Rhein-Emodin Combination Activates UQCRC1 to Attenuate MPP⁺-Induced Ferroptosis in Dopaminergic Neurons

Ferroptosis plays a critical role in Parkinson's disease (PD). This study investigates the neuroprotective effect of a combination of two natural anthraquinones, rhein and emodin, against ferroptosis, focusing on the mitochondrial complex III subunit UQCRC1. Using network pharmacology and experimental validation in erastin/MPP⁺-induced PC12 cells, we found that the optimal rhein-emodin combination potently inhibited ferroptotic cell death. This effect was associated with restored mitochondrial function, reduced lipid peroxidation, and the coordinated regulation of ferroptosis-related proteins, including the upregulation of GPX4 and FTH and downregulation of ACSL4. Crucially, the co-treatment markedly activated UQCRC1 expression. Furthermore, UQCRC1 knockdown abolished these anti-ferroptotic effects, establishing it as an essential mediator. Our findings demonstrate that the rhein-emodin combination attenuates ferroptosis primarily through UQCRC1 activation, highlighting its therapeutic promise and identifying UQCRC1 as a novel regulatory node for PD intervention.