2. Academic Validation
  3. Uncovering the metabolic landscape of aqueous humor in posterior subcapsular cataract associated with hyperuricemia

Uncovering the metabolic landscape of aqueous humor in posterior subcapsular cataract associated with hyperuricemia

  • Exp Eye Res. 2025 Nov 21:263:110767. doi: 10.1016/j.exer.2025.110767.
Yang Sun 1,  Ling Li 1,  Fulong Luo 2,  Yongjie Qin 3,  Hongyang Zhang 4
Affiliations

Affiliations

  • 1 Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 2 Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
  • 3 Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China. Electronic address: [email protected].
  • 4 Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: [email protected].
PMID: 41275899 DOI: 10.1016/j.exer.2025.110767
Abstract

The purpose of this study is to investigate the metabolic alterations underlying posterior subcapsular cataract (PSC) associated with hyperuricemia and to identify key metabolic pathways contributing to disease progression. Untargeted metabolomic profiling was conducted on aqueous humor samples obtained from twelve cataract patients classified into four groups based on PSC status and serum uric acid levels. Comparative analyses among hyperuricemic PSC (HP), normouricemic PSC (NP), hyperuricemic non-PSC (HC), and normouricemic non-PSC (NC) groups were performed. A total of 46 differentially expressed metabolites (DEMs) were identified between HP and NP groups, with enrichment in pathways related to glutathione metabolism, nitrogen homeostasis, and amino acid biosynthesis. Comparative analysis demonstrated that PSC under hyperuricemic conditions displayed distinct metabolic signatures, particularly involving enhanced glutaminolysis and altered redox homeostasis, compared to both normouricemic PSC and hyperuricemic non-PSC patients. Targeted amino acid profiling confirmed glutamine accumulation in lens epithelial cells (LECs) treated with uric acid, while 13C5-glutamine metabolic flux analysis showed increased flux into tricarboxylic acid (TCA) cycle intermediates and glutathione. Despite increased glutamine utilization, redox balance was impaired, as shown by decreased total glutathione (GSH), increased oxidized glutathione (GSSG), and a reduced GSH/GSSG ratio. At the protein level, GPX4 was downregulated, while GLS1 and GLS2 was upregulated in response to elevated uric acid levels. Taken together, these findings suggest that dysregulated glutaminolysis and impaired glutathione metabolism are key features of hyperuricemia-associated PSC, highlighting glutamine-dependent redox imbalance as a potential mechanistic link between systemic metabolic dysfunction and localized cataract formation.

Keywords

Glutamine metabolic flux; Glutathione metabolism; Hyperuricemia; Metabolomics; Posterior subcapsular cataract.

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