Related Experiment Video
Updated: Jun 30, 2026
Site-Specific Lysine Lactylation via Genetic Code Expansion in E. coli and Mammalian Cells
Published on: February 24, 2026
Histone Lactylation Links Glycolysis to Ferroptosis in Diabetic Cataract
Dan Tao1,2, He Wang1, Zeyuan Liu1
1Department of Ophthalmology, Kunming Medical University Affiliated Children's Hospital, Kunming City, China.
Aims:
This study aimed to delineate a novel mechanistic axis linking hyperglycemia-driven glycolytic reprogramming to ferroptotic death in lens epithelial cells (LECs) and to determine its therapeutic significance in diabetic cataract (DC). Specifically, we sought to define the integration of metabolic, epigenetic (histone lactylation), and post-translational (fucosylation) pathways in DC pathogenesis.
Results:
Under hyperglycemic conditions, LECs exhibited robust glycolytic activation and lactate accumulation. This metabolic shift drove selective histone H3K18 lactylation at the promoter of theTSTA3 gene, leading to its increased transcription. The upregulated TSTA3 protein then promoted the core fucosylation of the NF-κB p50 subunit, which facilitated its nuclear translocation. Inside the nucleus, p50 transcriptionally activatedNOX1, resulting in excessive reactive oxygen species (ROS) production and subsequent ferroptotic cell death. Critically, both pharmacological inhibition of glycolysis and genetic silencing ofTSTA3 effectively attenuated oxidative stress, restored redox balance, and ameliorated cataract severity in a diabetic rat model.
Innovation:
This work identifies a previously unrecognized pathogenic cascade-the glycolysis-histone lactylation-fucosylation-ferroptosis axis-that directly links metabolic flux to epigenetic and signaling control in DC. By positioning TSTA3 as a central, druggable node within this axis, our study redefines cataract pathogenesis beyond simple oxidative damage, integrating multiple layers of cellular regulation.
Conclusion:
The glycolysis-histone lactylation-TSTA3-fucosylation-NOX1-ferroptosis axis is a critical driver of LEC death in diabetic cataract. Targeting this newly defined pathway, particularly the TSTA3 node, offers novel opportunities for mechanism-based therapeutic interventions and biomarker development, with potential implications for other complications of metabolic disease. Antioxid. Redox Signal. 45, 474-490.
Insights
Diabetic cataract involves a new pathway where high blood sugar causes cell death. Targeting the TSTA3 gene may offer new treatments for diabetic complications.
Area of Science:
- Biochemistry
- Molecular Biology
- Ophthalmology
Background:
- Diabetic cataract (DC) pathogenesis involves lens epithelial cell (LEC) death.
- Hyperglycemia drives metabolic and signaling pathway dysregulation in DC.
- The interplay between metabolism, epigenetics, and cell death in DC remains incompletely understood.
Purpose of the Study:
- To elucidate a novel mechanistic axis linking hyperglycemia-induced glycolytic reprogramming to ferroptotic death in LECs.
- To investigate the therapeutic potential of targeting this axis in diabetic cataract.
- To define the integration of metabolic, epigenetic (histone lactylation), and post-translational (fucosylation) pathways in DC.
Main Methods:
- Investigated the glycolysis-histone lactylation-fucosylation-ferroptosis axis in LECs.
- Utilized pharmacological inhibition of glycolysis and genetic silencing of TSTA3.
- Assessed oxidative stress, redox balance, and cataract severity in a diabetic rat model.
Main Results:
- Hyperglycemia induced glycolytic activation and lactate accumulation in LECs.
- This led to histone H3K18 lactylation of the TSTA3 gene promoter, increasing TSTA3 transcription.
- Upregulated TSTA3 promoted NF-κB p50 fucosylation, nuclear translocation, and subsequent NOX1 activation, causing ferroptosis.
- Inhibition of glycolysis or TSTA3 attenuated oxidative stress and ameliorated DC in rats.
Conclusions:
- The identified glycolysis-histone lactylation-TSTA3-fucosylation-NOX1-ferroptosis axis is a key driver of LEC death in DC.
- Targeting TSTA3 presents a promising therapeutic strategy for diabetic cataract.
- This pathway offers potential for biomarker development and treatment of metabolic disease complications.
