Bin Song, Wenjuan Duan, Hui Liu
The hypoxia-HIF-1α-MMP signaling axis is a promising candidate mechanism in myopic scleral remodeling, with translational implications for both pharmacological and nonpharmacological strategies. However, key gaps remain, including the need for independent replication, longitudinal human evidence, and direct experimental validation in scleral fibroblasts. Future multiomics and targeted interventional studies are required to establish causality and translate these findings into clinical applications.
PURPOSE: Myopia, driven by pathological axial elongation, is a leading cause of visual impairment. This review synthesizes and critically evaluates the evidence for the "scleral hypoxia theory," focusing on the role of hypoxia-inducible factor-1α (HIF-1α) signaling in scleral remodeling during myopia progression.
METHODS: A comprehensive literature search was conducted on PubMed to 2026, focusing on scleral hypoxia, HIF-1α signaling, extracellular matrix (ECM) remodeling, and their interplay with inflammatory and metabolic pathways. Evidence was categorized into 3 tiers: direct scleral/myopia evidence, indirect ocular evidence, and extrapolative evidence from other tissue systems.
RESULTS: Converging evidence from human genetic studies, animal models, and cell-based experiments supports the scleral hypoxia theory. Reduced choroidal blood perfusion creates a hypoxic microenvironment in the sclera, stabilizing HIF-1α and activating downstream matrix metalloproteinases (MMPs), which promotes ECM degradation, scleral thinning, and biomechanical weakening, facilitating axial elongation. The HIF-1α pathway exhibits extensive crosstalk with transforming growth factor-β, AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1)/Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) metabolic signaling, oxidative stress, and inflammatory pathways. Emerging evidence suggests potential roles for macrophage polarization (M1/M2) in scleral remodeling. Notably, the majority of direct mechanistic evidence is derived from a limited number of landmark studies, and independent replication across diverse models is needed.
CONCLUSIONS: The hypoxia-HIF-1α-MMP signaling axis is a promising candidate mechanism in myopic scleral remodeling, with translational implications for both pharmacological and nonpharmacological strategies. However, key gaps remain, including the need for independent replication, longitudinal human evidence, and direct experimental validation in scleral fibroblasts. Future multiomics and targeted interventional studies are required to establish causality and translate these findings into clinical applications.