BRD4 is a novel therapeutic target for liver fibrosis

Significance Liver fibrosis and cirrhosis are chronic liver diseases, resulting in life-threatening conditions with no FDA-approved therapy. Here, we identify bromodomain-containing protein 4 (BRD4) as a critical regulator for enhancer-mediated profibrotic gene expression in hepatic stellate cells (HSCs). In support of this notion, we find BRD4-loaded enhancers are associated with multiple profibrotic pathways in HSCs and that pharmacological inhibition of BRD4 blocks HSC activation into myofibroblasts. Furthermore, small molecule inhibitors of BRD4 are not only protective against, but can limit the fibrotic response in CCl4-induced fibrosis in a mouse model. Thus, our studies implicate BRD4 as a global genomic regulator of the fibrotic gene regulatory network and suggest bromodomains as potential therapeutic targets to treat fibrotic complications in patients. Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) proteins, abrogate cytokine-induced activation of HSCs. Cistromic analyses reveal that BRD4 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, where BRD4 is colocalized with profibrotic transcription factors. Furthermore, we show that JQ1 is not only protective, but can reverse the fibrotic response in carbon tetrachloride-induced fibrosis in mouse models. Our results implicate that BRD4 can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription. This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications.

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