Diphlorethohydroxycarmalol inhibits Müller cell gliosis by disrupting CXCR4/CXCL12 interaction in violet-blue light-induced retinal phototoxicity

Müller gliosis is a complex process that impairs the ability of retinal Müller glial cells to respond to various forms of retinal injury or disease, leading to retinal damage. Blue light (BL) exposure is a known cause of retinal damage. In this study, we aimed to investigate the potential of DPHC in inhibiting Müller gliosis in models of BL-exposure. We conducted in silico binding analysis to evaluate the binding of DPHC to CXCR4. Then, we developed in vitro and <i>in vivo</i> experimental models to assess the effects of DPHC and BL exposure on Müller gliosis using MIO-M1 cells and zebrafish. Our findings show that DPHC can suppress the Müller gliosis process in BL-exposed MIO-M1 cells in vitro and in BL-exposed zebrafish <i>in vivo</i>. In silico molecular docking, we identified CXCR4 as the target of active site 1 of DPHC. In BL-exposed MIO-M1 cells, DPHC inhibited CXCR4 activity and altered the expression of Müller gliosis markers and NF-κB-related ERK and AKT signaling. In BL-exposed zebrafish, DPHC prevented retinal thickness reduction and inhibited CXCR4 expression and retinal cell apoptosis. This study suggests that DPHC could be a potential therapeutic agent for retinal diseases involving Müller gliosis. By inhibiting CXCR4 activity, DPHC downregulates the ERK/AKT/NF-κB pathway, reducing retinal cell apoptosis and altered expression of Müller gliosis markers. These findings highlight the potential of natural bioactive compounds for treating various diseases, and further research should investigate the therapeutic potential of DPHC and its derivatives.