The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University.
High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin, China.
Int J Biol Sci. 2023 Jun 12;19(10):3042-3056. doi: 10.7150/ijbs.80140. eCollection 2023.
Forkhead box protein O3 (FOXO3) has good inhibition ability toward fibroblast activation and extracellular matrix, especially for the treatment of idiopathic pulmonary fibrosis. How FOXO3 regulates pulmonary fibrosis remains unclear. In this study, we reported that FOXO3 had binding sequences with F-spondin 1 (SPON1) promoter, which can activate its transcription and selectively promote the expression of SPON1 circRNA (circSPON1) but not mRNA expression. We further demonstrated that circSPON1 was involved in the extracellular matrix deposition of HFL1. In the cytoplasm, circSPON1 directly interacted with TGF-β1-induced Smad3 and inhibited the activation of fibroblasts by inhibiting nuclear translocation. Moreover, circSPON1 bound to miR-942-5p and miR-520f-3p that interfered with Smad7 mRNA and promoted Smad7 expression. This study revealed the mechanism of FOXO3-regulated circSPON1 in the development of pulmonary fibrosis. Potential therapeutic targets and new insights into the diagnosis and treatment of idiopathic pulmonary fibrosis based on circRNA were also provided.
叉头框蛋白 O3（FOXO3）对成纤维细胞激活和细胞外基质具有良好的抑制作用，尤其在特发性肺纤维化的治疗中效果显著。然而，FOXO3 如何调节肺纤维化仍不清楚。在这项研究中，我们报道 FOXO3 与 F 钙黏蛋白 1（SPON1）启动子具有结合序列，可激活其转录并选择性促进 SPON1 环状 RNA（circSPON1）的表达，而不是 mRNA 的表达。我们进一步证明了 circSPON1 参与了 HFL1 细胞外基质的沉积。在细胞质中，circSPON1 可直接与 TGF-β1 诱导的 Smad3 相互作用，并通过抑制核转位抑制成纤维细胞的激活。此外，circSPON1 与 miR-942-5p 和 miR-520f-3p 结合，干扰 Smad7mRNA 的表达，并促进 Smad7 的表达。本研究揭示了 FOXO3 调节 circSPON1 在肺纤维化发生发展中的机制。该研究还为基于 circRNA 的特发性肺纤维化的诊断和治疗提供了潜在的治疗靶点和新的见解。
