Targeting lncRNA Carmn alleviates scleral remodeling in high myopia via Myrf-mediated repression of YAP activity

Pathological remodeling of the sclera, characterized by extracellular matrix (ECM) degradation and biomechanical weakening, is a central feature of axial elongation in high myopia. Scleral fibroblasts are the major cell type responsible for ECM homeostasis, and mechanotransduction pathways such as YAP signaling have been implicated in regulating fibroblast behavior and matrix turnover. However, the upstream regulators that control fibroblast function and ECM remodeling in the myopic sclera remain incompletely understood. Long noncoding RNAs (lncRNAs) have emerged as important modulators of gene regulation, but their contribution to scleral fibroblast dysfunction and ECM remodeling in high myopia is largely unexplored.

Integrated transcriptomic analyses were performed on scleral tissues from lens-induced myopic (LIM) mice and adults with high myopia to identify conserved dysregulated lncRNAs and mRNAs. Functional roles were examined using primary scleral fibroblasts through gain- and loss-of-function approaches, combined with assays of proliferation, migration, apoptosis, and ECM protein expression. RNA-protein interaction, chromatin immunoprecipitation, luciferase reporter, and competing endogenous RNA (ceRNA) analyses were conducted to interrogate molecular mechanisms. In vivo relevance was evaluated by sub-Tenon's AAV-mediated modulation of lncRNA expression in LIM mice.

Cross-species transcriptomic profiling identified lncRNA Carmn as a consistently downregulated lncRNA in myopic sclera. Reduced Carmn expression was associated with scleral thinning, collagen disorganization, and fibroblast dysfunction in both mice and humans. In vitro, modulation of Carmn levels was associated with changes in scleral fibroblast proliferation, migration, apoptosis, and expression of ECM-related proteins. Mechanistically, Carmn physically interacted with the transcription factor Myrf and was associated with altered YAP transcriptional activity. In parallel, Carmn functioned as a ceRNA by sequestering miR-1224-5p, thereby modulating Myrf expression at the post-transcriptional level. In vivo, AAV-mediated Carmn overexpression attenuated axial elongation and preserved scleral structure in LIM mice, whereas Carmn knockdown exacerbated myopic progression, accompanied by coordinated changes in the miR-1224-5p/Myrf/YAP axis.

LncRNA Carmn as a conserved regulatory factor associated with scleral remodeling in high myopia. Through combined RNA-protein interaction and ceRNA-mediated mechanisms, Carmn is linked to Myrf-YAP signaling and ECM homeostasis in scleral fibroblasts. This study provides mechanistic insight into lncRNA-mediated regulation of scleral biomechanics and highlights Carmn as a potential molecular target for modulating pathological axial elongation.

Not applicable.