finally, we discuss promising therapeutic strategies targeting this α-syn-ferroptosis axis, including α-syn aggregation inhibitors, iron chelators, and glia-modulating agents, highlighting their potential as disease-modifying interventions. Together, these insights underscore ferroptosis as a central mechanism in PD and offer new avenues for developing targeted therapies.

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