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<p>Cigarette smoke (CS) exposure is a significant environmental trigger for childhood asthma. Although S100 calcium-binding protein A10 (S100A10) is upregulated in asthma patients, its regulatory mechanism in CS-associated asthma remains unclear. This study aimed to elucidate how insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) influences S100A10 expression via the N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) modification pathway and to investigate the role of the IGF2BP3/S100A10 axis in CS-exposed childhood asthma. A total of 120 asthmatic children were enrolled, with 120 healthy children selected as controls. Serum levels of S100A10 and IGF2BP3 were measured. A murine model of asthma was established using ovalbumin (OVA) induction combined with CS exposure. Lentivirus-mediated overexpression or knockdown of IGF2BP3 or S100A10 was performed to evaluate lung function, inflammatory infiltration, immune cell proportions, and immunoglobulin E (IgE) levels. Airway epithelial cells (AECs) were isolated and treated with cigarette smoke extract (CSE) and OVA to assess apoptosis and inflammatory cytokine levels. RNA immunoprecipitation, m6A methylated RNA immunoprecipitation, and crosslinking immunoprecipitation (CLIP) were conducted to validate the regulatory mechanism between IGF2BP3 and S100A10. The expression of S100A10 and IGF2BP3 was elevated in asthmatic children and OVA-induced asthmatic mice. In OVA-induced asthmatic mice, CS exacerbated OVA-induced asthma phenotypes, including increased lung resistance, enhanced inflammatory infiltration, elevated T helper 2 (Th2) and T helper 17 (Th17) cell proportions, and raised IgE levels. Knockdown of S100A10 or IGF2BP3 ameliorated these pathological changes, while overexpression of S100A10 reversed the protective effects of IGF2BP3 knockdown. Mechanistically, IGF2BP3 bound to m6A modification sites on S100A10 mRNA and enhanced its stability. CSE and OVA promoted IGF2BP3 expression, thereby increasing S100A10 mRNA stability, leading to enhanced epithelial apoptosis and release of inflammatory factors (interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha). CS exposure aggravates childhood asthma by promoting IGF2BP3 expression and enhancing m6A-dependent stabilization of S100A10 mRNA. Targeting the IGF2BP3/S100A10 axis may provide a novel therapeutic strategy for CS-associated asthma.</p>

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m6A-Mediated Stabilization of S100A10 mRNA by IGF2BP3 Aggravates Environmental Cigarette Smoke-Induced Asthma in Children

  • 期刊论文

  • 发表日期：

    2026年8月5日

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  • LuYang Guo,
  • Li Wang,
  • MingZhao Feng,
  • LingFeng Kong,
  • YaHui Chai,
  • Bao Liu,
  • He Zhang

摘要

Cigarette smoke (CS) exposure is a significant environmental trigger for childhood asthma. Although S100 calcium-binding protein A10 (S100A10) is upregulated in asthma patients, its regulatory mechanism in CS-associated asthma remains unclear. This study aimed to elucidate how insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) influences S100A10 expression via the N6-methyladenosine (m6A) modification pathway and to investigate the role of the IGF2BP3/S100A10 axis in CS-exposed childhood asthma. A total of 120 asthmatic children were enrolled, with 120 healthy children selected as controls. Serum levels of S100A10 and IGF2BP3 were measured. A murine model of asthma was established using ovalbumin (OVA) induction combined with CS exposure. Lentivirus-mediated overexpression or knockdown of IGF2BP3 or S100A10 was performed to evaluate lung function, inflammatory infiltration, immune cell proportions, and immunoglobulin E (IgE) levels. Airway epithelial cells (AECs) were isolated and treated with cigarette smoke extract (CSE) and OVA to assess apoptosis and inflammatory cytokine levels. RNA immunoprecipitation, m6A methylated RNA immunoprecipitation, and crosslinking immunoprecipitation (CLIP) were conducted to validate the regulatory mechanism between IGF2BP3 and S100A10. The expression of S100A10 and IGF2BP3 was elevated in asthmatic children and OVA-induced asthmatic mice. In OVA-induced asthmatic mice, CS exacerbated OVA-induced asthma phenotypes, including increased lung resistance, enhanced inflammatory infiltration, elevated T helper 2 (Th2) and T helper 17 (Th17) cell proportions, and raised IgE levels. Knockdown of S100A10 or IGF2BP3 ameliorated these pathological changes, while overexpression of S100A10 reversed the protective effects of IGF2BP3 knockdown. Mechanistically, IGF2BP3 bound to m6A modification sites on S100A10 mRNA and enhanced its stability. CSE and OVA promoted IGF2BP3 expression, thereby increasing S100A10 mRNA stability, leading to enhanced epithelial apoptosis and release of inflammatory factors (interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha). CS exposure aggravates childhood asthma by promoting IGF2BP3 expression and enhancing m6A-dependent stabilization of S100A10 mRNA. Targeting the IGF2BP3/S100A10 axis may provide a novel therapeutic strategy for CS-associated asthma.