Insulin-like Growth Factor Signaling Promotes Corneal Myofibroblast Survival and Sustains Corneal Fibrosis

Corneal fibrosis is a major cause of visual impairment worldwide and is characterized by persistent stromal scarring that disrupts corneal transparency. Although transforming growth factor-β (TGF-β)-mediated myofibroblast differentiation is well established, the mechanisms that sustain myofibroblast survival and persistence remain poorly understood. In this study, we investigated the role of the insulin-like growth factor (IGF) signaling axis in corneal myofibroblast survival and evaluated the therapeutic potential of linsitinib, a dual IGF-1 receptor (IGF-1R)/insulin receptor (INSR) inhibitor. Primary corneal myofibroblasts were exposed to pro-apoptotic conditions and treated with IGF ligands in the presence or absence of linsitinib. The effects of IGF pathway inhibition were further examined in a mouse model of corneal fibrosis. IGF-1 and IGF-2 promoted myofibroblast survival under pro-apoptotic conditions, whereas pharmacologic inhibition of IGF-1R/INSR signaling with linsitinib blocked these pro-survival effects. In vivo, linsitinib treatment reduced myofibroblast persistence and attenuated corneal fibrosis. These findings identify the IGF axis as a critical regulator of corneal myofibroblast survival and suggest that persistent fibrosis is maintained, in part, by IGF-dependent resistance to apoptosis. Targeting survival pathways rather than myofibroblast differentiation may represent a novel therapeutic strategy for the treatment of corneal fibrosis.