Fig. 7: Schematic plot of DDR2 enhancing ferroptosis sensitivity via the Src-Hippo pathway in highly myopic cataract.

In highly myopic eyes, the elevated levels of TGF-β1 in the lens microenvironment contribute to an increased expression of DDR2. This, in turn, activates the Src kinase, which promotes the nuclear translocation of key effectors of the Hippo pathway: YAP1 and its homolog WWTR1. YAP1 upregulates the transcription of ACSL4 and TfR1, while simultaneously downregulating GPX4 at the post-translational level, which collectively enhance the lens’s sensitivity to ferroptosis, manifesting as increased levels of Fe2+, lipid peroxidation, and mitochondrial distortion. Ultimately, the heightened ferroptosis sensitivity accelerates the formation of nuclear cataracts in highly myopic lenses.