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Moreover, Stress granules (SGs) was found to enhance the stress adaptation capability of tumor cells, becoming an important mechanism for drug resistance in various cancers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We developed sunitinib-resistant patient-derived xenograft (PDX) and organoid (PDO) models to investigate sunitinib resistance in ccRCC. Proteomic analysis identified UBAP2L as a key mediator of this resistance. To explore its role in stress granule formation and sunitinib resistance, we conducted both in vitro and in vivo studies. We further elucidated the regulatory mechanisms of UBAP2L O-GlcNAcylation using immunoprecipitation, mass spectrometry, modification-based proteomics, RNA sequencing (RNA-seq), and RNA immunoprecipitation sequencing (RIP-seq).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In this study, enrichment of UBAP2L was elucidated to be significantly associated with sunitinib-resistant ccRCC patient-derived xenograft (PDX) model. Functional experiments showed that UBAP2L protected ccRCC from apoptosis and promoted ccRCC prolifecation and angiogenesis upon sunitinib treatment, thus enhancing drug resistance of ccRCC cells. Furthermore, mechanistic investigation demonstrated that O-GlcNAcylation of UBAP2L promoted its protein stability via inhibiting TRIM37-mediated ubiquitination and it regulated stress granule formation, thereby enhancing the mRNA stability of Melk and activating the PI3K signaling pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results validated the significant roles of O-GlcNAcylation of UBAP2L in ccRCC sunitinib resistance, which provided an innovative theoretical basis for the clinical diagnosis and therapy of ccRCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-025-03534-0","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T12:34:08Z","timestamp":1759235648000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["O-GlcNAcylation of UBAP2L regulates stress granule formation and sunitinib resistance in clear cell renal cell carcinoma"],"prefix":"10.1186","volume":"44","author":[{"given":"Jiajun","family":"Xing","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baochao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songbo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zengjun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenkui","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"issue":"8","key":"3534_CR1","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.1158\/1078-0432.CCR-21-2972","volume":"28","author":"F Meric-Bernstam","year":"2022","unstructured":"Meric-Bernstam F, Tannir NM, Iliopoulos O, Lee RJ, Telli ML, Fan AC, DeMichele A, Haas NB, Patel MR, Harding JJ, et al. 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The collection and analysis of tumor and clinical data were approved by the Ethics Committee of Nanjing Medical University (approval No. 2021-SR-430), and the research adhered to established ethical standards. Animal studies were conducted following approval from the Institutional Animal Care and Use Committee (IACUC) of Nanjing Medical University (approval No. 2406068). The construction of the xenotransplantation model complied with institutional guidelines and received approval from the IACUC of Nanjing Medical University.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All the authors consent for this manuscript publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"273"}}