Extrahepatic cholangiocarcinoma (ECC), a highly malignant type of cancer with increasing incidence, has a poor prognosis due to limited treatment options. Based on genomic analysis of ECC patient samples, here we report that aldo-keto reductase family 1 member C1 (AKR1C1) is highly expressed in human ECC tissues and closely associated with ECC progression and poor prognosis. Intriguingly, we show that inducible AKR1C1 knockdown triggers ECC cells to undergo ferroptosis. Mechanistically, AKR1C1 degrades the protein stability of the cytochrome P450 family member CYP1B1, a newly discovered mediator of ferroptosis, via ubiquitin-proteasomal degradation. Additionally, AKR1C1 decreases CYP1B1 mRNA level through the transcriptional factor aryl-hydrocarbon receptor (AHR). Furthermore, the AKR1C1–CYP1B1 axis modulates ferroptosis in ECC cells via the cAMP–PKA signaling pathway. Finally, in a xenograft mouse model of ECC, AKR1C1 depletion sensitizes cancer cells to ferroptosis and synergizes with ferroptosis inducers to suppress tumor growth. Therefore, the AKR1C1–CYP1B1–cAMP signaling axis is a promising therapeutic target for ECC treatment, especially in combination with ferroptosis inducers.

肝外胆管癌 （ECC） 是一种发病率不断增加的高度恶性癌症，由于治疗选择有限，预后较差。基于对 ECC 患者样本的基因组分析，我们在这里报道了醛酮还原酶家族 1 成员 C1 （AKR1C1） 在人类 ECC 组织中高度表达，并且与 ECC 进展和不良预后密切相关。有趣的是，我们表明诱导型 AKR1C1 敲低会触发 ECC 细胞进行铁死亡。从机制上讲，AKR1C1 通过泛素-蛋白酶体降解降低细胞色素 P450 家族成员 CYP1B1 的蛋白质稳定性，CYP1B1 是新发现的铁死亡介质。此外，AKR1C1 通过转录因子芳烃受体 （AHR） 降低 CYP1B1 mRNA 水平。此外，AKR1C1-CYP1B1 轴通过 cAMP-PKA 信号通路调节 ECC 细胞中的铁死亡。最后，在 ECC 的异种移植小鼠模型中，AKR1C1 耗竭使癌细胞对铁死亡敏感，并与铁死亡诱导剂协同抑制肿瘤生长。因此，AKR1C1-CYP1B1-cAMP 信号轴是 ECC 治疗的有前途的治疗靶点，尤其是与铁死亡诱导剂联合使用。