Serum hepcidin is associated with retinopathy of prematurity and modulates oxidative stress and angiogenic responses in retinal microvascular endothelial cells.

INTRODUCTION: Retinopathy of prematurity (ROP) is a vasoproliferative retinal disorder in preterm infants driven by impaired vascular development, hypoxia, oxidative stress, and pathological angiogenesis. Current treatments mainly target VEGF signaling but do not directly address upstream oxidative injury. Hepcidin, a key iron-homeostasis regulator, may modulate redox balance and angiogenic activation. However, whether hepcidin is reduced in ROP and whether supplementation mitigates hypoxia-induced oxidative stress and abnormal angiogenesis in retinal endothelial cells remain unclear.

OBJECTIVE: To investigate the effects of hepcidin on human retinal microvascular endothelial cells (hRMECs) under oxidative stress and assess its translational potential in ROP.

METHODS: Clinical data were collected from 35 preterm infants with gestational age <36 weeks, including 24 non-ROP controls and 11 ROP infants. Gestational age, birth weight, ROP stage, and serum hepcidin were analyzed. hRMECs were exposed to 1% O2 to establish a hypoxia model. Cell viability, VEGFA and HIF-1α mRNA expression, secreted VEGFA, intracellular reactive oxygen species (ROS), transcriptomic changes, and tube formation were evaluated. Hepcidin was added under hypoxia to assess its effects on oxidative stress and angiogenic activation.

RESULTS: Infants with ROP had lower gestational age and birth weight than controls, and gestational age differed across ROP stage groups. Serum hepcidin-related signals were numerically lower in ROP infants, but no significant stage-dependent decrease was observed. In hRMECs, 1% O2 altered cell viability, upregulated VEGFA and HIF-1α mRNA, increased secreted VEGFA, and promoted ROS accumulation, confirming a hypoxia-induced endothelial stress model. Transcriptomic analysis suggested that hepcidin affected hypoxia-responsive metabolic pathways, including cysteine and methionine, selenocompound, and tryptophan metabolism. Functional validation showed that hepcidin reduced VEGFA at transcript and secreted protein levels, decreased intracellular ROS, and suppressed hypoxia-induced tube formation by reducing junction points, branch points, and total tube length.

CONCLUSION: This study provides preliminary clinical and experimental evidence supporting a potential role of hepcidin-related signaling in ROP. Although the clinical findings are exploratory, the in vitro results indicate that hepcidin can attenuate hypoxia-induced oxidative stress and pathological angiogenic activation in retinal endothelial cells. Hepcidin may represent a biologically relevant pathway and potential candidate for further biomarker and therapeutic research in ROP.