Abstract

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. Graphical The rhein-emodin combination activates UQCRC1 to attenuate MPP + -induced ferroptosis in dopaminergic neurons.