Comparative proteomics of human anterior lens capsules reveals ATP6V1A-associated lysosomal dysregulation in age-related cataract with primary angle-closure glaucoma
6 affiliations
- 1Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan 410008 China
- 2Hunan Key Laboratory of Ophthalmology, Changsha, Hunan 410008 China
- 3National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, Hunan 410008 China
- 4FuRong Laboratory, Changsha, Hunan 410078 China
- 5National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, Hunan 410008 China
- 6Department of Laboratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan China
Abstract
Background: Lens-related mechanisms in primary angle-closure glaucoma (PACG) remain incompletely defined. The anterior lens capsule (ALC) is a biologically active interface, but its molecular landscape in PACG is largely unknown. We aimed to define proteomic alterations in human ALCs from age-related cataract (ARC) with PACG and to evaluate whether lysosome-associated changes are implicated.
Methods: We performed comparative data-independent acquisition proteomic profiling of human ALC specimens from patients with ARC alone and ARC combined with PACG. After quality control, 13 ARC and 10 PACG samples were included. Differential proteins were analyzed by enrichment, network, and receiver operating characteristic analyses. ATP6V1A was further evaluated in human ALC flat mounts, cell and animal stress models, peripheral blood mononuclear cells (PBMCs) from an additional small clinical cohort, and an exploratory UK Biobank (UKB) plasma proteomic dataset.
Results: A total of 1262 differentially expressed proteins were identified in PACG-associated ALCs. Proteins reduced in PACG were enriched for proteostasis-related chaperone and neddylation networks and converged on lysosome-related dysfunction. ATP6V1A and additional V-ATPase subunits, LAMP2, and Rag GTPase family members were coordinately decreased. Proteins increased in PACG were enriched for extracellular matrix remodeling and lipid/glycan metabolic pathways. Reduced ATP6V1A was confirmed in human ALC flat mounts, pressure-stressed lens epithelial cells, retinal stress models, and PBMCs from patients with PACG. Pharmacologic V-ATPase inhibition disrupted lysosomal homeostasis before overt loss of cell viability. UKB plasma proteomics did not recapitulate the ATP6V1A signal, but provided external support for glaucoma-associated lens-related and metabolic alterations.
Conclusions: PACG-associated ALCs show a distinct molecular signature characterized by impaired proteostasis and ATP6V1A-associated lysosomal dysregulation. These findings identify ATP6V1A-associated lysosomal dysfunction as a candidate molecular link between elevated IOP, lens epithelial injury, and the coexistence of PACG and ARC.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08934-0.
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BibTeX
@article{liu2026comparative,
title = {{Comparative proteomics of human anterior lens capsules reveals ATP6V1A-associated lysosomal dysregulation in age-related cataract with primary angle-closure glaucoma}},
author = {Jiamiao Liu and Jing Wang and Yi Zeng and Zeyi Zhao and Peng Zhu and Yixian Liu and Qing Dong and Junpeng Zhao and Xiaobo Xia and Rong Rong and Lexi Ding},
journal = {Journal of Translational Medicine},
year = {2026},
month = sep,
doi = {10.1186/s12967-026-08934-0},
url = {https://doi.org/10.1186/s12967-026-08934-0},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Comparative proteomics of human anterior lens capsules reveals ATP6V1A-associated lysosomal dysregulation in age-related cataract with primary angle-closure glaucoma
AU - Jiamiao Liu
AU - Jing Wang
AU - Yi Zeng
AU - Zeyi Zhao
AU - Peng Zhu
AU - Yixian Liu
AU - Qing Dong
AU - Junpeng Zhao
AU - Xiaobo Xia
AU - Rong Rong
AU - Lexi Ding
PY - 2026
DA - 2026/09/07
JO - Journal of Translational Medicine
DO - 10.1186/s12967-026-08934-0
UR - https://doi.org/10.1186/s12967-026-08934-0
AB - Background: Lens-related mechanisms in primary angle-closure glaucoma (PACG) remain incompletely defined. The anterior lens capsule (ALC) is a biologically active interface, but its molecular landscape in PACG is largely unknown. We aimed to define proteomic alterations in human ALCs from age-related cataract (ARC) with PACG and to evaluate whether lysosome-associated changes are implicated. Methods: We performed comparative data-independent acquisition proteomic profiling of human ALC specimens from patients with ARC alone and ARC combined with PACG. After quality control, 13 ARC and 10 PACG samples were included. Differential proteins were analyzed by enrichment, network, and receiver operating characteristic analyses. ATP6V1A was further evaluated in human ALC flat mounts, cell and animal stress models, peripheral blood mononuclear cells (PBMCs) from an additional small clinical cohort, and an exploratory UK Biobank (UKB) plasma proteomic dataset. Results: A total of 1262 differentially expressed proteins were identified in PACG-associated ALCs. Proteins reduced in PACG were enriched for proteostasis-related chaperone and neddylation networks and converged on lysosome-related dysfunction. ATP6V1A and additional V-ATPase subunits, LAMP2, and Rag GTPase family members were coordinately decreased. Proteins increased in PACG were enriched for extracellular matrix remodeling and lipid/glycan metabolic pathways. Reduced ATP6V1A was confirmed in human ALC flat mounts, pressure-stressed lens epithelial cells, retinal stress models, and PBMCs from patients with PACG. Pharmacologic V-ATPase inhibition disrupted lysosomal homeostasis before overt loss of cell viability. UKB plasma proteomics did not recapitulate the ATP6V1A signal, but provided external support for glaucoma-associated lens-related and metabolic alterations. Conclusions: PACG-associated ALCs show a distinct molecular signature characterized by impaired proteostasis and ATP6V1A-associated lysosomal dysregulation. These findings identify ATP6V1A-associated lysosomal dysfunction as a candidate molecular link between elevated IOP, lens epithelial injury, and the coexistence of PACG and ARC. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08934-0.
SN - 1479-5876
ER -