Piezo1 mechanobiology in high myopia and glaucoma: compartment-specific evidence, gaps, and a hypothesis-generating susceptibility framework

High myopia and glaucoma are clinically distinct but mechanobiologically connected conditions. High myopia is commonly associated with marked axial elongation, posterior-segment stretch, scleral remodeling, and altered posterior-pole and peripapillary biomechanics, whereas glaucoma involves intraocular pressure (IOP)-related outflow stress, optic nerve head (ONH) strain, and retinal ganglion cell (RGC) vulnerability. Both disorders therefore converge on chronic mechanical stress and compartment-specific susceptibility. Piezo1, a mechanically activated cation channel, is well positioned to connect membrane tension, extracellular matrix (ECM) state, Ca 2+ signaling, reactive oxygen species (ROS)-associated stress responses, and cellular remodeling. This review develops a hypothesis-driven but evidence-bound framework centered on a possible Piezo1-linked mechanobiological susceptibility axis between high myopia and glaucoma. The strongest ocular evidence remains in the trabecular meshwork and conventional outflow pathway, where activation, perturbation, Ca 2+ signaling, matrix and prostaglandin readouts, and outflow-related assays converge. Evidence in optic nerve head astrocytes is moderate, retinal ganglion cell evidence is emerging, and myopia-related evidence currently supports retinal or posterior-segment stress signaling more strongly than scleral fibroblast-specific ECM causality. Myopia-specific scleral fibroblast evidence and peripapillary-scleral evidence remain exploratory. Critically, current evidence does not demonstrate a continuous Piezo1-dependent causal chain linking scleral remodeling or peripapillary load redistribution to optic nerve head deformation and glaucomatous RGC degeneration. Accordingly, the proposed high-myopia–glaucoma susceptibility axis should be regarded as a hypothesis-generating framework rather than an established causal pathway. This evidence-graded approach distinguishes directly supported tissue-level mechanisms from cross-compartment relationships that require targeted experimental validation.