2. Academic Validation
  3. Pharmaceutical targeting of succinate dehydrogenase in fibroblasts controls bleomycin-induced lung fibrosis

Pharmaceutical targeting of succinate dehydrogenase in fibroblasts controls bleomycin-induced lung fibrosis

  • Redox Biol. 2021 Oct;46:102082. doi: 10.1016/j.redox.2021.102082.
Ziwen Wang 1,  Long Chen 2,  Yu Huang 3,  Min Luo 3,  Huilan Wang 4,  Zhongyong Jiang 2,  Jiancheng Zheng 2,  Zeyu Yang 5,  Zelin Chen 2,  Chi Zhang 2,  Lei Long 2,  Yawei Wang 2,  Xueru Li 6,  Fengying Liao 2,  Yibo Gan 2,  Peng Luo 2,  Yunsheng Liu 2,  Yu Wang 2,  XuTan 2,  Ziyuan Zhou 7,  Aihua Zhang 8,  Chunmeng Shi 9
Affiliations

Affiliations

  • 1 Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Department of Cardiology, Geriatric Cardiovascular Disease Research and Treatment Center, The 82nd Group Army Hospital of PLA (252 Hospital of PLA), Baoding, Hebei, 071000, China.
  • 2 Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • 3 Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, Guizhou Medical University, Guiyang, 550025, China.
  • 4 Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China; Institute of Clinical Medicine, Southwest Medical University, Luzhou, 646000, China.
  • 5 Breast and Thyroid Surgical Department, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, 401147, China.
  • 6 Department of Ophthalmology, Third Affiliated Hospital of Chongqing Medical University (Gener Hospital), Chongqing, 401120, China.
  • 7 Department of Environmental Health, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, China. Electronic address: ziyuanzhou@tmmu.edu.cn.
  • 8 Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, Guizhou Medical University, Guiyang, 550025, China. Electronic address: aihuagzykd@163.com.
  • 9 Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, 400038, China. Electronic address: shicm@sina.com.
PMID: 34343908 DOI: 10.1016/j.redox.2021.102082
Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix in the lung with fibroblast-to-myofibroblast transition, leading to chronically compromising lung function and death. However, very little is known about the metabolic alterations of fibroblasts in IPF, and there is still a lack of pharmaceutical agents to target the metabolic dysregulation. Here we show a glycolysis upregulation and fatty acid oxidation (FAO) downregulation in fibroblasts from fibrotic lung, and perturbation of glycolysis and FAO affects fibroblasts transdifferentiation. In addition, there is a significant accumulation of succinate both in fibrotic lung tissues and myofibroblasts, where Succinate Dehydrogenase (SDH) operates in reverse by reducing fumarate to succinate. Then succinate contributes to glycolysis upregulation and FAO downregulation by stabilizing HIF-1α, which promotes the development of lung fibrosis. In addition, we identify a near-infrared small molecule dye, IR-780, as a targeting agent which stimulates mild inhibition of Succinate Dehydrogenase subunit A (SDHA) in fibroblasts, and which inhibits TGF-β1 induced SDH and succinate elevation, then to prevent fibrosis formation and respiratory dysfunction. Further, enhanced cell retention of IR-780 is shown to promote severe inhibition of SDHA in myofibroblasts, which may contribute to excessive ROS generation and selectively induces myofibroblasts to Apoptosis, and then therapeutically improves established lung fibrosis in vivo. These findings indicate that targeting metabolic dysregulation has significant implications for therapies aimed at lung fibrosis and Succinate Dehydrogenase is an exciting new therapeutic target to treat IPF.

Keywords

IR-780; Idiopathic pulmonary fibrosis; Metabolic dysregulation; Succinate; Succinate dehydrogenase.

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