Targeting RUNX1 prevents pulmonary fibrosis and reduces expression of SARS-CoV-2 host mediators

O’Hare, Michael; Amarnani, Dhanesh; Whitmore, Hannah A.B.; An, Miranda; Marino, Claudia; Ramos, Leslie; Delgado-Tirado, Santiago; Hu, Xinyao; Chmielewska, Natalia; Chandrahas, Anita; Fitzek, Antonia; Heinrich, Fabian; Steurer, Stefan; Ondruschka, Benjamin; Glatzel, Markus; Krasemann, Susanne; Sepulveda-Falla, Diego; Lagares, David; Pedron, Julien; Bushweller, John H.; Liu, Paul; Arboleda-Velasquez, Joseph F.; Kim, Leo A.

Pulmonary fibrosis (PF) can arise from unknown causes as in idiopathic pulmonary fibrosis (IPF), or as a consequence of infections including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current treatments for PF slow, but do not stop disease progression. We report that treatment with a RUNX1 inhibitor (Ro24-7429), previously found to be safe, though ineffective, as a Tat inhibitor in patients with HIV, robustly ameliorates lung fibrosis and inflammation in the bleomycin-induced PF mouse model. RUNX1 inhibition blunted fundamental mechanisms downstream pathological mediators of fibrosis and inflammation including TGF-β1 and TNF-α in cultured lung epithelial cells, fibroblasts, and vascular endothelial cells indicating pleiotropic effects. RUNX1 inhibition also reduced the expression of ACE2 and FURIN, host proteins critical for SARS-CoV-2 infection, in mice and in vitro. A subset of human lungs with SARS-CoV-2 infection overexpress RUNX1. These data suggest that RUNX1 inhibition via repurposing of Ro24-7429 may be beneficial for PF and to battle SARS-CoV-2, by reducing expression of viral mediators and by preventing respiratory complications.