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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,29]]},"abstract":"<jats:p>Resistance to androgen receptor (AR)-targeted therapies remains a major clinical challenge in advanced prostate cancer. Here we identify follistatin (FST), TGF\u03b2 superfamily antagonist, as a key driver of AR-independence and treatment resistance. During anti-AR therapy, cancer cells progressively lose the positive feedback loop between AR and BMP signaling, leading to FST upregulation that further suppresses this circuit. FST antagonizes BMP11-dependent AR maintenance and upregulates the lineage plasticity regulator SOX9, conferring resistance to enzalutamide while promoting stem-like properties and metastatic capabilities. FST also remodels the tumor microenvironment by driving osteoclastogenesis and compromising T cell effector function. Clinically, FST inversely correlates with PSA levels and associates with poor outcomes in enzalutamide-treated patients. We developed FST-Trap, which effectively neutralizes FST, resensitizes resistant tumors to AR-targeted therapy, and enhances immunotherapy efficacy. This establishes FST as both a biomarker and therapeutic target for AR-independent prostate cancer.<\/jats:p>","DOI":"10.1073\/pnas.2603564123","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:59:47Z","timestamp":1790269187000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Follistatin drives AR-independent prostate cancer through BMP signaling inactivation and microenvironmental remodeling"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7031-9662","authenticated-orcid":false,"given":"Xiaoxian","family":"Shi","sequence":"first","affiliation":[{"name":"Sir Run Run Shaw Hospital of Zhejiang University School of Medicine, Life Sciences Institute, Zhejiang University","place":["Hangzhou, China"]},{"id":[{"id":"https:\/\/ror.org\/00a2xv884","id-type":"ROR","asserted-by":"publisher"}],"name":"Zhejiang Key Laboratory of Molecular Cancer Biology, 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Shi Data from \u201cldentification of Major FST-Bound BMP Ligands in Prostate Cancer Cells by LC-MS\/MS.\u201d ProteomeXchange. https:\/\/proteomecentral.proteomexchange.org\/ui?pxid=PXD070388. Deposited 6 November 2025."},{"key":"e_1_3_4_59_2","unstructured":"J. Li Data from \u201cSingle-cell transcriptional regulation and genetic evolution of neuroendocrine prostate cancer\u201d. National Genomics Data Center. https:\/\/ngdc.cncb.ac.cn\/gsa-human\/browse\/HRA002145. Deposited 16 August 2021."},{"key":"e_1_3_4_60_2","unstructured":"J. Wang W. Gao Data from \u201cSingle-cell analysis supports a luminal-neuroendocrine transdifferentiation in human prostate cancer.\u201d Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE137829. 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