The IGF2–ERK–Fos axis drives a Müller cell glial-mesenchymal transition-like response to disrupt retinal homeostasis in early myopia

Myopia is increasingly recognized as a complex pathology involving retinal remodeling, yet the cellular mechanisms linking early visual stress to this process remain unclear. This study investigated whether Müller glial (MG) cells undergo a glial-mesenchymal transition (GMT)-like response in early myopia and identified the upstream signaling axis driving this transformation. We integrated single-cell and spatial transcriptomic analyses to construct a high-resolution atlas of retinal cell heterogeneity in a guinea pig model of form-deprivation myopia (FDM). Single-cell analysis revealed an expanded MG population (18.9% vs. 6.9%) and identified a disease-enriched Fos⁺ MG subcluster exhibiting a transcriptional signature of GMT and activated extracellular matrix (ECM) remodeling. IGF2 signaling was elevated in myopic MG cells and correlated with ERK/Fos activation. In vivo siIGF2 attenuated myopia progression, preserved retinal function/structure, suppressed MG activation/proliferation and GMT/ECM marker expression, and reduced inner limiting membrane abnormalities and retinal stiffening. Conversely, in vitro, rhIGF2 activated the ERK/Fos pathway, promoting proliferation, migration, GMT-like response, and collagen synthesis in MIO-M1 cells. These findings demonstrate that early myopia involves Fos⁺ MG-driven retinal remodeling via GMT-like response, coupling visual stress to ECM and mechanical changes. The IGF2–ERK–Fos axis is a key upstream driver of this pathology, presenting a novel target for intervention to preserve retinal homeostasis. Form deprivation elevates retinal IGF2, activating the ERK‑Fos pathway in Müller glia and driving a glial‑to‑mesenchymal transition (GMT)-like response. This leads to excessive ECM deposition and retinal stiffening. Silencing IGF2 blocks this pathway, restores retinal homeostasis, and mitigates structural remodeling, highlighting IGF2–ERK–Fos as a targetable axis in early myopia. Created with BioRender.com.