Multi-omics identification and verification of <i>Dnajb14</i> as a modulator of retinal ganglion cell survival in glaucoma through ferroptosis

Yu Chen; Jie Wen; Qian Yang; Zixi Chen; Haibo Li; Zhenkai Wu; Quan Cheng; Dan Ji

doi:10.1016/j.jgg.2026.05.011

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

doi: 10.1016/j.jgg.2026.05.011

Yu Chen^a,b,c,
Jie Wen^d,
Qian Yang^a,b,c,
Zixi Chen^a,b,c,
Haibo Li^a,b,c,
Zhenkai Wu^e,
Quan Cheng^d,
Dan Ji^a,b,c

a. Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China;
b. Hunan Key Laboratory of Ophthalmology, Central South University, Changsha, Hunan 410028, China;
c. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410028, China;
d. Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410028, China;
e. Department of Ophthalmology, Changde Hospital (The first people's hospital of Changde city), Xiangya School of Medicine, Central South University, Changde, Hunan 415003, China

Funds:

This study was supported by grants from the National Key Research and Development Program of China (2021YFA1101200 &

2021YFA1101202), the National Natural Science Foundation of China (U23A20435, 82271091), Hunan Youth Science and Technology Talent Project (2023RC3074), Hunan Provincial Natural Science Foundation of China (2024JJ7015), Science and Technology Innovation Program of Changde city (2023YD21), Fundamental Research Funds for the Central Universities of Central South University (2026ZZTS0053) and Hunan Provincial Youth Student Basic Research Project of Natural Science Foundation of China (2026JJ90184).

Received Date: 2025-10-24
Accepted Date: 2026-05-20
Rev Recd Date: 2026-05-15

Abstract

Abstract

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.
- Glaucoma,
- Mendelian randomization,
- ScRNA-seq analysis,
- Ischemia-reperfusion,
- Ferroptosis

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