Wen Yang, Nie Jia-Hui, Qin Xue-Mei, Li Zhen-Yu
Modern Research Center for Traditional Chinese Medicine of Shanxi University, Taiyuan 030006, China.
Modern Research Center for Traditional Chinese Medicine of Shanxi University, Taiyuan 030006, China.
J Pharm Biomed Anal. 2025 Oct 15;264:116967. doi: 10.1016/j.jpba.2025.116967. Epub 2025 May 14.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible respiratory disease with poor survival rates. Despite significant research efforts, IPF still lacks a curative treatment. Excessive epithelial-mesenchymal transition (EMT) contributes to approximately one-third of fibroblasts in pulmonary fibrosis and plays a critical role in IPF pathogenesis. Identifying factors that regulate EMT is essential for developing effective therapeutic strategies for IPF. In this study, functional metabolomics revealed significant alterations in multiple metabolites in transforming growth factor-beta 1 (TGF-β1)-induced A549 cells, with pyroglutamic acid and 5-oxoprolinase (OPLAH) being identified as the most critical factors. Cellular experiments demonstrated that pyroglutamic acid effectively inhibited TGF-β1-induced EMT in A549 cells. Mechanistically, pyroglutamic acid inhibited IPF by suppressing EMT through the inhibition of Smad2/3 expression in TGF-β1-induced A549 cells. Bioinformatics analysis further elucidated the pyroglutamate is a potential metabolite that inhibits EMT. In addition, this study is the first to highlight the pivotal role of pyroglutamic acid and OPLAH in regulating EMT in IPF, offering novel insights into the metabolic mechanisms involved in IPF inhibition and providing a foundation for developing innovative therapeutic approaches for IPF.
特发性肺纤维化（IPF）是一种慢性、进行性且不可逆的呼吸系统疾病，生存率较低。尽管进行了大量研究，但IPF仍缺乏治愈性治疗方法。过度的上皮-间质转化（EMT）导致肺纤维化中约三分之一的成纤维细胞产生，在IPF发病机制中起关键作用。确定调节EMT的因素对于开发有效的IPF治疗策略至关重要。在本研究中，功能代谢组学揭示了转化生长因子-β1（TGF-β1）诱导的A549细胞中多种代谢物的显著变化，焦谷氨酸和5-氧脯氨酸酶（OPLAH）被确定为最关键的因素。细胞实验表明，焦谷氨酸可有效抑制TGF-β1诱导的A549细胞中的EMT。机制上，焦谷氨酸通过抑制TGF-β1诱导的A549细胞中Smad2/3的表达来抑制EMT，从而抑制IPF。生物信息学分析进一步阐明焦谷氨酸是一种潜在抑制EMT的代谢物。此外，本研究首次强调了焦谷氨酸和OPLAH在调节IPF中EMT的关键作用，为IPF抑制所涉及的代谢机制提供了新见解，并为开发IPF的创新治疗方法奠定了基础。
