{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T14:20:13Z","timestamp":1781706013630,"version":"3.54.5"},"reference-count":91,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:p>Cholesterol (CHOL) homeostasis is significantly modulated in prostate cancer (PCa) suggesting an active role in PCa development and progression. Several studies indicate a strong correlation between elevated CHOL levels and increased PCa risk and severity. Inhibition of CHOL biosynthesis at different steps, including lanosterol synthase (LSS), has shown significant efficacy against both hormone\u2010dependent and castration\u2010resistant PCa. Earlier, we reported proteasomal degradation of androgen receptor (AR)\/AR\u2010Vs and Mnk1\/2 as the primary mechanisms of action of VNPP433\u20103\u03b2 in inhibiting PCa cell proliferation and tumor growth. Through thermal proteome profiling, comparative proteomics and cellular thermal shift assay, we identified VNPP433\u20103\u03b2's ancillary effect of lowering CHOL by binding to LSS and lanosterol 14\u2010alpha demethylase, potentially inhibiting CHOL biosynthesis in PCa cells and tumors. Additionally, in conjunction with our previously reported transcriptome analysis, proteomics reveals that VNPP433\u20103\u03b2 modulated upstream regulators and pathways critical for PCa stem cell maintenance and recurrence. The inhibition of CHOL biosynthesis by VNPP433\u20103\u03b2 reinforces its multifaceted effects in PCa across all stages, highlighting its potential as a single\u2010agent therapy. Achieving reduced CHOL levels aligns with better treatment outcomes, further substantiating VNPP433\u20103\u03b2's therapeutic potential.<\/jats:p>","DOI":"10.1002\/1878-0261.70009","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T03:50:52Z","timestamp":1740541852000},"page":"2292-2309","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Thermal proteome profiling and proteome analysis using high\u2010definition mass spectrometry demonstrate modulation of cholesterol biosynthesis by next\u2010generation galeterone analog\n                    <scp>VNPP<\/scp>\n                    433\u20103\u03b2 in castration\u2010resistant prostate cancer"],"prefix":"10.1002","volume":"19","author":[{"given":"Retheesh S.","family":"Thankan","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Maryland School of Medicine  Baltimore MD USA"},{"name":"Isoprene Pharmaceuticals, Inc. 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