Flotillin-1 as a housekeeping target mediates Nrf2 inhibition of blood–retinal barrier ferroptosis in diabetic retinopathy

Abstract

Abstract Disruption of the blood-retinal barrier causes the development of diabetic retinopathy (DR). The mechanism of damage to retinal pigment epithelial (RPE) cells, retinal microvascular endothelial cells, and related targets is still awaiting in depth studies. In this study, flotillin-1, a key protein downregulated during the progression of DR, was screened by basic bioinformatics and was found to positively regulate Nrf2, which was further investigated and found to regulate the occurrence of SLC7A11-induced(a cystine-glutamate antiporter) ferroptosis. The downregulation of flotillin-1 levels that occurred at the time of DR due to the toxic stimulation of high glucose levels may have acted as a signal housekeeper on the surface of the cell membrane to participate in the bioregulation of intracellular and extracellular, releasing the downstream key sign. This notion was supported by the measured levels of glutathione peroxidase 4(GPX4), a negative regulator protein of ferroptosis and reactive oxygen species(ROS) concentration causing intracellular lipid peroxidation. By contrast, increasing the level of flotillin-1 could alleviate the ferroptosis mechanism of blood-retinal barrier(BRB) related cells and accelerate DR-induced damage to the RPE layer and disruption of the medial microvascular barrier. Thus, downregulation of flotillin-1 at the onset of DR can trigger the onset of SLC7A11-induced ferroptosis in blood-retinal barrier associated cells through downstream transmission of signals to downstream Nrf2, a phenomenon that can be mitigated by upregulating the expression level of flotillin-1. This finding suggests that targeting flotillin-1 can treat the onset and development of DR and improve the prognosis of patients.