Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis

The treatment of fibrosis remains a critically important unmet medical need, as nearly 45% of all natural deaths in the Western world are attributed to chronic fibroproliferative disease complications. Fibrosis is characterized by the excessive deposition of extracellular matrix proteins by resident fibroblast-derived myofibroblasts. From an imaging-based screen, we identified the antifungal drug itraconazole as an inhibitor of myofibroblast transdifferentiation from multiple resident fibroblast populations. A derivative of this drug was found to inhibit fibrotic disease progression in mouse models of lung, liver, and skin fibrosis, demonstrating that inhibiting differentiation to the myofibroblast cell state is a practical strategy to treat a wide range of fibrosis-related diseases.