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Through proteomic profiling of CRPC and primary PCa cells, we identify G Protein Nucleolar 3 (GNL3) as a novel AR coregulator. GNL3 physically interacts with AR, enhances its chromatin occupancy, and directly coactivates transcriptional programs that promote cell proliferation, including NEK2 and CDC20. Concurrently, GNL3 functions as a corepressor of immune\u2010responsive genes such as CXCL10 and TAP1 via class I histone deacetylases (HDACs), thereby facilitating CD8+ T cell elimination and establishing an immunosuppressive tumor microenvironment. GNL3 expression and AR\u2010GNL3 complex formation progressively increase from normal prostate to CRPC and correlate with poor clinical outcomes. Functionally, GNL3 knockdown sensitizes CRPC cells to AR antagonists and impairs tumor growth and metastasis. Furthermore, we demonstrate that combinatorial inhibition of NEK2, class I HDACs, and AR signaling can be a potential therapeutic strategy for CRPC. Overall, these findings establish GNL3 as a dual\u2010function AR coregulator and therapeutic target, providing mechanistic insights into transcriptional regulation and immune evasion in advanced PCa.<\/jats:p>","DOI":"10.1002\/advs.202516411","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T17:01:57Z","timestamp":1772989317000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["GNL3 Orchestrates AR Transcriptional Programs to Drive Castration\u2010Resistant Prostate Cancer and Immune Evasion"],"prefix":"10.1002","volume":"13","author":[{"given":"Cuiting","family":"Zhang","sequence":"first","affiliation":[{"name":"Cancer Centre University of Macau  Taipa Macau SAR China"},{"name":"Centre for Precision Medicine Research and Training University of Macau  Taipa Macau SAR China"},{"name":"MoE Frontiers Science Center for Precision Oncology University of Macau  Taipa Macau SAR China"},{"name":"Department of Biomedical Sciences Faculty of Health Sciences University of Macau  Taipa Macau SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tin Long","family":"Cheong","sequence":"additional","affiliation":[{"name":"Cancer Centre University of Macau  Taipa Macau SAR China"},{"name":"Centre for Precision Medicine Research and Training University of Macau  Taipa Macau SAR China"},{"name":"MoE Frontiers Science Center for Precision Oncology University of Macau  Taipa Macau SAR China"},{"name":"Department of Biomedical Sciences Faculty of Health Sciences University of Macau  Taipa Macau SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitin","family":"Narwade","sequence":"additional","affiliation":[{"name":"Cancer Centre University of Macau  Taipa Macau SAR China"},{"name":"Centre for Precision Medicine Research and Training University of Macau  Taipa Macau SAR China"},{"name":"MoE Frontiers Science Center for Precision Oncology University of Macau  Taipa Macau SAR China"},{"name":"Department of Biomedical Sciences Faculty of Health Sciences University of Macau  Taipa Macau SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Dong","sequence":"additional","affiliation":[{"name":"Fudan University Shanghai Cancer Center &amp; 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