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Integrative multi\u2010omics and machine\u2010learning analyses across independent cohorts identified CYYR1 as a frequently downregulated transmembrane protein in LUAD, with low expression associated with poor prognosis and promoter hypermethylation. CYYR1 restoration suppressed LUAD cell proliferation, migration, invasion, tumor growth, and metastasis. Mechanistically, CYYR1 facilitated TRIM21\u2010dependent ubiquitination and proteasomal degradation of HMMR, thereby reducing CDC20\u2010associated oncogenic signaling. Biochemical and cellular analyses supported this CYYR1\u2013TRIM21\u2013HMMR regulatory relationship, while a patient\u2010derived LUAD organoid model provided proof\u2010of\u2010concept evidence that CYYR1 restoration inhibited organoid growth and reduced HMMR, CDC20, and Ki67 expression. CYYR1 restoration also increased cisplatin sensitivity. Genistein treatment was associated with CDC20 modulation and enhanced cisplatin response, and cellular thermal shift assays provided evidence consistent with CDC20 engagement, although CDC20 dependence of the Genistein response remains unproven. Collectively, these findings identify CYYR1 as an epigenetically dysregulated tumor\u2010suppressive factor that regulates HMMR stability through a TRIM21\u2010dependent mechanism and reveal a potential therapeutic vulnerability in CYYR1\u2010deficient LUAD.<\/jats:p>","DOI":"10.1002\/advs.77890","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T02:57:36Z","timestamp":1791773856000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Silencing of CYYR1 Promotes Lung Adenocarcinoma Progression Through TRIM21\u2010Dependent Regulation of HMMR Stability"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4202-9173","authenticated-orcid":false,"given":"Fengsheng","family":"Dai","sequence":"first","affiliation":[{"name":"Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis Chongqing University Cancer Hospital Chongqing 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