Antar Samar A, Mensah Eric, Dahlka Jacob, Aziz Michael, Halouani Aymen, Imani Seun, Parashar Aanandi, Raslan Ahmed A, Benezra Robert, Fraidenraich Diego, Ligresti Giovanni, Sassi Yassine
Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia, USA.
Icahn School of Medicine at Mount Sinai, New York, USA.
bioRxiv. 2025 Jul 26:2025.07.24.665373. doi: 10.1101/2025.07.24.665373.
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which novel therapeutic approaches are desperately needed. Inhibitor of DNA binding (ID) proteins are regulated by Transforming Growth Factor-b. However, the regulation and the effects of ID proteins in IPF remain poorly understood. We aimed to assess the expression of ID proteins in IPF and determine the effects of ID proteins on human lung fibroblasts (HLF) and pulmonary fibrosis .
The expression of ID proteins in lungs and lung fibroblasts from mice and human patients with pulmonary fibrosis was evaluated. The effects of ID1/ID3 inhibition and overexpression on HLF were assessed. Genetic and pharmacological approaches were used to determine the role of ID1/ID3 in pulmonary fibrosis.
ID1/ID3 levels were elevated in HLFs isolated from pulmonary fibrosis-diseased patients and mice. ID1/ID3 knockdown decreased IPF-diseased HLF proliferation and differentiation into myofibroblasts. Bleomycin-exposed ID1/ID3 KO mice displayed improved lung function and presented with decreased lung fibrosis when compared to WT mice. A pharmacological inhibitor of ID1/ID3 decreased IPF-diseased HLF proliferation and differentiation and attenuated pulmonary fibrosis . A lung specific inhibition of ID1/ID3, using adeno-associated viruses expressing short hairpins targeting ID1 and ID3, reversed pulmonary fibrosis in mice. Mechanistically, ID1/ID3 inhibition decreased fibroblast proliferation through cell cycle genes and inhibited fibroblast differentiation through the MEK/ERK pathway.
Our data indicate that a simultaneous inhibition of ID1 and ID3 attenuates pulmonary fibrosis. ID1/ID3 inhibition holds potential as a novel therapeutic treatment for IPF.
特发性肺纤维化（IPF）是一种致命的肺部疾病，迫切需要新的治疗方法。DNA结合抑制因子（ID）蛋白受转化生长因子-β调控。然而，ID蛋白在IPF中的调控及作用仍知之甚少。我们旨在评估ID蛋白在IPF中的表达，并确定ID蛋白对人肺成纤维细胞（HLF）和肺纤维化的影响。
评估了小鼠和人类肺纤维化患者肺组织及肺成纤维细胞中ID蛋白的表达。评估了ID1/ID3抑制和过表达对HLF的影响。采用基因和药理学方法确定ID1/ID3在肺纤维化中的作用。
从肺纤维化疾病患者和小鼠中分离出的HLF中，ID1/ID3水平升高。敲低ID1/ID3可降低IPF疾病HLF的增殖及向肌成纤维细胞的分化。与野生型小鼠相比，博来霉素处理的ID1/ID3基因敲除小鼠肺功能改善，肺纤维化减轻。ID1/ID3的药理学抑制剂可降低IPF疾病HLF的增殖和分化，并减轻肺纤维化。使用表达靶向ID1和ID3短发夹的腺相关病毒对ID1/ID3进行肺特异性抑制，可逆转小鼠的肺纤维化。机制上，抑制ID1/ID3可通过细胞周期基因降低成纤维细胞增殖，并通过MEK/ERK途径抑制成纤维细胞分化。
我们的数据表明，同时抑制ID1和ID3可减轻肺纤维化。抑制ID1/ID具有作为IPF新型治疗方法的潜力。
