Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Int J Biol Sci. 2024 Sep 3;20(12):4635-4653. doi: 10.7150/ijbs.101039. eCollection 2024.
Darolutamide, an androgen receptor inhibitor, has been approved by the Food and Drug Administration (FDA) for the treatment of prostate cancer (PCa), especially for patients with androgen receptor mutations. Owing to the unique lipidomic profile of PCa and the effect of darolutamide, the relationship between darolutamide and ferroptosis remains unclear. The present study showed that darolutamide significantly induces ferroptosis in AR PCa cells. Mechanistically, darolutamide promotes ferroptosis by downregulating SREBP1, which then inhibits the transcription of FASN. FASN knockdown modulates phospholipid remodeling by disrupting the balance between polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFAs), which induces ferroptosis. Clinically, SREBP1 and FASN are significantly overexpressed in PCa tissues and are related to poor prognosis. Moreover, the synergistic antitumor effect of combination therapy with darolutamide and ferroptosis inducers (FINs) was confirmed in PCa organoids and a mouse xenografts model. Overall, these findings revealed a novel mechanism of darolutamide mediated ferroptosis in PCa, laying the foundation for the combination of darolutamide and FINs as a new therapeutic strategy for PCa patients.
达罗他胺是一种雄激素受体抑制剂，已被美国食品和药物管理局（FDA）批准用于治疗前列腺癌（PCa），特别是用于携带雄激素受体突变的患者。由于 PCa 独特的脂质组学特征和达罗他胺的作用，达罗他胺与铁死亡之间的关系尚不清楚。本研究表明，达罗他胺可显著诱导 AR PCa 细胞发生铁死亡。在机制上，达罗他胺通过下调 SREBP1 促进铁死亡，进而抑制 FASN 的转录。FASN 的敲低通过破坏多不饱和脂肪酸（PUFAs）和饱和脂肪酸（SFAs）之间的平衡来调节磷脂重塑，从而诱导铁死亡。临床上，SREBP1 和 FASN 在 PCa 组织中明显过表达，与预后不良有关。此外，在 PCa 类器官和小鼠异种移植模型中证实了达罗他胺联合铁死亡诱导剂（FINs）的协同抗肿瘤作用。总的来说，这些发现揭示了达罗他胺介导的 PCa 中铁死亡的新机制，为达罗他胺联合 FINs 作为治疗 PCa 患者的新策略奠定了基础。
