Ezetimibe derivative L14-8 suppresses advanced prostate cancer by activating PLK1/TP53-SAT1-induced ferroptosis

Androgen receptor signaling inhibitors (ARSIs) have demonstrated a survival benefit in metastatic prostate cancer (PCa). 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, there is an urgent need to develop novel treatments to improve patient outcomes. Here we report that L14-8, a small molecule derived and optimized from ezetimibe, significantly suppressed prostate cancer growth by inducing ferroptosis in vitro and in vivo without obvious toxicity. Further mechanism studies demonstrate that L14-8 bound to and enhanced the stability of PLK1 and promoted the phosphorylation and expression of TP53, which enhanced its enrichment at the promoter of SAT1, a ferroptosis inducer, and increased its transcriptional activity. Overall, our studies developed a novel anti-tumor agent for treating lethal prostate cancer in an AR-independent manner and provided mechanistic insights into its action by targeting the PLK1-mediated TP53-SAT1 axis-induced ferroptosis.