Darolutamide 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)，特别是雄激素受体突变的患者。由于 PCa 独特的脂质组学特征和达洛鲁胺的作用，达洛鲁胺与铁死亡之间的关系仍不清楚。本研究表明，darolutamide 显着诱导 AR PCa 细胞铁死亡。从机制上讲，darolutamide 通过下调 SREBP1 促进铁死亡，然后抑制 FASN 的转录。 FASN 敲低通过破坏多不饱和脂肪酸 (PUFA) 和饱和脂肪酸 (SFA) 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组织中显着过表达，与不良预后相关。此外，在 PCa 类器官和小鼠异种移植模型中证实了达洛鲁胺和铁死亡诱导剂 (FIN) 联合治疗的协同抗肿瘤作用。总的来说，这些发现揭示了 darolutamide 介导 PCa 铁死亡的新机制，为 darolutamide 和 FINs 联合作为 PCa 患者的新治疗策略奠定了基础。© 作者。

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.© The author(s).