环状RNA（circRNA）已成为生理学和人类疾病的重要调节因子。然而，在癌症中具有有效功能的进化保守的circRNA却很少被报道。在这项研究中，哺乳动物保守的 circRNA circLARP1B 被确定在肝细胞癌 (HCC) 中发挥关键作用。 circLARP1B 水平高的患者预后阶段较晚，总生存期较差。 CircLARP1B 通过促进 HCC 中的脂肪酸合成来促进细胞转移特性和脂质积累。 CircLARP1B 缺陷小鼠在诱导 HCC 模型中表现出转移减少和脂质积累减少。多项证据表明，circLARP1B 与细胞质中的异质核核糖核蛋白 D (HNRNPD) 结合，从而影响 HNRNPD 与敏感转录物（包括肝激酶 B1 (LKB1) mRNA）的结合。这种调节导致 LKB1 mRNA 稳定性降低和 LKB1 蛋白水平降低。与 circLARP1B 中的 HNRNPD 结合位点互补的反义寡脱氧核苷酸增加了 HNRNPD 与 LKB1 mRNA 的结合。 circLARP1B通过HNRNPD-LKB1-AMPK通路促进HCC转移和脂质积累。在小鼠模型中 AAV8 介导的肝细胞定向敲除 circLARP1B 或 Lkb1 的结果也证明了肝细胞 circLARP1B 调节途径在 HCC 转移和脂质积累中的关键作用，并表明 circLARP1B 可能是 HCC 治疗的潜在靶标。© 2023 作者。 《先进科学》由 Wiley-VCH GmbH 出版。

Circular RNAs (circRNAs) have emerged as crucial regulators in physiology and human diseases. However, evolutionarily conserved circRNAs with potent functions in cancers are rarely reported. In this study, a mammalian conserved circRNA circLARP1B is identified to play critical roles in hepatocellular carcinoma (HCC). Patients with high circLARP1B levels have advanced prognostic stage and poor overall survival. CircLARP1B facilitates cellular metastatic properties and lipid accumulation through promoting fatty acid synthesis in HCC. CircLARP1B deficient mice exhibit reduced metastasis and less lipid accumulation in an induced HCC model. Multiple lines of evidence demonstrate that circLARP1B binds to heterogeneous nuclear ribonucleoprotein D (HNRNPD) in the cytoplasm, and thus affects the binding of HNRNPD to sensitive transcripts including liver kinase B1 (LKB1) mRNA. This regulation causes decreased LKB1 mRNA stability and lower LKB1 protein levels. Antisense oligodeoxynucleotide complementary to theHNRNPD binding sites in circLARP1B increases the HNRNPD binding to LKB1 mRNA. Through the HNRNPD-LKB1-AMPK pathway, circLARP1B promotes HCC metastasis and lipid accumulation. Results from AAV8-mediated hepatocyte-directed knockdown of circLARP1B or Lkb1 in mouse models also demonstrate critical roles of hepatocytic circLARP1B regulatory pathway in HCC metastasis and lipid accumulation, and indicate that circLARP1B may be potential target of HCC treatment.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.