Therapeutic targets in fibrotic pathways.

The pathogenetic heterogeneity of pulmonary fibrosis yields both challenges and opportunities for therapy. Its complexity implicates a variety of cellular processes, signaling pathways, and genetics as drivers of disease. TGF-β stimulation is one avenue, and is central to pro-fibrotic protein expression, leading to decreased pulmonary function. Here we report our recent findings, introducing the E3 ligase Fibrosis Inducing E3 Ligase 1 (FIEL1) as an important regulator of TGF-β signaling through the selective degradation of PIAS4. FIEL1 exacerbates bleomycin-induced murine pulmonary fibrosis, while its silencing attenuates the fibrotic phenotype. Further, we developed a small molecule inhibitor of FIEL1 (BC-1485) that inhibits the degradation of PIAS4, and ameliorates fibrosis in murine models. New understanding of this pathway illustrates the many targeting opportunities among the complexity of pulmonary fibrosis in the continuing search for therapy.