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The AR signaling pathway plays a central role in the development of prostate cancer. Metabolic reprogramming of androgen synthesis and aberrant activation of AR signaling collectively drive CRPC development. Under therapeutic pressure, AR signaling adapts through AR amplification, ligand-binding domain mutations, splice variants, and alternative activation by cytokines\/growth factors, maintaining AR transcriptional activity in low-androgen environments. Concurrently, somatic alterations (like PTEN loss) and crosstalk with key pathways such as PI3K\/AKT, coupled with the evolving multifocal spatial heterogeneity, further complicate the role of AR signaling in CRPC treatment resistance. Innovations in single-cell and spatial technologies reveal tumor heterogeneity and lineage plasticity governed by genetic and epigenetic alterations. Current therapeutic innovations, including approaches such as CYP11A1 inhibition, targeting of the AR N-terminal domain, and bipolar androgen therapy, are showing promise in clinical trials. Overcoming CRPC effectively requires cotargeting androgen\/AR-associated pathways and suppressing lineage plasticity through dynamic monitoring and precision interventions.<\/jats:p>","DOI":"10.34133\/research.1128","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T08:20:17Z","timestamp":1768206017000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":9,"title":["Intratumoral Androgens and Genetic Variants Driving Therapy Resistance in Prostate Cancer"],"prefix":"10.34133","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3020-5996","authenticated-orcid":false,"given":"Junjiang","family":"Ye","sequence":"first","affiliation":[{"name":"Urology &amp; Nephrology Center, Department of Urology, Zhejiang Provincial People\u2019s Hospital (Affiliated People\u2019s Hospital), \rHangzhou Medical College, Hangzhou, 310014 Zhejiang, China."},{"name":"Department of Urology, Institute of Urology, West China Hospital, \rSichuan University, Chengdu, Sichuan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yandong","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Urology, Nanfang Hospital, \rSouthern Medical University, Guangzhou, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, Institute of Urology, West China Hospital, \rSichuan University, Chengdu, Sichuan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruicheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Urology, Institute of Urology, West China Hospital, \rSichuan University, Chengdu, Sichuan, China."},{"name":"Division of Surgery and Interventional Science, \rUniversity College London, London W1W 7TS, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dengxiong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, \rThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang Province, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koo Han","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Urology, \rKyung Hee University, Seoul, South Korea."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dilinaer","family":"Wusiman","sequence":"additional","affiliation":[{"name":"Purdue Institute for Cancer Research, \rPurdue University, West Lafayette, IN 47907, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, Queen Elizabeth Hospital, Hongkong SAR","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaojie","family":"Lyu","sequence":"additional","affiliation":[{"name":"Department of Urology, Institute of Precision Medicine, \rPeking University Shenzhen Hospital, Shenzhen 518036, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8587-6959","authenticated-orcid":true,"given":"Dechao","family":"Feng","sequence":"additional","affiliation":[{"name":"Urology &amp; Nephrology Center, Department of Urology, Zhejiang Provincial People\u2019s Hospital (Affiliated People\u2019s Hospital), \rHangzhou Medical College, Hangzhou, 310014 Zhejiang, China."},{"name":"Division of Surgery and Interventional Science, \rUniversity College London, London W1W 7TS, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2026,2,24]]},"reference":[{"issue":"1","key":"e_1_3_3_2_2","first-page":"12","article-title":"Global burden and cross-country inequalities in urinary tumors from 1990 to 2021 and predicted incidence changes to 2046","volume":"12","author":"Feng DC","year":"2025","unstructured":"Feng DC, Li DX, Wu RC, Wang J, Xiao YH, Yoo KH, Ye X, Wei WR, Kong DP, Tuo ZT. 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