Selective BD2 Inhibitor Exerts Anti-Fibrotic Effects via BRD4/FoxM1/Plk1 Axis in Orbital Fibroblasts From Patients With Thyroid Eye Disease

PURPOSE: We investigated the therapeutic potential of ABBV744, a bromodomain and extra-terminal (BET) inhibitor with selectivity for the second bromodomain (BD2) in thyroid eye disease (TED). The anti-fibrotic effects of ABBV744 and its underlying mechanism were explored in cultured orbital fibroblasts (OFs) from patients with TED. METHODS: Immunohistochemistry (IHC) and real-time quantitative polymerase chain reaction (RT-qPCR) assays were conducted on orbital connective tissues from TED and controls. RT-qPCR, Western blot, Cell-counting Kit-8 (CCK-8), and 5-ethynyl-2′-deoxyuridine (EdU) cell proliferation assays were conducted on OFs isolated from patients with TED. RESULTS: The expression of BRD4 was upregulated in the orbital tissues of patients with TED relative to controls and in TED OFs stimulated with TGF-β1. Further, we showed that BRD4 modulated the profibrotic process through the interaction with Forkhead Box M1 (FoxM1) and its downstream molecule Polo-like kinase 1 (Plk1) in cultured TED OFs. Inhibition of BRD4 both by BD2 selective inhibitor ABBV744 and pan-BET inhibitor JQ1 exerted anti-fibrotic effects, whereas ABBV744 displayed superior anti-fibrotic effects and acceptable safety compared to JQ1. CONCLUSIONS: We conclude that BDR4 may modulate the profibrotic process in OFs of patients with TED via the FoxM1/Plk1 axis, and that selectively targeting BD2 domain of BRD4 may therefore be a potential therapeutic option for treating patients with TED.