Sun Wenqing, Zhou Siyun, Peng Lan, Wang Wei, Liu Yi, Wang Ting, Cheng Demin, Li Ziwei, Xiong Haojie, Jia Xinying, Lian Wenxiu, Jiao Jiandong, Ni Chunhui
The Affiliated Wuxi Center for Disease Control and Prevention of Nanjing Medical University, Wuxi Center for Disease Control and Prevention, Wuxi Medical Center, Nanjing medical university, Nanjing, 211166, China.
Department of Occupational Medical and Environmental Health, Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.
Adv Sci (Weinh). 2025 Feb;12(7):e2407134. doi: 10.1002/advs.202407134. Epub 2024 Dec 25.
Silicosis is a fatal occupational pulmonary disease that is characterized by irreversible replacement of lung parenchyma by aberrant Exracellular matrix (ECM). Metabolic reprogramming is a crucial mechanism for fibrosis. However, how the metabolic rewiring shifts the ECM homeostasis toward overaccumulation remains unclear. Herein, a phenotype with reduction in fatty acid oxidation (FAO) but enhanced glycolysis in myofibroblasts is shown. Perturbation of the glycolytic and FAO pathways, respectively, reveals distinct roles in the metabolic distribution of ECM deposition and degradation. Suppressed glycolysis leads to a decrease in insoluble ECM, primarily due to the inhibition of ECM-modifying enzyme activity and a decrease in glycine synthesis. Notably, promoted FAO facilitates the intracellular degradation pathway of ECM. In addition, the findings revealed that hypoxia-inducible factor-1 alpha (HIF-1α) serves as a crucial metabolic regulator in the transition from FAO to glycolysis, thereby playing a significant role in ECM deposition in silica-induced pulmonary fibrosis. Further, the promotion of FAO, inhibition of glycolysis and HIF-1α reduce ECM production and promote ECM degradation, ultimately impeding the progression of fibrosis and providing therapeutic relief for established pulmonary fibrosis in vivo. These findings unveil the metabolic rewire underpinning the deposition of ECM in silica-induced lung fibrosis and identify novel targets for promoting regression of pulmonary fibrosis.
矽肺是一种致命的职业性肺部疾病，其特征是异常的细胞外基质（ECM）不可逆地取代肺实质。代谢重编程是纤维化的关键机制。然而，代谢重排如何使ECM稳态向过度积累转变仍不清楚。本文显示了一种表型，即肌成纤维细胞中脂肪酸氧化（FAO）减少但糖酵解增强。分别干扰糖酵解和FAO途径，揭示了它们在ECM沉积和降解的代谢分布中的不同作用。糖酵解受抑制导致不溶性ECM减少，主要是由于ECM修饰酶活性的抑制和甘氨酸合成的减少。值得注意的是，促进FAO有助于ECM的细胞内降解途径。此外，研究结果表明，缺氧诱导因子-1α（HIF-1α）在从FAO向糖酵解的转变中作为关键的代谢调节因子，从而在二氧化硅诱导的肺纤维化的ECM沉积中发挥重要作用。此外，促进FAO、抑制糖酵解和HIF-1α可减少ECM产生并促进ECM降解，最终阻碍纤维化进展并为体内已形成的肺纤维化提供治疗缓解。这些发现揭示了二氧化硅诱导的肺纤维化中ECM沉积的代谢重排，并确定了促进肺纤维化消退的新靶点。
