MeCP2 suppresses ferroptosis to drive EMT in retinal pigment epithelial cells: Implications for PVR pathogenesis

Proliferative vitreoretinopathy (PVR), a leading complication of retinal detachment with high recurrence rates and no effective pharmacological treatments, is driven by retinal pigment epithelium (RPE) cells through epithelial‑mesenchymal transition (EMT), a process promoted by methyl‑CpG binding protein 2 (MeCP2). There is bidirectional crosstalk between ferroptosis, an iron‑dependent cell death pathway characterized by lipid peroxidation and EMT, suggesting their interaction may influence PVR pathogenesis. However, the mechanistic involvement of ferroptosis in PVR and its interaction with the MeCP2/EMT axis remain poorly understood. In the present study, a scratch assay demonstrated that MeCP2 enhanced ARPE‑19 cell migration, which was markedly suppressed by erastin. Cell Counting Kit‑8 assays and western blot analysis confirmed that Erastin inhibited cell proliferation without triggering apoptosis. Western blotting and corresponding assay kits both revealed that MeCP2 upregulated glutathione peroxidase 4 (GPX4), glutamate‑cysteine ligase modifier subunit and solute carrier family 7 member 11, increased glutathione levels and decreased malondialdehyde and Fe²⁺ concentrations, indicating ferroptosis suppression. Erastin reversed EMT by reducing fibronectin (FN) and α‑smooth muscle actin (α‑SMA) expression and restoring E‑cadherin, as shown by western blotting. Further investigation revealed that GPX4 activation exacerbated EMT marker expression (FN, α‑SMA and N‑cadherin), while GPX4 inhibition mitigated these effects, confirming that MeCP2 regulates EMT through GPX4‑dependent ferroptosis. Erastin inhibited MeCP2‑driven ARPE‑19 proliferation, migration and EMT via ferroptosis induction, independent of apoptosis. MeCP2 suppressed ferroptosis through GPX4 upregulation, using this pathway to orchestrate EMT, thus revealing a critical GPX4‑dependent mechanism that links ferroptosis to RPE plasticity in PVR. These findings highlighted ferroptosis modulation as a promising therapeutic strategy for PVR.