Pirfenidone and nintedanib target transforming growth factor-beta 1 (TGFβ1) signaling and mediate antifibrotic effects in idiopathic pulmonary fibrosis (IPF), according to a new study published in Scientific Reports.
“We used an agnostic approach to identify markers of early TGFβ1-induced fibrogenesis and found TGFβ1 induced genes annotated as associated with pirfenidone and nintedanib treatment,” the authors said.
Pirfenidone and nintedanib are likely to influence the expression of several TGFβ1-regulated genes, according to their findings. These include BASP1, HSD17B6, CDH11, and TNS1 in the case of pirfenidone, and CLINT1, CADM1, MTDH, SYDE1, and MCTS1 in the case of nintedanib. Some of these genes, such as CDH11, TNS1, CADM1, and MTDH, encode proteins that are known to participate in the fibrotic process.
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They identified 264 and 150 genes to be specifically associated with the response to pirfenidone and nintedanib treatments, respectively, as well as 149 genes that were common to both treatments.
“This may indicate the clinical efficacy of pirfenidone and nintedanib in patients with fibrotic lung disease may involve both shared (common) pathways and single genes that mediate pro-fibrotic effects,” the authors said. “The multifunctional effects of these drugs may also explain the need for combinatorial therapeutic approaches or single agents with pleiotropic effects.
They also found that TGFβ1 differentially regulated 780 genes: 416 were upregulated and 364 were downregulated. These genes were particularly involved in collagen deposition in the extracellular matrix, apoptosis, extracellular signaling, and epithelial-mesenchymal transition.
Moreover, TGFβ1 altered the levels of 8 proteins: it increased the expression of PDZ and LIM domain protein 5, calponin 1, collagen alpha-1 V chain, tensin 1, calponin 3, and LIM domain and actin-binding protein 1, while decreasing the expression of calpain 2 catalytic subunit and collagen alpha-1 IV chain 1.
Wilson AC, Chiles J, Ashish S, et al. Integrated bioinformatics analysis identifies established and novel TGFβ1-regulated genes modulated by anti-fibrotic drugs. Sci Rep. 2022;12(1):3080. doi:10.1038/s41598-022-07151-1