Hu Yan, Yang Lulu, Huang Liting, Zeng Chao, Ren Siying
Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.
Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital of Central South University, No. 139 Middle Renmin Road, Changsha, 410011, China.
Cell Mol Life Sci. 2025 Apr 12;82(1):157. doi: 10.1007/s00018-025-05673-1.
N6-methyladenosine (m6A) modification, a dynamically reversible epigenetic mechanism, is implicated in pulmonary fibrosis (PF) progression. The function and molecular mechanisms of m6A reader, insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) in PF remain elusive. This study investigates the mechanistic contributions of IGF2BP1 to PF development. We found IGF2BP1 was overexpressed in macrophages of PF mice. IGF2BP1 knockdown markedly attenuated bleomycin (BLM)-induced lung pathology, as evidenced by reduced inflammatory cell infiltration, fibroblast accumulation, Ashcroft fibrosis scores, and hydroxyproline deposition. Furthermore, IGF2BP1 knockdown downregulated PF-associated markers in lung tissues and embryonic lung fibroblasts (ELFs), including TGF-β1, α-SMA, Collagen-I/III, Arg1, CCL18, Ym1, CD163, IL-6, IL-1β, and TIMP1, while decreasing the CD68/CD163 macrophage proportion. Mechanistic studies revealed that IGF2BP1 bound to and stabilized thrombospondin-1 (THBS1) in an m6A-dependent manner. THBS1 overexpression rescued the suppression of macrophage M2 polarization caused by IGF2BP1 knockdown. Additionally, THBS1 overexpression counteracted IGF2BP1 knockdown-mediated inhibition of glycolysis, restoring HK2, LDHA, and PKM2 expression, lactate/glucose metabolism, and ATP production. Intriguingly, THBS1 physically interacted with toll-like receptor 4 (TLR4), and TLR4 overexpression reversed the inhibitory effect of THBS1 knockdown on macrophage M2 polarization and glycolytic reprogramming. Collectively, our findings demonstrate that IGF2BP1 drives PF progression by stabilizing THBS1 mRNA via m6A modification, thereby promoting TLR4-mediated macrophage M2 polarization and glycolytic activation. This study unveils a novel IGF2BP1/THBS1/TLR4 regulatory axis in PF pathogenesis, offering potential therapeutic targets.
N6-甲基腺苷（m6A）修饰是一种动态可逆的表观遗传机制，与肺纤维化（PF）的进展有关。m6A阅读蛋白胰岛素样生长因子2 mRNA结合蛋白1（IGF2BP1）在PF中的功能和分子机制仍不清楚。本研究探讨了IGF2BP1对PF发展的作用机制。我们发现IGF2BP1在PF小鼠的巨噬细胞中过表达。IGF2BP1基因敲低显著减轻了博来霉素（BLM）诱导的肺部病理变化，表现为炎症细胞浸润减少、成纤维细胞积聚减少、阿什克罗夫特纤维化评分降低和羟脯氨酸沉积减少。此外，IGF2BP1基因敲低下调了肺组织和胚胎肺成纤维细胞（ELF）中与PF相关的标志物，包括转化生长因子-β1、α-平滑肌肌动蛋白、胶原蛋白-I/III、精氨酸酶1、CCL18、Ym1、CD163、白细胞介素-6、白细胞介素-1β和金属蛋白酶组织抑制因子1，同时降低了CD68/CD163巨噬细胞比例。机制研究表明，IGF2BP1以m6A依赖的方式结合并稳定血小板反应蛋白-1（THBS1）。THBS1过表达挽救了IGF2BP1基因敲低对巨噬细胞M2极化的抑制作用。此外，THBS1过表达抵消了IGF2BP1基因敲低介导的糖酵解抑制作用，恢复了己糖激酶2、乳酸脱氢酶A和丙酮酸激酶M2的表达、乳酸/葡萄糖代谢以及ATP生成。有趣的是，THBS1与Toll样受体4（TLR4）发生物理相互作用，TLR4过表达逆转了THBS1基因敲低对巨噬细胞M2极化和糖酵解重编程的抑制作用。总的来说，我们的研究结果表明，IGF2BP1通过m6A修饰稳定THBS1 mRNA，从而促进TLR4介导的巨噬细胞M2极化和糖酵解激活，进而推动PF进展。本研究揭示了PF发病机制中一个新的IGF2BP1/THBS1/TLR4调控轴，为潜在的治疗靶点提供了依据。
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