A novel protein encoded by circFOXP1 enhances ferroptosis and inhibits tumor recurrence in intrahepatic cholangiocarcinoma

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.