HCA2 activation confers neuroprotection in Parkinson's disease models by suppressing oxidative stress and ferroptosis via the Nrf2/MGST1/GPX4 pathway.

Abstract

Emerging evidence implicates oxidative stress and ferroptosis as key contributors to Parkinson's disease (PD) progression. While the niacin receptor HCA2 has been linked to antioxidant effects, its role in modulating neuronal oxidative damage and ferroptosis remains unexplored. This study focuses on the impact of HCA2 on inhibiting neuronal oxidative damage and mitigating ferroptosis. Results revealed that HCA2-deficient mice demonstrated increased vulnerability to MPTP-induced PD pathogenesis. Mechanistically, HCA2 activation inhibits oxidative stress and ferroptosis via Nrf2/MGST1/GPX4-mediated reduction of ROS and mitochondrial damage. Furthermore, in vivo results showed that activation of HCA2 in dopaminergic neurons significantly alleviated MPTP-induced neurodegeneration and motor dysfunction through upregulation of MGST1, supporting its therapeutic potential. In conclusion, this study provides robust evidence that HCA2 offers neuroprotection in PD models by concurrently suppressing oxidative stress and ferroptosis. These findings position HCA2 as a promising target for therapeutic intervention in neurodegenerative disorders.