Targeting oxidative stress and mitochondrial dysfunction via URG7 overexpression in an in vitro Parkinson's disease neuronal model

Unlabelled: Neurodegenerative diseases represent a major healthcare challenge for aging populations, characterized by the progressive decline of neuronal function and subsequent brain atrophy. Despite differences in the brain regions affected and the underlying causes, these pathologies share common cellular and molecular mechanisms, including oxidative stress and mitochondrial dysfunction. Among neurodegenerative disorders, Parkinson’s disease (PD) is particularly associated with oxidative stress–driven dopaminergic neurodegeneration, in which reactive oxygen species (ROS) play a crucial role by contributing to cellular damage and neuronal death. This study investigates the role of Up-Regulated Gene 7 (URG7), a protein localized in the endoplasmic reticulum, in modulating oxidative stress in genetically engineered SH-SY5Y neuroblastoma cells overexpressing URG7, exposed to 6-hydroxydopamine (6-OHDA), a neurotoxin used as a Parkinson’s disease mimetic. We hypothesized that URG7 overexpression mechanistically modulates oxidative stress responses and mitochondrial integrity in neuronal cells subjected to Parkinson’s disease–related oxidative insult. Our results demonstrate that URG7 significantly reduces cell death and oxidative stress by enhancing cellular antioxidant defenses. Specifically, URG7 upregulates key antioxidant enzymes, including catalase and superoxide dismutase 2, and activates the Nrf2 signaling pathway, crucial for cellular detoxification. Furthermore, URG7 preserves mitochondrial membrane potential and regulates the expression of proteins involved in mitochondrial quality control, such as PINK1, Parkin, and DJ-1. Overall, these findings suggest that URG7 acts as a protective sentinel against oxidative stress and mitochondrial dysfunction, highlighting its potential as a therapeutic target for neurodegenerative diseases, particularly Parkinson’s disease. Further investigation into the molecular mechanisms of URG7, building on the biological evidence provided here, could pave the way for new neuroprotective strategies aimed at counteracting oxidative damage and promoting neuronal survival. Supplementary information: The online version contains supplementary material available at 10.1038/s41598-026-38925-6.