Dimethyl Fumarate ameliorates pulmonary arterial hypertension and lung fibrosis by targeting multiple pathways

Pulmonary arterial hypertension (PAH) is a fatal condition for which there is no cure. Dimethyl Fumarate (DMF) is an FDA approved anti-oxidative and anti-inflammatory agent with a favorable safety record. The goal of this study was to assess the effectiveness of DMF as a therapy for PAH using patient-derived cells and murine models. We show that DMF treatment is effective in reversing hemodynamic changes, reducing inflammation, oxidative damage, and fibrosis in the experimental models of PAH and lung fibrosis. Our findings indicate that effects of DMF are facilitated by inhibiting pro-inflammatory NFκB, STAT3 and cJUN signaling, as well as βTRCP-dependent degradation of the pro-fibrogenic mediators Sp1, TAZ and β-catenin. These results provide a novel insight into the mechanism of its action. Collectively, preclinical results demonstrate beneficial effects of DMF on key molecular pathways contributing to PAH, and support its testing in PAH treatment in patients.