Role of Autophagy in Scleral Remodeling During Form‐Deprivation Myopia

ABSTRACT

Autophagy has been implicated in tissue remodeling, but its role in scleral remodeling during myopia development and in atropine‐mediated myopia control remains unclear. We investigated this issue using complementary in vitro and in vivo models. Human scleral fibroblasts (HSFs) were exposed to hypoxia and treated with rapamycin (RAPA) or 3‐methyladenine (3‐MA). Beclin‐1 knockdown and bafilomycin A1 (BafA1)‐based LC3B II accumulation assays were used to assess the functional contribution of autophagy and autophagic flux. In vivo, form‐deprivation myopia (FDM) was induced in guinea pigs, followed by atropine, RAPA, or 3‐MA intervention. Refractive error, axial length, scleral histology, extracellular matrix remodeling, autophagy‐related markers, and AMPK/mTOR/P70S6K signaling were evaluated. Hypoxia induced a remodeling phenotype in HSFs, characterized by decreased COL1A1 and increased MMP2/α‐SMA, accompanied by increased autophagy. 3‐MA attenuated these changes, whereas RAPA aggravated them. Beclin‐1 knockdown similarly suppressed hypoxia and RAPA‐associated remodeling changes and reduced autophagic flux, supporting a functional role of autophagy in hypoxia‐induced scleral fibroblast remodeling. In FDM guinea pigs, scleral tissue showed increased HIF‐1α expression, autophagy activation, and extracellular matrix remodeling. Both 0.05% and 1% atropine slowed myopia progression and axial elongation, improved scleral structural abnormalities, and suppressed autophagy‐related changes, with no significant difference between the two concentrations. Subconjunctival RAPA exacerbated, whereas 3‐MA alleviated, myopia progression and scleral remodeling. These findings suggest that excessive scleral autophagy links hypoxic stress to scleral extracellular matrix remodeling in experimental myopia. This process may also contribute to the anti‐myopic action of atropine.