2. Academic Validation
  3. Ezetimibe Engineered L14-8 Suppresses Advanced Prostate Cancer by Activating PLK1/TP53-SAT1-Induced Ferroptosis

Ezetimibe Engineered L14-8 Suppresses Advanced Prostate Cancer by Activating PLK1/TP53-SAT1-Induced Ferroptosis

  • Adv Sci (Weinh). 2025 Jun 19:e04192. doi: 10.1002/advs.202504192.
Yu Zhang 1 2,  Xiao-Wen Song 3,  Na Zhang 4,  Xue-Hui Li 3 5,  Fan-Chen Wu 3,  Yu-Ang Wei 6,  Dong-Liang Xu 6,  Ling-Fan Xu 7,  Fu-Wen Yuan 3
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 2 School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan, 453007, China.
  • 3 The Center for Cancer Research, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 4 Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China.
  • 5 Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200082, China.
  • 6 Department of Urology, Shuang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 7 Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230001, China.
PMID: 40536697 DOI: 10.1002/advs.202504192
Abstract

Androgen Receptor signaling inhibitors (ARSIs) have demonstrated a survival benefit in metastatic prostate Cancer. 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 L14-8, 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, L14-8 binds to and promotes the ubiquitin-mediated PLK1 degradation, resulting in an increase of downstream TP53 protein phosphorylation, which is further enriched at the promoter of SAT1, a well-established Ferroptosis inducer, and boosting SAT1 transcription thus triggers ferroptosis-mediated Cancer cell death. Importantly, in vivo studies further demonstrate a potent anti-tumor efficacy of L14-8 without obvious toxicity. Overall, this study develops a novel small molecular engineered from ezetimibe for treating lethal prostate Cancer in an AR-independent manner and provides mechanistic insights into its action by triggering PLK1-TP53-SAT1 axis-mediated Ferroptosis in lethal PCa models independent of the AR signaling pathway.

Keywords

SAT1; TP53; drug design and optimization; ferroptosis; prostate cancer.

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