Abstract Binding of the bromodomain and extra-terminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription. This study sought to determine the anti-fibrotic efficacy and potential mechanisms of BET inhibition in systemic sclerosis (SSc). Blockade of BETs was done using a pan BET inhibitor JQ1, BRD2 inhibitor BIC1, or BRD4 inhibitors AZD5153 or ARV825. BET inhibition, specifically BRD4 blockade, showed anti-fibrotic effects in an animal model of scleroderma and in patient-derived diffuse cutaneous (dc)SSc fibroblasts. Transcriptome analysis of JQ1-treated dcSSc fibroblasts revealed differentially expressed genes related to extracellular matrix, cell cycle, and calcium signaling. The anti-fibrotic effect of BRD4 inhibition was at least in part mediated by downregulation of Ca 2+/ calmodulin-dependent protein kinase II α (CaMKII-α) and reduction of intracellular calcium concentrations. These results suggest that targeting calcium pathways or BRD4 might be novel therapeutic approaches for progressive tissue fibrosis.

Inhibition of histone readers bromodomain extra-terminal proteins alleviates skin fibrosis in experimental models of scleroderma