{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T23:26:17Z","timestamp":1793229977998,"version":"4.5.0"},"reference-count":155,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32170707"],"award-info":[{"award-number":["32170707"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32170784"],"award-info":[{"award-number":["32170784"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32570918"],"award-info":[{"award-number":["32570918"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["32470803"],"award-info":[{"award-number":["32470803"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Huntingtin (HTT) is a large, ubiquitously expressed scaffold protein that participates in multiple cellular processes, including vesicular transport, transcriptional regulation, and energy metabolism. The mutant form of HTT (mHTT), characterized by an abnormal polyglutamine (polyQ) expansion in its N-terminal region, is the causative agent of Huntington\u2019s disease (HD), a progressive neurodegenerative disorder. Current therapeutic efforts for HD have primarily focused on lowering HTT levels through gene silencing or promoting mHTT degradation. However, accumulating evidence suggests that post-translational modifications (PTMs) of HTT\u2014such as phosphorylation, ubiquitination, acetylation, and SUMOylation\u2014play pivotal roles in modulating HTT\u2019s conformation, aggregation propensity, subcellular localization, and degradation pathways. These modifications regulate the balance between HTT\u2019s physiological functions and pathological toxicity. Importantly, dysregulation of PTMs has been linked to mHTT accumulation and selective neuronal vulnerability, highlighting their relevance as potential therapeutic targets. A deeper understanding of how individual PTMs and their crosstalk regulate HTT homeostasis may not only provide mechanistic insights into HD pathogenesis but also uncover novel, more specific strategies for intervention. In this review, we summarize recent understanding on HTT PTMs, discuss their implications for disease modification, and outline critical knowledge gaps that remain to be addressed.<\/jats:p>","DOI":"10.3390\/ijms262210907","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T08:57:41Z","timestamp":1762851461000},"page":"10907","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Post-Translational Modifications of Huntingtin: Mechanistic Insights and Therapeutic Opportunities in Huntington\u2019s Disease"],"prefix":"10.3390","volume":"26","author":[{"given":"Xiaoxia","family":"Zhang","sequence":"first","affiliation":[{"name":"Biomedical Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengping","family":"Zhang","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuangui","family":"Wang","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, School of Life Sciences and Medicine, Shandong University of Technology, Zibo 255049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S1474-4422(10)70245-3","article-title":"Huntington\u2019s disease: From molecular pathogenesis to clinical treatment","volume":"10","author":"Ross","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.1523\/JNEUROSCI.19-07-02522.1999","article-title":"Nuclear and Neuropil Aggregates in Huntington\u2019s Disease: Relationship to Neuropathology","volume":"19","author":"Gutekunst","year":"1999","journal-title":"J. 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