REV-ERBα inhibitor rescues MPTP/MPP-induced ferroptosis of dopaminergic neuron through regulating FASN/SCD1 signaling pathway.

Circadian disruption is a risk factor for Parkinson's disease (PD). Ferroptosis, a cellular death process, assumes a pivotal role in the degeneration of dopaminergic neurons in PD. Despite its significance, the potential contribution of circadian clock proteins to PD through the modulation of ferroptosis remains elusive. Our investigation unveiled a reduction in the circadian clock protein REV-ERBα in both MPTP/MPP and ferroptosis models. REV-ERBα actively promotes ferroptosis by binding to the RORE cis-element and suppressing the transcription of and , two genes that inhibit ferroptosis. Notably, inhibiting REV-ERBα exhibited a discernible mitigating effect on ferroptosis and the ensuing dopaminergic neuron damage induced by MPTP/MPP. Consequently, targeting REV-ERBα emerges as a promising strategy for inhibiting ferroptosis and presents a novel therapeutic avenue for PD.