The carcinogenic role of FASN by regulating lipid metabolism reprogramming has been well-established in multiple tumors. However, whether mechanisms during intrahepatic cholangiocarcinoma (ICC) progression, such as circRNAs, regulate FASN expression remains unknown. Here we demonstrate a lipid metabolism-related circRNA, circMBOAT2 (hsa_circ_0007334 in circBase), frequently upregulated in ICC tissues, and positively correlated with ICC malignant features. CircMBOAT2 knockdown inhibits the growth and metastasis of ICC cells. Mechanistically, circMBOAT2 combines with PTBP1 and protects PTBP1 from ubiquitin/proteasome-dependent degradation, impairing the function of PTBP1 to transfer FASN mRNA from the nucleus to the cytoplasm. Moreover, circMBOAT2 and FASN have the same effect on fatty acid profile, unsaturated fatty acids instead of saturated fatty acids are primarily regulated and associated with malignant behaviors of ICC cells. The levels of lipid peroxidation and ROS were significantly higher when FASN was knocked down and recovered when circMBOAT2 was overexpressed. Our results identified that circMBOAT2 was upregulated in ICC and promoted progression by stabilizing PTBP1 to facilitate FASN mRNA cytoplasmic export, which altered lipid metabolic profile and regulated redox homeostasis in ICC, suggesting that circMBOAT2 may serve as an available therapeutic target for ICC with active lipid metabolism.

FASN 通过调节脂质代谢重编程的致癌作用已在多种肿瘤中得到证实。然而，肝内胆管癌 (ICC) 进展过程中的机制（如 circRNA）是否调节 FASN 表达仍然未知。在这里，我们展示了一种与脂质代谢相关的 circRNA，circMBOAT2（circBase 中的 hsa_circ_0007334），在 ICC 组织中经常上调，并且与 ICC 恶性特征呈正相关。CircMBOAT2敲低抑制ICC细胞的生长和转移。从机制上讲，circMBOAT2 与 PTBP1 结合并保护 PTBP1 免受泛素/蛋白酶体依赖性降解，从而损害 PTBP1 将 FASN mRNA 从细胞核转移到细胞质的功能。此外，circMBOAT2 和 FASN 对脂肪酸谱具有相同的影响，主要调节的是不饱和脂肪酸而不是饱和脂肪酸，它与 ICC 细胞的恶性行为有关。当 FASN 被敲低并在 circMBOAT2 过表达时恢复时，脂质过氧化和 ROS 的水平显着升高。我们的研究结果表明，circMBOAT2 在 ICC 中上调并通过稳定 PTBP1 促进 FASN mRNA 细胞质输出来促进进展，这改变了 ICC 中的脂质代谢谱并调节了氧化还原稳态，表明 circMBOAT2 可能作为具有活跃脂质代谢的 ICC 的可用治疗靶点.