CircRNA参与多种肿瘤类型的发生和发展。然而，circRNA在肝内胆管癌（ICC）进展和复发中的具体作用和潜在机制仍知之甚少。利用 53 例 ICC 冷冻肿瘤标本进行 CircRNA 测序，筛选与术后 ICC 复发相关的 circRNA。我们发现，与经历术后复发的患者相比，circFOXP1在术后未复发患者的肿瘤组织中高表达。功能实验表明，circFOXP1 在体外和体内均可抑制 ICC 进展。然后我们发现 circFOXP1 通过编码一种新蛋白 circFOXP1-231aa 抑制 ICC 进展。从机制上讲，circFOXP1-231aa直接与OTUD4相互作用，OTUD4通过去泛素化修饰调节NCOA4蛋白稳定性，从而增强ICC细胞的铁死亡。对临床 ICC 样本的检查发现 circFOXP1 表达水平与 OTUD4 和 NCOA4 水平之间呈正相关。这三个因素是 ICC 患者预后的预测因素。总的来说，我们鉴定了 circFOXP1 编码的 circFOXP1-231aa，它与 OTUD4 相互作用，抑制 NCOA4 的泛素化，从而促进铁死亡并抑制 ICC 复发。版权所有 © 2024。由 Elsevier B.V. 出版。

CircRNAs participates in the development and occurrence of multiple tumor types. However, the specific effects and underlying mechanisms of circRNA in intrahepatic cholangiocarcinoma (ICC) progression and recurrence remain poorly understood. CircRNA sequencing was performed to screen circRNAs related to ICC recurrence after surgery using 53 ICC frozen tumor specimens. We found that compared with patients who experienced postsurgical recurrence, circFOXP1 had high expression in tumor tissues from patients with no postoperative recurrence. Functional experiments revealed that circFOXP1 inhibited ICC progression in vitro and in vivo. We then found that circFOXP1 inhibited ICC progression via encoding a novel protein, circFOXP1-231aa. Mechanistically, circFOXP1-231aa directly interacted with OTUD4, which regulates NCOA4 protein stability via deubiquitination modification, and thereby enhances ferroptosis of ICC cells. Examination of clinical ICC samples found positive correlations between circFOXP1 expression levels and levels of OTUD4 and NCOA4. These three factors are predictors of prognosis in patients with ICC. Collectively, we identified circFOXP1 encoded circFOXP1-231aa, which interacted with OTUD4 to suppress ubiquitination of NCOA4 and, thereby, promoted ferroptosis and inhibited ICC recurrence.Copyright © 2024. Published by Elsevier B.V.