Melatonin Alleviates Retina Angiogenesis by Targeting Fibronectin and the VEGF Pathway

ABSTRACT Diabetic retinopathy (DR) and retinopathy of prematurity (ROP) continue to be significant causes of vision impairment despite the well‐established role of vascular endothelial growth factor (VEGF) in pathological angiogenesis. We still need to deeply understand retinal angiogenesis's molecular mechanisms and identify potential alternate therapeutic targets. We used RNA sequencing (RNA‐seq) and found fibronectin ( FN1 ), an extracellular matrix protein, was significantly upregulated during retinal angiogenesis in the oxygen‐induced retinopathy (OIR) model. Employing a deep learning model (BioNet) to identify potential FN1 inhibitors among FDA‐approved drugs, we discovered that melatonin effectively reduced FN1 expression and inhibited VEGF‐induced angiogenesis by decreasing VEGFR2 phosphorylation. In vivo, melatonin administration significantly reduced preretinal tufts in the OIR model while suppressing FN1 expression and VEGFR2 activation. This study highlights the power of computer‐driven drug discovery, with BioNet successfully identifying melatonin as a potential therapeutic agent for retinal angiogenesis. The ability of melatonin to inhibit both FN1 and VEGF signaling highlights the potential of integrating advanced computational methods with rigorous experimental validation to uncover novel therapies for complex diseases.