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Recent studies have identified THs as drivers of prostate cancer (PCa) development and progression. We reported that the T3-scavenger protein \u00b5-crystallin (CRYM) regulates the development and progression of PCa and that this involved crosstalk with androgen receptor (AR) signaling. However, the mechanisms remain incompletely understood. Here, we explored the role of thyroid hormone receptor \u03b2 (TR\u03b2), which is the main effector of TH signaling, in the context of PCa. The use of the TR\u03b2-selective antagonist NH-3 inhibited PCa cell proliferation in vitro and reduced tumor size in PCa xenograft models in vivo. Notably, NH-3 was highly effective in the engrafted 22Rv1 cell line, a model for castration-resistant PCa (CRPC). Mechanistic studies revealed that NH-3 downregulates AR and the AR target genes <jats:italic>Nkx3.1<\/jats:italic> and <jats:italic>KLK3<\/jats:italic> (<jats:italic>PSA<\/jats:italic>). NH-3 was a more effective anticancer agent than enzalutamide, and their combined use was synergistic. Evidence from human datasets corroborates our findings, whereby elevated TR\u03b2 expression and mutations in the TH signaling pathway are associated with the onset of PCa. Collectively, these results establish TR\u03b2 as a mediator of tumorigenesis in PCa and identify NH-3 as a promising therapeutic agent for targeting AR signaling, particularly in CRPC.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical Abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1186\/s12943-025-02451-2","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T13:13:44Z","timestamp":1760447624000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Thyroid hormone receptor beta signaling is a targetable driver of prostate cancer 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