Synergistic Anti-Ferroptosis with a Minimalistic, Peroxide-Triggered Carbon Monoxide Donor for Parkinson's Disease.

Parkinson's disease (PD) is a debilitating neurodegenerative disease, with current treatments primarily focusing on improving dopaminergic activity, providing symptomatic relief but failing to halt disease progression. Ferroptosis drives PD pathogenesis and is a potential therapeutic target. Herein, we introduce a novel peroxide-activated carbon monoxide (CO) donor, PCOD, featuring a streamlined structure designed to potentially enhance blood-brain barrier (BBB) penetration and optimize therapeutic outcomes. PCOD releases CO upon activation by nucleophilic peroxides, e.g., ONOO- and H2O2. This mechanism provides a potent strategy against ferroptosis: first, scavenging peroxides that generate oxidative radicals involved in ferroptosis, and second, CO is proposed to inhibit Fenton chemistry through coordination to Fe2+. In MPTP-treated mice, PCOD prevents dopaminergic neuron loss in the substantia nigra and alleviates PD symptoms. This peroxide-triggered CO release offers a promising and innovative strategy to combat ferroptosis and neurodegeneration in PD.