Marine bromophenols suppressed choroidal neovascularization by targeting HUWE1 through NF-κb signaling pathway

Inflammation plays a key role in the progression of choroidal neovascularization (CNV). Regular intravitreal injection of anti-VEGF medication is required for many patients to sustain eye condition as CNV always recurs due to persistent chronic inflammation in the retina and choroid. Marine bromophenols (BDB) have been widely studied due to their diverse bioactivities, including anti-inflammatory effect, though the mechanism of which remained unclear. Our study demonstrated that BDB could restricted endothelial cells' function and suppressed choroidal explants both in vitro and in vivo without out affecting the cells viability. BDB also significantly reduced numerous inflammatory cytokines in both raw cells and choroidal tissue, including IL-1β, IL-6, TNF-α, IL-4 and MMP-9. Moreover, we demonstrated that BDB down regulated phosphorylation of NF-κB p65 in the raw cells. By Co-IP assay, HUWE1 was found to be bound with BDB and the binding location was at sequences position 4214. When overexpressed HUWE1 in HUVECs, the suppression of endothelial cells' function by BDB became more significant. Taken together, the findings in this study showed that BDB suppressed endothelial cells' function and choroidal neovascularization by targeting HUWE1 through NF-κB pathway, which suggested that BDB could be a potential therapeutic candidate in treating chronic inflammation in choroidal neovascularization.