Key result
Integrative 'omics analysis identified a co-expressed transcriptomic and proteomic module significantly correlated with TGFβ1 treatment that was enriched with genes associated with pirfenidone and nintedanib treatment.
Why the study?
Pirfenidone and nintedanib are approved to treat fibrosis, but their mechanisms of action remain poorly understood.
Integrative bioinformatics analysis identified novel TGFβ1 signaling targets associated with the anti-fibrotic drugs pirfenidone and nintedanib, providing new insights for future mechanistic studies.
Novel TGFβ1 targets for pirfenidone/nintedanib warrant validation; leaves open clinical translation in fibrosis.
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.
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Wilson et al. (2022) studied Fibrosis (n=6). TGFβ1 vs. No TGFβ1 treatment was evaluated on Differentially expressed genes and proteins. Integrative 'omics analysis identified a co-expressed transcriptomic and proteomic module significantly correlated with TGFβ1 treatment that was enriched with genes associated with pirfenidone and nintedanib treatment.
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