Aleksandra Fesiuk Aleksandra Fesiuk Daniel Pölöske Daniel Pölöske Elvin D. de Araujo Elvin D. de Araujo Geordon A. Frere Geordon A. Frere Timothy B. Wright Timothy B. Wright Gary Tin Gary Tin Yasir S. Raouf Yasir S. Raouf Olasunkanmi O. Olaoye Olasunkanmi O. Olaoye Ji Sung Park Ji Sung Park Nicolas Blavet Nicolas Blavet Boris Tichý Boris Tichý Michaela Schlederer Michaela Schlederer Sandra Högler Sandra Högler Michael Wolf Michael Wolf Cécile Philippe Cécile Philippe Osman Aksoy Osman Aksoy Adam Varady Adam Varady Alejandro Medaglia Mata Alejandro Medaglia Mata Maxim Varenicja Maxim Varenicja Boglárka Szabó Boglárka Szabó Theresa Weiss Theresa Weiss Gabriel Wasinger Gabriel Wasinger Torben Redmer Torben Redmer Heidi A. Neubauer Heidi A. Neubauer Martin Susani Martin Susani Clemens P. Spielvogel Clemens P. Spielvogel Jing Ning Jing Ning Maik Dahlhoff Maik Dahlhoff Martin Schepelmann Martin Schepelmann Richard Kennedy Richard Kennedy Richard Moriggl Richard Moriggl Geoffrey Brown Geoffrey Brown Jenny Persson Jenny Persson Christopher Gerner Christopher Gerner Vojtech Bystry Vojtech Bystry Oldamur Hollóczki Oldamur Hollóczki David M. Heery David M. Heery Patrick T. Gunning Patrick T. Gunning Olaf Merkel Olaf Merkel Brigitte Hantusch Brigitte Hantusch Lukas Kenner Lukas Kenner Aleksandra Fesiuk Aleksandra Fesiuk Springer 2025 Thyroid hormone (TH) signaling plays a major role in the development, energy homeostasis, and metabolism of most tissues. Recent studies have identified THs as drivers of prostate cancer (PCa) development and progression. We reported that the T3-scavenger protein µ-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 β (TRβ), which is the main effector of TH signaling, in the context of PCa. The use of the TRβ-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 Nkx3.1 and KLK3 (PSA). 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 TRβ expression and mutations in the TH signaling pathway are associated with the onset of PCa. Collectively, these results establish TRβ as a mediator of tumorigenesis in PCa and identify NH-3 as a promising therapeutic agent for targeting AR signaling, particularly in CRPC. PDFDocument eng 2026-03-30T08:41:11.159064Z 2025 Thyroid Hormone Receptor β Prostate Cancer NH-3 Androgen Receptor Murine PCa Model 8584378 b application/pdf http://creativecommons.org/licenses/by/4.0/