Key role of transcription factors network in proliferative vitreoretinal diseases development

Proliferative vitreoretinal diseases (PVDs) encompass severe ocular disorders such as proliferative vitreoretinopathy (PVR), proliferative diabetic retinopathy (PDR), and epiretinal membranes (ERM), characterized by the formation of fibrovascular membranes that often lead to retinal detachment and vision loss. A central mechanism driving these conditions is the epithelial-to-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells, orchestrated by a network of transcription factors (TFs). Among these, zinc finger E-box binding homeobox 1 (ZEB1) emerges as a pivotal regulator by repressing epithelial markers like E-cadherin and inducing mesenchymal markers such as N-cadherin and vimentin, thereby promoting cell migration and fibrotic membrane formation. nuclear factor of activated T cells 5 (NFAT5) contributes to this process by mediating osmotic stress responses and upregulating inflammatory cytokines, which further act upon EMT and fibrosis. activator protein 1 (AP-1) and hypoxia inducible factor 1 subunit alpha (HIF-1α) participate in driving inflammation, extracellular matrix (ECM) remodeling, and angiogenesis. While HIF-1α triggers vascular endothelial growth factor (VEGF) expression under hypoxic conditions, AP-1 modulates matrix metalloproteinases (MMPs) essential for ECM degradation and remodeling. Additional TFs, including Kruppel-like factor 4 (KLF4) and microphthalmia-associated transcription factor (MITF), are vital in maintaining RPE cell identity. Their downregulation under pathological conditions disrupts epithelial integrity and predisposes cells to undergo EMT. Moreover, β-catenin, through its role in the wingless-related integration site (Wnt) signaling pathway, reinforces EMT and ECM remodeling, further enhancing fibrotic progression. Adipocyte enhancer-binding protein 1 (AEBP1) and ZFP36 ring finger protein like 1 (ZFP36L1) also regulate inflammatory responses and ECM dynamics, providing novel post-transcriptional targets for therapeutic intervention. Overall, the synergistic interactions among these TFs create complex feedback loops that amplify pathological changes in PVDs. Targeting these molecular pathways offers promising avenues for developing multi-targeted therapies aimed at saving vision-threatening disease while reducing invasive surgical interventions.