PRDX2 Mediates the Neuroprotective Role of Umbilical Cord Blood Exosomes via the CYP2J2/8,9-EET Pathway in Models of Parkinson's Disease.
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Parkinson's disease (PD) is a severe neurodegenerative disorder marked by progressive dopaminergic loss, oxidative stress, metabolic dysregulation, and neuroinflammation. Umbilical cord blood-derived exosomes (UCB-Exos) have emerged as a promising cell-free therapeutic strategy, yet the precise molecular mechanisms underlying their neuroprotective properties remain largely unknown. This study highlights Peroxiredoxin-2 (PRDX2) as an important antioxidant protein within UCB-Exos that mediates their neuroprotective effects in PD models. Using advanced multi-omics approaches, including proteomics, metabolomics, and transcriptomics, we demonstrate that PRDX2 is selectively enriched in UCB-Exos compared to peripheral blood-derived exosomes. UCB-Exos, through the delivery of PRDX2, partially restore antioxidant defenses in neurons, attenuate neuroinflammation, and promote cellular survival. Moreover, UCB-Exos were found to modulate arachidonic acid metabolism by upregulating the levels of 8,9-epoxyeicosatrienoic acid (8,9-EET), a key metabolite with anti-inflammatory properties. Mechanistically, PRDX2 appears to protect the enzyme CYP2J2 from oxidative degradation, facilitating the production of 8,9-EET and reducing the NF-κB/COX-2-driven inflammatory response, thus potentially mitigating neurodegeneration. This study provides evidence for a potential pathway, the PRDX2-mediated metabolic regulatory pathway, and highlights the therapeutic potential of UCB-Exos, offering a novel strategy in the development of exosome-based treatments targeting oxidative stress and neuroinflammation in neurodegenerative diseases.