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This study primarily investigates the expression, function, and mechanisms of UCHL3 in GC. Clinical samples and bioinformatics analysis indicated that UCHL3 is overexpressed in GC tissues compared to adjacent normal tissues, with higher expression levels correlating with worse prognosis. Functional assays demonstrated that UCHL3 promotes GC cell proliferation, invasion, and migration, accelerates cell cycle progression, and induces epithelial\u2013mesenchymal transition (EMT). In vivo studies using a cell line-derived xenograft (CDX) model confirmed that UCHL3 enhances GC proliferation, and its therapeutic potential was validated in patient-derived xenografts (PDX). Mechanistically, transcriptomic analysis and validation experiments identified the AKT\/CCND1 signaling pathway as a key mediator of UCHL3-driven GC progression. Co-immunoprecipitation (Co-IP) and liquid chromatography-mass spectrometry identified potential UCHL3-binding proteins, notably the AKT activator ENO1. Molecular docking simulations, Co-IP, and GST-pull down assays further confirmed the interaction, mapping the binding regions between UCHL3 (AA 179-230) and ENO1 (AA 140-434). Cycloheximide (CHX) and in vivo ubiquitination assays demonstrated that UCHL3 deubiquitinates and stabilizes ENO1, thus extending its half-life, while UCHL3 inhibition produced the opposite effect. A C95A point mutation significantly impaired UCHL3\u2019s deubiquitination function on ENO1. Further studies revealed UCHL3 removes K48-linked polyubiquitin chains from ENO1 at lysine 92, activating the AKT\/CCND1 signaling pathway. In addition, the small-molecule inhibitor TCID, specific for UCHL3, inhibited this deubiquitination, counteracting pro-tumorigenic effects. In vitro and in vivo experiments demonstrated that TCID increased the sensitivity of GC cells to CDK4\/6 inhibitors palbociclib. These findings suggest that UCHL3 contributes to GC progression and represents a promising therapeutic target for GC treatment.<\/jats:p>","DOI":"10.1038\/s41419-025-08153-3","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T14:23:29Z","timestamp":1763735009000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["UCHL3 depletion inhibits gastric cancer progression and enhances palbociclib sensitivity by regulating the AKT\/CCND1 signaling axis via ENO1 ubiquitination"],"prefix":"10.1038","volume":"16","author":[{"given":"Weiqi","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Le","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanjuan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjiao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2626-4870","authenticated-orcid":false,"given":"Jinbo","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingru","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianping","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3674-156X","authenticated-orcid":false,"given":"Ziling","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8734-584X","authenticated-orcid":false,"given":"Xiaojun","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"8153_CR1","first-page":"209","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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All methods were performed in accordance with the relevant guidelines and regulations. Informed consent was obtained from all participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"850"}}