A secretome screen in primary human lung fibroblasts identifies FGF9 as a novel regulator of cellular senescence

Senescent cells contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF), a disease with significant unmet need and therefore, there is an interest in discovering new drug targets that regulate this process. We design and perform a phenotypic screen with a secreted protein library in primary human lung fibroblasts to identify modulators of cell senescence. We identify FGF9 as a suppressor of several senescence phenotypes reducing stimulated p21 expression, enlarged morphology, DNA damage and SASP secretion, which is consistent with both DNA-damage and ROS induced senescence. We also show that FGF9 reduces fibroblast activation in both healthy and IPF fibroblasts shown by a reduction in pro-fibrotic markers such as α-smooth muscle actin and COL1A1 mRNA. Our findings identify FGF9 as a suppressor of both senescence and fibrotic features in lung fibroblasts and therefore could be targeted as a new therapeutic strategy for respiratory diseases such as IPF.