Scholarlink

<p>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<sup>+</sup>/CD163<sup>+</sup> 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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

m6A reader IGF2BP1 facilitates macrophage glycolytic metabolism and fibrotic phenotype by stabilizing THBS1 mRNA to promote pulmonary fibrosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月12日

查看全文
  • Yan Hu,
  • Lulu Yang,
  • Liting Huang,
  • Chao Zeng,
  • Siying Ren

摘要

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.