The HIF-1α–Mitochondria Axis in Alzheimer's Disease: Therapeutic Potential of Roxadustat in Restoring Neuronal Bioenergetics and Cognitive Function

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, tau pathology, mitochondrial dysfunction, oxidative stress, neuroinflammation, and cerebral hypoperfusion. Emerging evidence suggests that dysregulation of the hypoxia-inducible factor-1 alpha (HIF-1α)-mitochondria axis plays a central role in linking impaired oxygen sensing to neuronal metabolic failure and neurodegeneration. In AD, an inadequate HIF-1α response contributes to reduced glucose utilization, impaired mitophagy, excessive reactive oxygen species production, and mitochondrial dysfunction, ultimately accelerating neuronal loss and cognitive decline. Roxadustat, an orally active hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor approved for chronic kidney disease-associated anemia, has emerged as a potential neuroprotective agent through pharmacological stabilization of HIF-1α. Activation of HIF-1α signaling promotes metabolic adaptation, enhances mitochondrial quality control, reduces oxidative stress, and modulates neuroinflammatory responses. Preclinical studies involving PHD inhibition, hypoxic preconditioning, and related neurodegenerative models provide evidence supporting the therapeutic relevance of this pathway. This review summarizes the role of the HIF-1α–mitochondria axis in AD pathogenesis and evaluates the potential of roxadustat as a disease-modifying therapeutic strategy. Although direct evidence in AD remains limited, targeting HIF-1α-mediated mitochondrial adaptation represents a promising approach that may complement existing therapies and warrants further preclinical and clinical investigation.