Integrated bioinformatics analysis identifies established and novel TGFβ1-regulated genes modulated by anti-fibrotic drugs.

Abstract

Fibrosis is a leading cause of morbidity and mortality worldwide. Although fibrosis may involve different organ systems, transforming growth factor-β (TGFβ) has been established as a master regulator of fibrosis across organs. Pirfenidone and Nintedanib are the only currently-approved drugs to treat fibrosis, specifically idiopathic pulmonary fibrosis, but their mechanisms of action remain poorly understood. To identify novel drug targets and uncover potential mechanisms by which these drugs attenuate fibrosis, we performed an integrative 'omics analysis of transcriptomic and proteomic responses to TGFβ1-stimulated lung fibroblasts. Significant findings were annotated as associated with pirfenidone and nintedanib treatment in silico via Coremine. Integrative 'omics identified a co-expressed transcriptomic and proteomic module significantly correlated with TGFβ1 treatment that was enriched (FDR-p = 0.04) with genes associated with pirfenidone and nintedanib treatment. While a subset of genes in this module have been implicated in fibrogenesis, several novel TGFβ1 signaling targets were identified. Specifically, four genes (BASP1, HSD17B6, CDH11, and TNS1) have been associated with pirfenidone, while five genes (CLINT1, CADM1, MTDH, SYDE1, and MCTS1) have been associated with nintedanib, and MYDGF has been implicated with treatment using both drugs. Using the Clue Drug Repurposing Hub, succinic acid was highlighted as a metabolite regulated by the protein encoded by HSD17B6. This study provides new insights into the anti-fibrotic actions of pirfenidone and nintedanib and identifies novel targets for future mechanistic studies.

• Authors: Ava C Wilson, Joe Chiles, Shah Ashish, Diptiman Chanda, Preeti L Kumar, James A Mobley, Enid R Neptune, Victor J Thannickal, Merry-Lynn N McDonald
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 3080 (02 23 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35197532 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Adaptor Proteins, Vesicular Transport
• Antifibrotic Agents
• BASP1 protein, human
• CADM1 protein, human
• CLINT1 protein, human
• Cadherins
• Cell Adhesion Molecule-1
• Extracellular Matrix Proteins
• Indoles
• Interleukins
• MYDGF protein, human
• Membrane Proteins
• Nerve Tissue Proteins
• Pyridones
• Repressor Proteins
• TNS1 protein, human
• Tensins
• Transforming Growth Factor beta
• betaIG-H3 protein
• osteoblast cadherin
• pirfenidone
• HSD17B6 protein, human
• Racemases and Epimerases
• nintedanib

Topics

• Adaptor Proteins, Vesicular Transport (genetics, metabolism)
• Antifibrotic Agents (pharmacology, therapeutic use)
• Cadherins (genetics, metabolism)
• Cell Adhesion Molecule-1 (genetics, metabolism)
• Computational Biology (methods)
• Extracellular Matrix Proteins (physiology)
• Female
• Gene Expression Regulation (drug effects, genetics)
• Humans
• Idiopathic Pulmonary Fibrosis (drug therapy, genetics, pathology)
• Indoles (pharmacology, therapeutic use)
• Interleukins (genetics, metabolism)
• Male
• Membrane Proteins (genetics, metabolism)
• Nerve Tissue Proteins (genetics, metabolism)
• Pyridones (pharmacology, therapeutic use)
• Racemases and Epimerases (genetics, metabolism)
• Repressor Proteins (genetics, metabolism)
• Tensins (genetics, metabolism)
• Transforming Growth Factor beta (physiology)