Scleral Postn Drives Myopia via Promoting Myofibroblast Transdifferentiation

We previously found that scleral hypoxia led to a cascade involving glycolysis-lactate-histone H3 lysine 18 lactylation (H3K18la), which contributes to myopia. Since Cut&Tag identified Postn as a primary H3K18la-enriched extracellular matrix (ECM) gene, which encodes the periostin (Postn) protein, this study aimed to investigate whether Postn drives myopia by modulating scleral ECM remodeling.

H3K18la enrichment at the Postn promoter was validated via CUT&Tag-quantitative PCR. Scleral Postn levels were assessed via reverse-transcription quantitative PCR (RT-qPCR) and immunoblotting during form deprivation myopia (FDM) in mice. Gain- or loss-of-function experiments were conducted to evaluate the role of scleral Postn in normal refractive development or FDM. Mechanisms were explored in FDM mice and human scleral fibroblasts (HSFs) using immunoblotting, co-immunoprecipitation, gene manipulation, and recombinant human POSTN (rhPOSTN) protein treatment.

H3K18la enrichment in the Postn promoter region and Postn mRNA and protein levels were increased during myopia. In HSFs, POSTN knockdown inhibited the hypoxia- or lactate-induced rise in fibroblast-to-myofibroblast transdifferentiation (FMT) and rescued type I collagen decline. Scleral Postn overexpression induced myopia in mice, while its knockdown attenuated FDM development. Mechanistically, Postn binds to integrin αvβ3 and αvβ5 receptors to activate the AKT signaling pathway, driving FMT and suppressing type I collagen.

Scleral Postn contributes to myopia by promoting FMT in the sclera.