Wang Jing, Chao Jie
Department of Physiology, School of Medicine, Southeast University, Nanjing 210009, China.
Jiangsu Provincial Key Laboratory of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China.
Pharmaceuticals (Basel). 2025 May 28;18(6):812. doi: 10.3390/ph18060812.
Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease characterized by chronic epithelial injury and excessive deposition of extracellular matrix (ECM) driven by dysregulated repair. Increasing evidence has shown that epithelial cell dysfunction plays a key role in PF, involving epithelial-mesenchymal transition (EMT), chronic oxidative stress, disruption of epithelial-immune interactions, and promoting pathological remodeling. Single-cell analyses have identified functionally distinct subpopulations of type 2 alveolar (AT2) cells with pro-fibrotic potential. Epithelial cells exhibit metabolic and epigenetic alterations during PF, which provide new approaches for therapeutic targets. This review summarizes the molecular mechanisms driving epithelial dysfunction in fibrosis progression, with a focus on key regulatory pathways, including transforming growth factor-beta (TGF-β), Wnt, and Notch signaling pathways, as well as miRNA-mediated networks. We also explored emerging epithelial-targeted therapies, ranging from FDA-approved agents (pirfenidone, nintedanib) to experimental inhibitors targeting Galectin-3 and Wnt/β-catenin, providing insights into precision anti-fibrosis strategies for clinical translation.
肺纤维化（PF）是一种进行性致命性间质性肺疾病，其特征为慢性上皮损伤以及由失调修复驱动的细胞外基质（ECM）过度沉积。越来越多的证据表明，上皮细胞功能障碍在PF中起关键作用，涉及上皮-间质转化（EMT）、慢性氧化应激、上皮-免疫相互作用的破坏以及促进病理重塑。单细胞分析已鉴定出具有促纤维化潜能的功能不同的2型肺泡（AT2）细胞亚群。上皮细胞在PF期间表现出代谢和表观遗传改变，这为治疗靶点提供了新方法。本综述总结了在纤维化进展中驱动上皮功能障碍的分子机制，重点关注关键调控途径，包括转化生长因子-β（TGF-β）、Wnt和Notch信号通路以及miRNA介导的网络。我们还探讨了新兴的上皮靶向疗法，从美国食品药品监督管理局（FDA）批准的药物（吡非尼酮、尼达尼布）到靶向半乳糖凝集素-3和Wnt/β-连环蛋白的实验性抑制剂，为临床转化的精准抗纤维化策略提供见解。
