TY - JOUR T1 - Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in Idiopathic Pulmonary Fibrosis JF - bioRxiv DO - 10.1101/2021.01.15.425870 SP - 2021.01.15.425870 AU - E. Marchal-Duval AU - M. Homps-Legrand AU - A. Froidure AU - M. Jaillet AU - M. Ghanem AU - L. Deneuville AU - A. Justet AU - A. Maurac AU - A. Vadel AU - E. Fortas AU - A. Cazes AU - A. Joannes AU - L. Giersch AU - H. Mal AU - P. Mordant AU - C.M. Mounier AU - K. Schirduan AU - M. Korfei AU - A. Gunther AU - B. Mari AU - F. Jaschinski AU - B. Crestani AU - A.A. Mailleux Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/26/2021.01.15.425870.abstract N2 - Matrix remodeling is a salient feature of idiopathic pulmonary fibrosis (IPF). Targeting cells driving matrix remodeling could be a promising avenue for IPF treatment. Analysis of transcriptomic database identified the mesenchymal transcription factor PRRX1 as upregulated in IPF.PRRX1, strongly expressed by lung fibroblasts, was regulated by a TGF-β/PGE2 balance in vitro in control and IPF fibroblasts, while IPF fibroblast-derived matrix increased PRRX1 expression in a PDGFR dependent manner in control ones.PRRX1 inhibition decreased fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-β driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to TGF-β response global decrease.Finally, targeted inhibition of Prrx1 attenuated fibrotic remodeling in vivo with intra-tracheal antisense oligonucleotides in bleomycin mouse model of lung fibrosis and ex vivo using precision-cut lung slices.Our results identified PRRX1 as a mesenchymal transcription factor driving lung fibrogenesis.Brief Summary Inhibition of a single fibroblast-associated transcription factor, namely paired-related homeobox protein 1, is sufficient to dampen lung fibrogenesis.Competing Interest StatementThe authors have declared no competing interest. ER -