〔Abstract〕 Objective To investigate the role of growth arrest-specific 6(Gas6)/Mer tyrosine kinase(MerTK) signaling pathway in ferroptosis in diabetes retinopathy(DR). Methods Human retinal pigment epithelial cells(ARPE-19) were divided into control group, HG group, HG+sh-Gas6 group, and HG+Gas6 group. Cells were exposed to 25 mmol/L D-glucose for simulating anin vitrohyperglycemic(HG) environment. The control group was exposed to a 20 mmol/L mannitol+5.5 mmol/L glucose environment. Rats were randomly divided into normal control group, DR group, and DR+Gas6 group, with 20 rats in each group. A DR model was established by intraperitoneal injection of STZ solution. Cell proliferation was evaluated using the cell count kit 8(CCK-8) assay. Lipid reactive oxygen species(ROS) levels were measured by flow cytometry, and levels of malondialdehyde(MDA), superoxide dismutase(SOD), and glutathione peroxidase(GSH-Px) were measured by biochemical assays to evaluate iron death. The expression of Gas6 and MerTK proteins was analyzed by Western blot. Results Compared with HG group, the cell viability, SOD, GSH-Px levels in HG+Gas6 group increased significantly(P<0.05), while the levels of lipid-ROS and MDA decreased significantly(P<0.05). In HG+sh-Gas6 group, the cell viability, SOD and GSH-Px levels decreased significantly(P<0.05), while the levels of lipid-ROS and MDA increased significantly(P<0.05). In addition, the expression of GPX4 protein in HG+Gas6 group was significantly higher than that in HG group(P<0.05), and the expression of GPX4 protein in HG+sh-Gas6 group was significantly lower than that in HG group(P<0.05). Compared with the control group, the average thickness of retinal nerve fiber layer in DR group significantly decreased(P<0.05), while that in DR+Gas6 group increased significantly(P<0.05). In addition, the levels of MDA and iron in retinal pigment epithelium(RPE) tissues of DR+Gas6 group decreased significantly(P<0.05), while the levels of GSH and the expressions of Gas6, MerTK and GPX4 proteins increased significantly(P<0.05). Conclusion HG treatment accelerates the clearance of GPX4 by inhibiting the Gas6/MerTK signaling pathway, inducing ferroptosis and cell growth inhibition in ARPE-19 cells. In addition, up-regulating the expression of Gas6/MerTK signal in DR rat retina can alleviate ferroptosis and oxidative stress in RPE tissue, and help to restore the average retinal nerve fiber layer thickness.