1. Pharmacological inhibition of TAK1 prevents and induces regression of experimental organ fibrosis.
- Author
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Bale S, Verma P, Yalavarthi B, Scarneo SA, Hughes P, Amin MA, Tsou PS, Khanna D, Haystead TA, Bhattacharyya S, and Varga J
- Subjects
- Mice, Animals, Fibrosis, Fibroblasts metabolism, Scleroderma, Systemic pathology, Pulmonary Fibrosis drug therapy, Pulmonary Fibrosis prevention & control, Pulmonary Fibrosis metabolism
- Abstract
Multiorgan fibrosis in systemic sclerosis (SSc) accounts for substantial mortality and lacks effective therapies. Lying at the crossroad of TGF-β and TLR signaling, TGF-β-activated kinase 1 (TAK1) might have a pathogenic role in SSc. We therefore sought to evaluate the TAK1 signaling axis in patients with SSc and to investigate pharmacological TAK1 blockade using a potentially novel drug-like selective TAK1 inhibitor, HS-276. Inhibiting TAK1 abrogated TGF-β1 stimulation of collagen synthesis and myofibroblasts differentiation in healthy skin fibroblasts, and it ameliorated constitutive activation of SSc skin fibroblasts. Moreover, treatment with HS-276 prevented dermal and pulmonary fibrosis and reduced the expression of profibrotic mediators in bleomycin-treated mice. Importantly, initiating HS-276 treatment even after fibrosis was already established prevented its progression in affected organs. Together, these findings implicate TAK1 in the pathogenesis of SSc and identify targeted TAK1 inhibition using a small molecule as a potential strategy for the treatment of SSc and other fibrotic diseases.
- Published
- 2023
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