Expression profiles of nintedanib-targeting molecules in progressive fibrotic interstitial lung diseases (non-IPF-PF) and IPF

Abstract

Abstract Background: Idiopathic pulmonary fibrosis (IPF) and other types of progressive fibrotic interstitial lung diseases (non-IPF-PF), such as chronic hypersensitivity pneumonitis (cHP), systemic sclerosis (SSc), non-specific interstitial pneumonia (NSIP), and sarcoidosis, are common interstitial lung diseases. Nintedanib is one of the two approved therapies that can significantly slow the progression of IPF. However, the potential of nintedanib in non-IPF-PF has not been fully evaluated. Methods: We reanalyzed the single-cell data of IPF and non-IPF-PF and identified the main target genes of nintedanib (FGFR1, FGFR2, FGFR3, FLT1, FLT4, KDR, and PDGFRA) by subgroup classification and functional analysis of gene expression profiles in both IPF and non-IPF-PF. Results: We found that the main target genes of nintedanib were upregulated in IPF and various cell subpopulations of non-IPF-PF, including cHP, SSc, NSIP, and sarcoidosis, with Fgfr1 being the most elevated subpopulation. In fibroblasts, Fgfr1 was found to be elevated in both IPF and cHP. We identified nintedanib-sensitive cell subpopulations by analyzing the expression profiles of fibroblasts after nintedanib treatment. We also found that nintedanib could inhibit the nintedanib-sensitive gene set in mice treated with nintedanib in vivo. Furthermore, we demonstrated that key regulatory genes of nintedanib were positively correlated with survival in lung adenocarcinoma, providing further support for the potential anti-tumor activity of nintedanib in vivo. Conclusion: Our findings provide comprehensive evidence of the target expression of nintedanib in non-IPF-PF and IPF, highlighting the potential of nintedanib for the treatment of non-IPF-PF.