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However, despite its initial efficacy, therapeutic resistance invariably develops in many RCC patients, underscoring the urgent need for novel strategies to overcome this limitation. We constructed patient\u2010derived xenograft (PDX) models using surgically resected RCC tissues and subsequently established stable sunitinib\u2010resistant and sunitinib\u2010sensitive PDX models. Proteomic profiling was performed to identify key regulators involved in sunitinib resistance. Mechanistic studies were conducted to investigate the molecular interactions among DHODH, TRIM28, and VEGFA. The therapeutic potential of lisaftoclax was evaluated in combination with sunitinib. Proteomic profiling identified DHODH as a key regulator in the development of sunitinib resistance in RCC. Mechanistically, DHODH competes with the E3 ligase TRIM37 for binding to TRIM28, thereby stabilizing TRIM28 by inhibiting its ubiquitination. TRIM28 subsequently activates VEGFA transcription, which promotes sunitinib resistance in RCC. Lisaftoclax, a small\u2010molecule inhibitor that disrupts the DHODH\u2010TRIM28 interaction, potentiates sunitinib efficacy and exerts a synergistic therapeutic effect. Collectively, our findings identify DHODH as a critical therapeutic target for overcoming sunitinib resistance in RCC and provide a novel strategy for the treatment of RCC.<\/jats:p>","DOI":"10.1002\/advs.76266","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T19:43:18Z","timestamp":1782243798000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["DHODH Drives Sunitinib Resistance Via a Non\u2010Enzymatic Mechanism by Inhibiting TRIM28 Ubiquitination and Consequent VEGFA Activation in RCC"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2227-7740","authenticated-orcid":false,"given":"Shijie","family":"Qian","sequence":"first","affiliation":[{"name":"Department of Urology First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9982-0000","authenticated-orcid":false,"given":"Shihang","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Urology First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhipeng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Urology First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiheng","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Urology First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Urology First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baochao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohai","family":"Xi","sequence":"additional","affiliation":[{"name":"Department of Urology First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7583-4750","authenticated-orcid":false,"given":"Zengjun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5679-4805","authenticated-orcid":false,"given":"Jiajun","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Urology First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1947-5167","authenticated-orcid":false,"given":"Aiming","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Urology First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21763"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2005.11.035"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.05.061"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059817"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059796"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12222"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.9"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.02.2574"},{"key":"e_1_2_14_10_1","first-page":"327","article-title":"In Vivo Antitumor Activity of SU11248, a Novel Tyrosine Kinase Inhibitor Targeting Vascular Endothelial Growth Factor and Platelet\u2010derived Growth Factor Receptors: Determination of a Pharmacokinetic\/Pharmacodynamic Relationship","volume":"9","author":"Mendel D. 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