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Here, we find that obesity is associated with poorer clinical outcomes during enzalutamide treatment. Lipidomic profiling reveals that 1-palmitoyl-2-linoleoyl phosphatidylethanolamine (PLPE) is markedly enriched in tumors from these individuals. Mechanistically, elevated PLPE directly binds to the SH2 domain of protein tyrosine kinase 6 (PTK6), driving its membrane translocation and functional activation. Furthermore, PLPE facilitates PTK6-fatty acid synthase (FASN) interaction, enabling PTK6 to mediate FASN phosphorylation at T976 via dual mechanisms: steric occupancy and kinase cascade amplification. This hyperactivation of FASN exacerbates lipid metabolic dysregulation, ultimately conferring enzalutamide resistance. Importantly, FASN-derived palmitic acid serves as a substrate for further PLPE synthesis, thereby reinforcing PTK6 membrane retention in a positive feedback loop. Collectively, this study identifies a PLPE\u2013PTK6\u2013FASN feedback loop that drives lipid metabolic reprogramming and enzalutamide resistance in CRPC with obesity, highlighting the therapeutic potential of cotargeting lipid metabolism and kinase signaling.<\/jats:p>","DOI":"10.34133\/research.1461","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T06:58:08Z","timestamp":1790924288000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":0,"title":["Obesity-Induced PLPE\u2013PTK6\u2013FASN Feedback Loop Drives Enzalutamide Resistance by Exacerbating Lipid Metabolic Dysregulation in Castration-Resistant Prostate Cancer"],"prefix":"10.34133","volume":"9","author":[{"given":"Zhuo","family":"Xing","sequence":"first","affiliation":[{"name":"Department of Urology, The Second Xiangya Hospital, \rCentral South University, Changsha, Hunan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewen","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Urology, Qilu Hospital, \rCheeloo College of Medicine, Jinan, Shandong, China."},{"name":"Key Laboratory of Urinary Precision Diagnosis and Treatment in Universities of Shandong","place":["China"]},{"name":"Shandong Provincial Engineering Research Center for Precision Diagnosis and Treatment of Urological and Male Reproductive Diseases","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Banking","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Urology, Qilu Hospital, \rCheeloo College of Medicine, Jinan, Shandong, China."},{"name":"Key Laboratory of Urinary Precision Diagnosis and Treatment in Universities of Shandong","place":["China"]},{"name":"Shandong Provincial Engineering Research Center for Precision Diagnosis and Treatment of Urological and Male Reproductive Diseases","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruilin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Xiangya Hospital, \rCentral South University, Changsha, Hunan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruijiang","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Xiangya Hospital, \rCentral South University, Changsha, Hunan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangqing","family":"Ren","sequence":"additional","affiliation":[{"name":"Robotic Minimally Invasive Surgery Center, Sichuan Provincial People\u2019s Hospital, School of Medicine, \rUniversity of Electronic Science and Technology of China, Chengdu, Sichuan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zexian","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Xiangya Hospital, \rCentral South University, Changsha, Hunan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingxia","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Xiangya Hospital, \rCentral South University, Changsha, Hunan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Xiangya Hospital, \rCentral South University, Changsha, Hunan, China."},{"name":"Guilin Hospital of the Second Xiangya Hospital of Central South University","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxiang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, \rSun Yat-sen University, Shenzhen, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The Affiliated Wuxi People\u2019s Hospital of Nanjing Medical University, Wuxi People\u2019s Hospital, Wuxi Medical Center, \rNanjing Medical University, Wuxi, Jiangsu, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6461-6005","authenticated-orcid":true,"given":"Xin","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Xiangya Hospital, \rCentral South University, Changsha, Hunan, China."},{"name":"FuRong Laboratory","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"issue":"1","key":"e_1_3_4_2_2","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel RL","year":"2025","unstructured":"Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. 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