Pharmacological inhibition of TAK1 prevents and induces regression of experimental organ fibrosis.
JCI Insight
; 8(14)2023 07 24.
Article
in En
| MEDLINE
| ID: mdl-37306632
ABSTRACT
Multiorgan fibrosis in systemic sclerosis (SSc) accounts for substantial mortality and lacks effective therapies. Lying at the crossroad of TGF-ß and TLR signaling, TGF-ß-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-ß1 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pulmonary Fibrosis
/
Scleroderma, Systemic
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
JCI Insight
Year:
2023
Document type:
Article
Affiliation country:
United States