Metabolic and Redox Adaptations of the Corneal Endothelium: From Metabolic Plasticity to Therapeutic Opportunities

The corneal endothelium, a monolayer of nonregenerating cells on the posterior cornea, maintains corneal transparency through active fluid pumping. This review examines how corneal endothelial cells (CEnCs) meet high energy demands and adapt metabolically from quiescence to stress, with particular emphasis on their intrinsic metabolic plasticity. In CEnCs, ATP is generated through both glycolysis and oxidative phosphorylation (OXPHOS), with their relative contributions shifting according to oxygen tension and cellular state; OXPHOS remains relatively stable, whereas glycolysis increases during repair and stress. Environmental factors, including pH and temperature, further modulate metabolic flux and pump activity. CEnCs are also continuously exposed to oxidative stress arising from mitochondrial respiration, NADPH oxidase activity, and UVA exposure. Under physiological conditions, antioxidant networks involving NRF2/DJ-1 and related enzymes limit reactive oxygen species (ROS) accumulation. However, in ageing and endothelial disorders such as FECD and diabetes, these defences become impaired. We discuss how disrupted mitochondrial dynamics and mitophagy contribute to bioenergetic failure and endothelial cell loss across disease contexts. Finally, we critically review emerging therapeutic strategies, including metabolic modulators, gene-based approaches, organelle-targeted interventions, and cell-based endothelial replacement. By integrating these mechanisms, this review highlights how therapeutic modulation of metabolism and organelle quality control, together with strategies to address translational barriers, may protect the corneal endothelium, improve graft survival, and delay the need for corneal transplantation. • Metabolic plasticity in corneal endothelial cells sustains pump-leak function • Glycolysis-OXPHOS balance shifts with oxygen, pH, temperature and cell state • Redox failure and mitochondrial dysfunction drive endothelial ageing and disease • Targeting metabolism, redox and organelle quality control offers new therapies • Cell and organelle therapies show promise but face translational barriers