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Here, we demonstrate that NDST3\u2010mediated epigenetic reprogramming halts neuronal degeneration and restores motor function in an animal model of PD. Following NDST3 administration, the DN and its associated circuits in the substantia nigra and striatum showed marked revitalization, accompanied by a considerable alleviation of PD\u2010like motor deficits. Integrative single\u2010cell and spatial RNA sequencing with CUT&amp;RUN revealed that NDST3\u2010driven reactivation of pathways is linked to neuronal survival, synaptic integrity, and steering of compromised cells toward a resilient phenotype. By recalibrating the epigenetic landscape, NDST3 promotes cellular maintenance and functional recovery in key motor circuits. These findings highlight NDST3's therapeutic potential as an epigenetic modulator of PD. These findings provide insights into the mechanisms underlying neuronal revitalization and highlight the potential of NDST3 as a novel agent for restoring brain function in neurodegenerative conditions.<\/jats:p>","DOI":"10.1002\/advs.202507323","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T10:10:36Z","timestamp":1763719836000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["NDST3\u2010Induced Epigenetic Reprogramming Reverses Neurodegeneration in Parkinson's Disease"],"prefix":"10.1002","volume":"13","author":[{"given":"Yujung","family":"Chang","sequence":"first","affiliation":[{"name":"Laboratory of Regenerative Medicine for Neurodegenerative Disease Stand Up Therapeutics Inc. 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