Work

Hyperglycemia Aggravates 6‐Hydroxydopamine‐Induced Neuronal Ferroptosis via SLC7A11 ‐Dependent Pathway in Diabetic PD Rat Model

Year: 2025

Type: article

Abstract: BACKGROUND: The epidemiological link between diabetes mellitus (DM) and Parkinson's disease (PD) is well-established, but the mechanistic basis remains unclear. Chronic hyperglycemia, a hallmark of DM, may exacerbate PD pathogenesis, though the underlying molecular pathways are poorly defined. METHODS: Using an integrative approach combining metabolomic profiling, proteomic analysis, and molecular characterization in vitro and in vivo models, we investigated the role of the cystine/glutamate antiporter system in glucose-induced neuronal vulnerability. SLC7A11 expression was genetically restored, and adeno-associated viral vectors delivered SLC7A11 to the nigrostriatal pathway in a streptozotocin-induced diabetic PD rat model to evaluate neuroprotection. RESULTS: Chronic high glucose impaired SLC7A11 function, reducing cystine uptake and depleting intracellular glutathione in dopaminergic neurons, increasing susceptibility to 6-hydroxydopamine-induced ferroptosis. SLC7A11 restoration rescued neuronal viability, restored redox homeostasis, and attenuated motor deficits and dopaminergic neuron loss in the diabetic PD model. Mechanistically, SLC7A11 enhanced glutathione synthesis and suppressed ferroptosis signaling pathways. CONCLUSION: Chronic hyperglycemia disrupts the cystine/SLC7A11/glutathione axis, accelerating neuronal degeneration and linking DM to PD susceptibility. SLC7A11 emerges as a potential therapeutic target to mitigate neurodegeneration in diabetic individuals at risk for PD.

Source: CNS Neuroscience & Therapeutics

DOI: 10.1111/cns.70487

Authors: Ya Zhao, Dan Wang, Yanwei Wang, Dan Mu, Lang Qu, Rong Li

Institutions: North Sichuan Medical University, Jiaxing University, Affiliated Hospital of North Sichuan Medical College

Language: English

Topic: Parkinson's Disease Mechanisms and Treatments

Subfield: Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,140