A near-infrared ratiometric optical sensor for real-time monitoring hydroxyl radical levels in ferroptosis-mediated Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder with complex pathogenesis. Ferroptosis, an iron-regulated cell death driven by lipid peroxidation, is closely linked to PD progression. Excessive hydroxyl radical (•OH) accumulation can cause severe neural damage and is associated with neurodegenerative diseases, but its role in PD remains unclear. Currently, there are no fluorescent probes to monitor •OH changes during ferroptosis and PD. Here, we developed a series of •OH-responsive ratiometric near-infrared (NIR) sensors (DCM-PD1∼8) to monitor •OH levels in ferroptosis-mediated PD. DCM-PD2, which showed the best photophysical properties, demonstrated high sensitivity for detecting •OH (detection limit ∼22.9 nM), excellent selectivity, a response time under 30 min, and deep tissue penetration. With superior membrane permeability and low toxicity, DCM-PD2 is ideal for tracking both endogenous and externally introduced •OH variations. Importantly, it can cross the blood-brain barrier (BBB), enabling real-time imaging of •OH activity in the brains of PD model mice for the first time. The imaging results revealed a significant increase in •OH levels in the brain regions of PD model mice. Additionally, using DCM-PD2, we demonstrated that curcumin (Cur) exerts neuroprotective effects in PD models primarily by regulating ferroptosis through the Nrf2/SLC7A11 signaling pathway. These findings highlight DCM-PD2 as a reliable and effective tool for the precise diagnosis and treatment of ferroptosis-mediated PD.