{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T14:34:08Z","timestamp":1782398048141,"version":"3.54.5"},"reference-count":48,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["21961142009"],"award-info":[{"award-number":["21961142009"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82360805"],"award-info":[{"award-number":["82360805"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Parkinson's disease (PD) is a common neurodegenerative movement disorder, mainly characterized by the degeneration and loss of dopaminergic neurons in the substantia nigra. Oxidative stress is considered to be a key contributor to dopaminergic neuronal degeneration, triggering a series of downstream events such as mitochondrial dysfunction, neuroinflammation and misfolded protein aggregation, which ultimately exacerbate the development of PD. Deubiquitinating enzymes (DUBs) regulate oxidative stress, but their roles in PD remain unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>GEO database analysis and western blotting were used to analyze the expression of YOD1in PD patients and PD mouse models. Genetic knockout (KO) of YOD1 was performed to assess its effects in PD pathogenesis. The substance of YOD1 was measured via co\u2010immunoprecipitation (Co\u2010IP) coupled with LC\u2010MS\/MS analysis. Then the effect of YOD1\u2010mediated motor deficits and oxidative damage were investigated using open field test, swimming test, pole test, immunofluorescence (IF) and cellular analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>YOD1 was highly expressed in PD patients and 6\u2010OHDA\u2010induced PD model mice and mediated reactive oxygen species (ROS) production. YOD1 KO ameliorated motor impairments and oxidative stress in PD model mice. YOD1 directly bound PKM2 and reduces its ubiquitination level by removing the K63\u2010linked ubiquitin chain of PKM2, thereby increasing the tetramer level and reducing the dimer level of PKM2. It then inhibited dimerized PKM2 entry into the nucleus and regulated Nrf2\u2010mediated antioxidant responses, but YOD1 does not change the stability of PKM2 protein.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study identifies YOD1 as a oxidative\u2010sensitive regulator of PD progression, operating via the YOD1\u2010PKM2\u2010Nrf2 axis. Targeting YOD1 may offer a novel therapeutic strategy for PD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>YOD1 is highly elevated in different PD model mice and patients with PD.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>YOD1 is a key regulator in oxidative stress and PD pathology.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>YOD1\u2010deficient exhibit a protective effect on neuronal oxidative injury.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>YOD1 targets PKM2-Nrf2 axis in response to oxidative stress.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.70420","type":"journal-article","created":{"date-parts":[[2025,7,19]],"date-time":"2025-07-19T02:29:48Z","timestamp":1752892188000},"source":"Crossref","is-referenced-by-count":5,"title":["YOD1 regulates oxidative damage of dopamine neurons in Parkinson's disease by deubiquitinating 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