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However, the reactivation of AR signaling during antiandrogen therapy remains a major factor contributing to resistance against currently used clinical antagonists. As a result, strategies aimed at degrading the AR protein have garnered substantial attention for CRPC therapy. In this study, we first established a high\u2010throughput screening (HTS) model for AR degraders based on Cell\u2010ELISA technology. Using this model to screen our in\u2010house chemical database, we identified a novel AR degrader, ZC9. Functional evaluations demonstrated that ZC9 exhibits significant inhibitory activity against CRPC cell proliferation and effectively downregulates AR protein levels. Mechanistic studies revealed that ZC9 directly binds to AR and inhibits dihydrotestosterone (DHT)\u2010induced nuclear translocation of AR. Furthermore, ZC9 promotes AR degradation via the ubiquitin\u2013proteasome system (UPS) and suppresses AR transcriptional activity. Collectively, these findings highlight ZC9 as a promising lead compound for the treatment of CRPC.<\/jats:p>","DOI":"10.1096\/fj.202403170rr","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T15:15:09Z","timestamp":1760714109000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell\u2010\n                    <scp>ELISA<\/scp>\n                    \u2010Based High\u2010Throughput Screening Leads to the Discovery of Androgen Receptor Degraders to Conquer Castration\u2010Resistant Prostate Cancer"],"prefix":"10.1096","volume":"39","author":[{"given":"Yang","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Biology Zhejiang Normal University  Jinhua P. R. China"},{"name":"Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry Zhejiang Normal University  Jinhua P. R. 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