Hong Jeongmin, Pham Tho X, Lee Jisu, Raslan Ahmed A, Nicolas Kristina, Sharov Andrei, Meridew Jeffrey A, Urrutia Raul A, Lomberk Gwen, Huang Steven K, Ligresti Giovanni
Department of Medicine.
Pulmonary Center, and.
Am J Respir Cell Mol Biol. 2025 Jun;72(6):627-642. doi: 10.1165/rcmb.2024-0255OC.
Idiopathic pulmonary fibrosis (IPF) is characterized by the sustained activation of interstitial fibroblasts leading to excessive collagen deposition and progressive organ failure. Epigenetic and metabolic abnormalities have been shown to contribute to the persistent activated state of scar-forming fibroblasts. However, how epigenetic changes regulate fibroblast metabolic responses to promote fibroblast activation and progressive fibrosis remains largely unknown. Here, we show that the epigenetic regulator CBX5 (chromobox protein homolog 5) is critical to the transition of quiescent fibroblasts to activated collagen-producing fibroblasts in response to bleomycin-induced lung injury. Loss of mesenchymal CBX5 attenuated fibrosis development, and this effect was accompanied by the downregulation of pathogenic fibroblast genes, including , , and , and by the upregulation of metabolic genes with antifibrotic activity such as and . Single-cell RNA sequencing and immunohistochemistry analyses revealed that CBX5 expression was enriched in pathogenic fibroblasts and fibroblastic foci of IPF lungs. Bulk RNA-sequencing analysis combined with metabolic assessments demonstrated that CBX5 silencing in IPF fibroblasts potently inhibited transforming growth factor-stimulated glycolysis while enhancing AMPK signaling and mitochondrial metabolism. Finally, interruption of the CBX5 pathway in IPF fibroblasts and in IPF lung explants synergistically potentiated the activation of metformin-induced AMP-activated protein kinase activation and inhibited collagen secretion. Collectively, our findings identify CBX5 as an epigenetic regulator linking metabolic maladaptation to the persistent activated state of lung fibroblasts during IPF progression.
特发性肺纤维化（IPF）的特征是间质成纤维细胞持续活化，导致胶原蛋白过度沉积和进行性器官衰竭。表观遗传和代谢异常已被证明促成了形成瘢痕的成纤维细胞的持续活化状态。然而，表观遗传变化如何调节成纤维细胞的代谢反应以促进成纤维细胞活化和进行性纤维化在很大程度上仍不清楚。在此，我们表明表观遗传调节因子CBX5（染色体盒蛋白同源物5）对于静息成纤维细胞在博来霉素诱导的肺损伤后转变为活化的胶原蛋白生成成纤维细胞至关重要。间充质CBX5的缺失减弱了纤维化发展，这种作用伴随着致病成纤维细胞基因（包括[此处原文缺失具体基因名称]、[此处原文缺失具体基因名称]和[此处原文缺失具体基因名称]）的下调，以及具有抗纤维化活性的代谢基因（如[此处原文缺失具体基因名称]和[此处原文缺失具体基因名称]）的上调。单细胞RNA测序和免疫组化分析表明，CBX5表达在IPF肺的致病成纤维细胞和成纤维细胞灶中富集。批量RNA测序分析结合代谢评估表明，IPF成纤维细胞中CBX5沉默有效抑制了转化生长因子刺激的糖酵解，同时增强了AMPK信号传导和线粒体代谢。最后，在IPF成纤维细胞[此处原文缺失具体条件]和IPF肺外植体[此处原文缺失具体条件]中中断CBX5途径协同增强了二甲双胍诱导的AMP活化蛋白激酶激活并抑制了胶原蛋白分泌。总之，我们的研究结果确定CBX5是一种表观遗传调节因子，在IPF进展过程中将代谢适应不良与肺成纤维细胞的持续活化状态联系起来。
