Multi-omics identification and verification of Dnajb14 as a modulator of retinal ganglion cell survival in glaucoma through ferroptosis.

Glaucoma is a leading cause of irreversible blindness and necessitates the identification of unreported therapeutic targets. Here, we report eight stable plasma protein targets for glaucoma, identified through a large-scale proteome-wide association study integrated with Mendelian randomization and colocalization analyses. Among these candidates, we show that the DnaJ heat shock protein family member B14 (DNAJB14) acts as a critical neuroprotective factor. Using single-cell and bulk transcriptomics, we demonstrate that Dnajb14 is characteristically expressed in retinal ganglion cells (RGCs) and that its abundance is inversely correlated with ferroptosis under ischemic stress. Furthermore, our results reveal that Dnajb14 preserve RGC survival and structural and functional integrity in multiple acute and chronic murine models. Mechanistically, Dnajb14 overexpression robustly alleviate ischemia-reperfusion-induced retinal injury, whereas targeted knockdown exacerbate lipid peroxidation, mitochondrial dysfunction, and ferroptosis. Taken together, our findings highlight that Dnajb14 is a key regulator of RGC survival through inhibition of ferroptosis, thereby making it a promising therapeutic candidate for glaucoma treatment.