Targeting metabolic dysregulation for fibrosis therapy

• Published in: Nature reviews. Drug discovery Vol. 19; no. 1; pp. 57 - 75
• Main Authors: Zhao, Xiao, Kwan, Jennifer Yin Yee, Yip, Kenneth, Liu, Peter P., Liu, Fei-Fei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2020; Nature Publishing Group
• Subjects: 631/154; 692/4020/1503/1607/1605; 692/4022/1585/3182; 692/699/67; Amino acids; Biomedical and Life Sciences; Biomedicine; Biotechnology; Bone morphogenetic proteins; Cancer Research; Cellular Reprogramming; Chronic diseases; Development and progression; Extracellular matrix; Extracellular Matrix Proteins - metabolism; Fibrosis; Fibrosis - drug therapy; Fibrosis - metabolism; Fibrosis - pathology; Humans; Kidney diseases; Liver cirrhosis; Medicinal Chemistry; Metabolic Diseases - drug therapy; Metabolic Diseases - metabolism; Metabolic Diseases - pathology; Metabolism; Molecular Medicine; Molecular Targeted Therapy; Pharmacology/Toxicology; Physiological aspects; Respiratory tract diseases; Review Article; Scleroderma (Disease); Signal Transduction - drug effects; Systemic scleroderma; Transforming Growth Factor beta; Canada
• ISSN: 1474-1776; 1474-1784; 1474-1784
• DOI: 10.1038/s41573-019-0040-5

Fibrosis is the abnormal deposition of extracellular matrix, which can lead to organ dysfunction, morbidity, and death. The disease burden caused by fibrosis is substantial, and there are currently no therapies that can prevent or reverse fibrosis. Metabolic alterations are increasingly recognized as an important pathogenic process that underlies fibrosis across many organ types. As a result, metabolically targeted therapies could become important strategies for fibrosis reduction. Indeed, some of the pathways targeted by antifibrotic drugs in development — such as the activation of transforming growth factor-β and the deposition of extracellular matrix — have metabolic implications. This Review summarizes the evidence to date and describes novel opportunities for the discovery and development of drugs for metabolic reprogramming, their associated challenges, and their utility in reducing fibrosis. Fibrotic therapies are potentially relevant to numerous common diseases such as cirrhosis, non-alcoholic steatohepatitis, chronic renal disease, heart failure, diabetes, idiopathic pulmonary fibrosis, and scleroderma. Fibrosis features in numerous chronic diseases, such as non-alcoholic steatohepatitis and heart failure, and no existing therapies can prevent or reverse this abnormal deposition of extracellular matrix, which leads to organ dysfunction. Here, Liu and colleagues describe how this energy-intensive process could be targeted by therapies that interfere with metabolism, including the metabolic implications of drugs directed at transforming growth factor-β and the deposition of extracellular matrix.