Liu Bo, Liu Weili, Li Hongbo, Zhai Nailiang, Lv Changjun, Song Xiaodong, Yang Shuanying
Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China.
Department of Respiratory and Critical Care Medicine, Binzhou Medical University Hospital, Binzhou Medical University, Binzhou, 256603, Shandong, China.
Cell Mol Life Sci. 2025 Feb 19;82(1):79. doi: 10.1007/s00018-025-05613-z.
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial pneumonia, with increasing incidence and prevalence. One of the cellular characteristics is the differentiation of fibroblasts to myofibroblasts. However, the metabolic-related signaling pathway regulated by circular RNAs (circRNAs) during this process remains unclear. Here, we demonstrated that circ0066187 promoted fibroblast-to-myofibroblast differentiation by metabolic-related signaling pathway. Mechanism analysis research identified that circ0066187 directly targeted signal transducer and activator of transcription 3 (STAT3)-mediated metabolism signal pathway to enhance fibroblast-to-myofibroblast differentiation by sponging miR-29b-2-5p, resulting in pulmonary fibrosis. Integrative multi-omics analysis of metabolomics and proteomics revealed three pathways co-enriched in proteomics and metabolomics, namely, Protein digestion and absorption, PI3K-Akt signaling pathway, and FoxO signaling pathway. In these three signaling pathways, seven differentially expressed metabolites such as L-glutamine, L-proline, adenosine monophosphate (AMP), L-arginine, L-phenylalanine, L-lysine and L-tryptophan, and six differentially expressed proteins containing dipeptidyl peptidase-4 (DPP4), cyclin D1 (CCND1), cyclin-dependent kinase 2 (CDK2), fibroblast growth factor 2 (FGF2), collagen type VI alpha 1 (COL6A1) and superoxide dismutase 2 (SOD2) were co-enriched. Gain-and loss-of-function studies and rescue experiments were performed to verify that circ0066187 promoted STAT3 expression by inhibiting miR-29b-2-5p expression to control the above metabolites and proteins. As a result, these metabolites and proteins provided the material basis and energy requirements for the progression of pulmonary fibrosis. In conclusion, circ0066187 can function as a profibrotic metabolism-related factor, and interference with circ0066187 can prevent pulmonary fibrosis. The finding supported that circ0066187 can be a metabolism-related therapeutic target for IPF treatment.
特发性肺纤维化（IPF）是一种慢性进行性间质性肺炎，其发病率和患病率呈上升趋势。细胞特征之一是成纤维细胞向肌成纤维细胞分化。然而，在此过程中由环状RNA（circRNA）调控的代谢相关信号通路仍不清楚。在此，我们证明circ0066187通过代谢相关信号通路促进成纤维细胞向肌成纤维细胞分化。机制分析研究确定，circ0066187直接靶向信号转导和转录激活因子3（STAT3）介导的代谢信号通路，通过海绵吸附miR-29b-2-5p增强成纤维细胞向肌成纤维细胞分化，导致肺纤维化。代谢组学和蛋白质组学的综合多组学分析揭示了蛋白质组学和代谢组学中共富集的三条通路，即蛋白质消化和吸收、PI3K-Akt信号通路和FoxO信号通路。在这三条信号通路中，共富集了七种差异表达的代谢物，如L-谷氨酰胺、L-脯氨酸、一磷酸腺苷（AMP）、L-精氨酸、L-苯丙氨酸、L-赖氨酸和L-色氨酸，以及六种差异表达的蛋白质，包括二肽基肽酶-4（DPP4）、细胞周期蛋白D1（CCND1）、细胞周期蛋白依赖性激酶2（CDK2）、成纤维细胞生长因子2（FGF2）、VI型胶原α1（COL6A1）和超氧化物歧化酶2（SOD2）。进行了功能获得和功能缺失研究以及挽救实验，以验证circ0066187通过抑制miR-29b-2-5p表达来促进STAT3表达，从而控制上述代谢物和蛋白质。结果，这些代谢物和蛋白质为肺纤维化的进展提供了物质基础和能量需求。总之，circ0066187可作为一种促纤维化代谢相关因子，干扰circ0066187可预防肺纤维化。这一发现支持circ0066187可作为IPF治疗的代谢相关治疗靶点。
