The SDF-1α/MTDH axis inhibits ferroptosis and promotes the formation of anti-VEGF-resistant choroidal neovascularization by facilitating the nuclear translocation of SREBP1

Abstract Age-related macular degeneration (AMD) has been well recognized as the first ranked blinding ocular fundus diseases among older individuals, particularly in developed regions, owing to its progressive nature and high prevalence in aging populations. Anti-vascular endothelial growth factor (VEGF) agents injected into patients’ vitreous cavity is the preferred treatment regimen for neovascular AMD. However, many patients exhibit resistance to anti-VEGF treatment, which is an urgent clinical problem. In this study, we treated mouse and endothelial cells with anti-VEGF drug Ranibizumab and stromal cell-derived factor-1α (SDF-1α) and found that ferroptosis was induced by Ranibizumab but inhibited by SDF-1α. SDF-1α inhibited ferroptosis by promoting transport of Sterol regulatory element binding protein 1 (SREBP1) from endoplasmic reticulum (ER) to Golgi transportation and SREBP1 maturation. Furthermore, we found that metadherin (MTDH) mediates SREBP1’ s movement from the endoplasmic reticulum (ER) to Golgi apparatus by inhibiting SREBP1 binding to INSIG1/INSIG2. Our study revealed the important role of SDF-1α/MTDH/SREBP1 axis in regulating anti-VEGF treatment resistance in patients with AMD. Graphical Abstract 1. SDF-1α mediates the development of anti-VEGF drug resistance by inhibiting ferroptosis. 2. SDF-1α reduces the sensitivity of endothelial cells to ferroptosis via the SREBP1/SCD1 signaling pathway. 3. SDF-1α promotes the maturation and nuclear translocation of SREBP1 through MTDH.