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Here, we reveal that the deubiquitinase OTU deubiquitinase 7\u2009A (OTUD7A) critically regulates CNS regeneration by modulating histidine triad nucleotide-binding protein 1 (HINT1) stability. OTUD7A stabilizes HINT1 protein through specific removal of K63-linked ubiquitin chains at lysine 7. Screening of the small-molecule deubiquitinase inhibitor PR-619 identified HINT1 as a key ubiquitination-regulated target. Notably, genetic knockdown of\n                    <jats:italic>Hint1<\/jats:italic>\n                    alone was sufficient to improve RGC survival and promote optic nerve regeneration, thereby activating mTOR signaling, while PR-619 administration enhanced tissue preservation and axon repair after spinal cord injury. A multi-gene therapeutic strategy further enhanced optic nerve regeneration in the optic nerve crush (ONC) model. These findings identify the OTUD7A\u2013HINT1\u2013mTOR axis as a potential therapeutic target in CNS regeneration.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-09005-4","type":"journal-article","created":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T10:35:38Z","timestamp":1781951738000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting OTUD7A-HINT1 deubiquitination activates mTOR signaling for CNS regeneration"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8682-6520","authenticated-orcid":false,"given":"Zhen-Gang","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5391-6660","authenticated-orcid":false,"given":"Yong-Quan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lai-Yang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze-Yu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling-Wei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1525-9969","authenticated-orcid":false,"given":"Feng-Quan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5273-2145","authenticated-orcid":false,"given":"Bo-Yin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2941-4667","authenticated-orcid":false,"given":"Chang-Mei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,20]]},"reference":[{"key":"9005_CR1","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1038\/s41392-025-02177-z","volume":"10","author":"Q Zhang","year":"2025","unstructured":"Zhang Q, Niu Y, Li Y, Xia C, Chen Z, Chen Y, et al. 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