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However, patients taking these agents inevitably acquire resistance and even develop neuroendocrine prostate cancer (NEPC), in which stage the AR signaling is inactive, and therapies are limited for these lethal cases. Therefore, developing novel treatments independent of the AR signaling pathway is urgently needed. Here it is reported that L14\u20108, a small molecule is derived and optimized from ezetimibe, a marketed drug primarily used for intestinal cholesterol and phytosterol absorption, significantly suppresses cell growth in advanced prostate cancer by inducing ferroptosis. Mechanistically, L14\u20108 binds to and promotes the ubiquitin\u2010mediated PLK1 degradation, resulting in an increase of downstream TP53 protein phosphorylation, which is further enriched at the promoter of\n                    <jats:italic>SAT1<\/jats:italic>\n                    , a well\u2010established ferroptosis inducer, and boosting\n                    <jats:italic>SAT1<\/jats:italic>\n                    transcription thus triggers ferroptosis\u2010mediated cancer cell death. Importantly, in vivo studies further demonstrate a potent anti\u2010tumor efficacy of L14\u20108 without obvious toxicity. Overall, this study develops a novel small molecular engineered from ezetimibe for treating lethal prostate cancer in an AR\u2010independent manner and provides mechanistic insights into its action by triggering PLK1\u2010TP53\u2010\n                    <jats:italic>SAT1<\/jats:italic>\n                    axis\u2010mediated ferroptosis in lethal PCa models independent of the AR signaling pathway.\n                  <\/jats:p>","DOI":"10.1002\/advs.202504192","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T11:09:36Z","timestamp":1750331376000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Ezetimibe Engineered L14\u20108 Suppresses Advanced Prostate Cancer by Activating PLK1\/TP53\u2010\n                    <i>SAT1<\/i>\n                    \u2010Induced Ferroptosis"],"prefix":"10.1002","volume":"12","author":[{"given":"Yu","family":"Zhang","sequence":"first","affiliation":[{"name":"Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine  Shanghai 201203 China"},{"name":"School of Chemistry and Chemical Engineering Henan Normal University  Xinxiang Henan 453007 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010wen","family":"Song","sequence":"additional","affiliation":[{"name":"The Center for Cancer Research School of Integrative Medicine Shanghai University of Traditional Chinese Medicine  Shanghai 201203 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine Shanghai East Hospital Tongji University School of Medicine  Shanghai 200123 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