Effect of exportin-1 inhibitors on profibrotic responses in human lung fibroblasts.

Idiopathic pulmonary fibrosis is a progressive lung disorder with limited therapeutic options. Fibroblasts and myofibroblasts are major effector cells in fibrosis through excessive extracellular matrix production and increased contractility. In this study, we investigated the effects of exportin-1 (XPO1) inhibitors on profibrotic responses in human lung fibroblasts. MRC-5 cells, primary control human lung fibroblasts, and idiopathic pulmonary fibrosis-derived human lung fibroblasts were stimulated with transforming growth factor-β1 (TGF-β1) in the presence of the XPO1 inhibitors KPT-185, eltanexor, or selinexor. XPO1 inhibition enhanced TGF-β1-induced profibrotic responses, as reflected by increased expression of fibrotic markers and greater fibroblast contractility. Similar effects were observed in both control and idiopathic pulmonary fibrosis-derived primary fibroblasts. The tested concentrations did not reduce cell viability. Although prior literature suggested that XPO1 inhibition might be antifibrotic, our results show that it worsens profibrotic activation rather than suppressing it.