Predominance of Ferroptotic Cell Death Mechanisms in Substantia Nigra Neurodegeneration in Parkinson's Disease.

Our findings implicate ferroptosis, and to a lesser extent necroptosis, in PD neuronal death, with ferroptosis potentially playing a larger role in advanced disease. We propose a "2-hit" model where early synucleinopathy-driven insults are amplified in advanced disease by a neuromelanin-iron-driven feedback loop, establishing ferroptosis as the predominant cell death mechanism. This stage-dependent shift provides critical insights into PD pathogenesis and suggests distinct therapeutic windows for neuroprotection. ANN NEUROL 2026.