2. Academic Validation
  3. Lactate-binding protein DNMT3A in HRMECs promotes angiogenesis by upregulating VEGFA through HIF-1α lactylation

Lactate-binding protein DNMT3A in HRMECs promotes angiogenesis by upregulating VEGFA through HIF-1α lactylation

  • Genome Biol. 2025 Oct 30;26(1):377. doi: 10.1186/s13059-025-03845-7.
Xiaotang Wang # 1 2 3,  Jiaxing Huang # 1 2 3,  Wei Fan # 1 2 3,  Na Li # 4,  Hui Yang 5,  Wenxian Yang 5,  Wanqian Li 1 2 3,  Ruonan Li 1 2 3,  Jiangyi Liu 1 2 3,  Xingran Li 1 2 3,  Qian Zhou 1 2 3,  Shengping Hou 6
Affiliations

Affiliations

  • 1 The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Chongqing Key Laboratory of Ophthalmology, Chongqing, China.
  • 3 Chongqing Eye Institute, Chongqing, China.
  • 4 Department of Laboratory Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, 100005, China.
  • 5 Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
  • 6 Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China. sphou828@163.com.
  • # Contributed equally.
PMID: 41168862 DOI: 10.1186/s13059-025-03845-7
Abstract

Background: Ocular neovascularization is a leading cause of blindness. Hypoxia is associated with retinal angiogenesis. Hypoxia results in lactate accumulation, which typically precedes protein lactylation, and this plays a crucial role in ocular neovascularization. However, the underlying mechanism remains unclear. Here, we investigate the role of the DNA Methyltransferase, DNMT3A, in regulating lactylation following hypoxia in ocular neovascularization.

Results: DNMT3A controls endothelial cell angiogenesis via regulating lactate-derived HIF-1α lactylation. During oxygen-induced retinopathy progression, we detected increased levels of DNMT3A, HIF-1α lactylation, and vascular endothelial growth factor (VEGF) in endothelial cells. Exogenous lactate administration significantly enhances vascularization, while inhibiting lactate uptake in the presence or absence of DNMT3A prevents endothelial cell angiogenesis and attenuates HIF-1α lactylation. We demonstrate that modulating DNMT3A expression alters HIF-1α lactylation levels, influencing angiogenesis in vitro and in vivo.

Conclusions: DNMT3A facilitates lactate transport into the nucleus, where it promotes VEGFA upregulation through HIF-1α lactylation, thereby stimulating endothelial cell angiogenesis. Targeting the lactate-DNMT3A/HIF-1α lactylation/VEGFA pathway could provide new therapeutic strategies for treating ocular neovascularization disorders.

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