Chem Biol Interact. 2026 Jul 2:112229. doi: 10.1016/j.cbi.2026.112229. Online ahead of print.
ABSTRACT
Hypoxia disrupts corneal physiological function by impairing energy metabolism. We identify AMP-activated protein kinase (AMPK) as a central regulator of coordinated metabolic adaptation in the hypoxic cornea. Using human corneal epithelial cells and an alkali burn-induced mouse model of corneal hypoxia, we combined metabolic flux analysis, mitochondrial morphology assessment and pathway-specific pharmacological and molecular approaches to characterize AMPK-dependent metabolic regulation. We demonstrate that hypoxia-induced AMPK activation is not merely a stress response but an essential driver of metabolic adaptation. Importantly, we found that AMPK coordinates bidirectional metabolic reprogramming. It enhances glycolytic flux through the AMPK/TXNIP/GLUT1 axis and improves mitochondrial oxidative capacity by regulating mitochondrial biogenesis via PGC1α, mitochondrial dynamics via MFF/DRP1 and MTFR1L/OPA1, and mitophagy via ULK1. This coordinated regulation of fuel supply and energy production suggests an integrative role of AMPK in the corneal epithelium. Pharmacological activation of AMPK with AICAR recapitulated this coordinated response, restored energy homeostasis, and mitigated hypoxic damage. Our findings indicate AMPK as a important regulator of glycolysis and mitochondrial function in the hypoxic cornea, highlighting a metabolic network with therapeutic potential. By demonstrating that AICAR rescues corneal energy failure through this dual mechanism, our findings support a potential metabolic restoration strategy that extends beyond single-pathway targeting and may provide a new approach for treating corneal diseases associated with metabolic dysregulation.
PMID:42392248 | DOI:10.1016/j.cbi.2026.112229