HK2 promotes angiogenesis through H3K18 lactylation in peripheral arterial disease PMID: 42209711

ADC Targets in Oncology

2026-04-10

HK2 promotes angiogenesis through H3K18 lactylation in peripheral arterial disease

Commun Biol. 2026 May 28. doi: 10.1038/s42003-026-10293-x.

Jing Chen ¹ ² ³ , Yue Wang ² ⁴ ⁵ , Xuan Wang ² ⁴ , Jin Li ² ⁴ , Yu Liu ³ , Jipeng Zhou ² ⁴ , Chuanchang Li ⁶ ⁷ ⁸ ⁹ , Wanzhou Wu ¹⁰ ¹¹ ¹² ¹³ , Yongping Bai ¹⁴ ¹⁵ ¹⁶ ¹⁷ ¹⁸

Affiliations

1. Coronary Circulation Center, Xiangya Hospital, Central South University, Changsha, China.
2. National Clinical Research Center for Geriatric Disease, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China.
3. Taikang Ningbo Hospital, Ningbo, Zhejiang, China.
4. Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China.
5. Department of Cardiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
6. Coronary Circulation Center, Xiangya Hospital, Central South University, Changsha, China. [email protected].
7. National Clinical Research Center for Geriatric Disease, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China. [email protected].
8. Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China. [email protected].
9. Aging Research Center, Xiangya Hospital, Central South University, Changsha, China. [email protected].
10. Coronary Circulation Center, Xiangya Hospital, Central South University, Changsha, China. [email protected].
11. National Clinical Research Center for Geriatric Disease, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China. [email protected].
12. Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China. [email protected].
13. Aging Research Center, Xiangya Hospital, Central South University, Changsha, China. [email protected].
14. Coronary Circulation Center, Xiangya Hospital, Central South University, Changsha, China. [email protected].
15. National Clinical Research Center for Geriatric Disease, Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China. [email protected].
16. Department of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, China. [email protected].
17. Aging Research Center, Xiangya Hospital, Central South University, Changsha, China. [email protected].
18. Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, China. [email protected].

Abstract

Peripheral arterial disease (PAD) is characterized by impaired angiogenesis, yet the molecular mechanisms linking metabolic dysregulation to epigenetic reprogramming in endothelial cells (ECs) remain poorly understood. Here, we identify Hexokinase 2 (HK2) as a critical regulator of angiogenesis through histone lactylation in PAD. In clinical specimens and murine hindlimb ischemia (HLI) models, HK2 expression was significantly downregulated. Functional assays in hypoxia-serum starved (HSS) human umbilical vein ECs (HUVECs) demonstrated that HK2 overexpression rescued angiogenesis by enhancing proliferation, migration, tube formation, and pro-angiogenic protein expression (VEGFA), while HK2 knockdown suppressed these phenotypes. Mechanistically, HK2 deficiency selectively reduced histone H3 lysine 18 lactylation (H3K18la) among eight tested histone lactylation sites, and HK2 restoration under HSS restored H3K18la level. Exogenous lactate reversed angiogenic defects in HK2-knockdown HUVECs by elevating H3K18la, which directly activated VEGFA transcription, as shown by Chromatin Immunoprecipitation coupled with quantitative Polymerase Chain Reaction (ChIP-qPCR). Furthermore, Sirtuin 2 (SIRT2), as a de-lactylase, inhibition in HK2-knockdown HUVECs restored H3K18la, angiogenesis, and pro-angiogenic protein expression. In HLI mice, SIRT2 Inhibitor treatment improved blood flow recovery, increased EC density, and upregulated H3K18la. Our findings establish HK2 as a metabolic-epigenetic nexus driving angiogenesis via lactate-dependent H3K18la modification and propose SIRT2 inhibition as a novel therapeutic strategy to bypass HK2 deficiency in PAD.