Translocation of SIRT6 promotes glycolysis reprogramming to exacerbate diabetic angiopathy

Kemiao Pang; Jiayi Huang; Shiwu Zhang; Yinghui Guan; Ning Zou; Jiaxin Kang; Haining Du; Dechao Zhao; Denis V Abramochkin; Heyu Chen; Nan Zhang; Yunyan Gu; Ning Liu; Yining Niu; Ziqi Xiong; Xueya Zhang; Fanghao Lu; Huitao Fan; Jinwei Tian; Bo Yu; Shuijie Li; Weihua Zhang

doi:10.1016/j.redox.2025.103736

Translocation of SIRT6 promotes glycolysis reprogramming to exacerbate diabetic angiopathy

Redox Biol. 2025 Jun 24:85:103736. doi: 10.1016/j.redox.2025.103736. Online ahead of print.

Authors

Kemiao Pang¹, Jiayi Huang¹, Shiwu Zhang¹, Yinghui Guan², Ning Zou³, Jiaxin Kang¹, Haining Du¹, Dechao Zhao⁴, Denis V Abramochkin⁵, Heyu Chen¹, Nan Zhang⁶, Yunyan Gu⁶, Ning Liu¹, Yining Niu¹, Ziqi Xiong¹, Xueya Zhang¹, Fanghao Lu¹, Huitao Fan⁷, Jinwei Tian⁸, Bo Yu⁹, Shuijie Li¹⁰, Weihua Zhang¹¹

Affiliations

¹ Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China.
² Department of Vascular Surgery, First Affiliated Hospital of Harbin Medical University, China.
³ Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, China.
⁴ Department of Cardiology, First Affiliated Hospital of Harbin Medical University, China.
⁵ Department of Human and Animal Physiology, Biological Faculty, Lomonosov Moscow State University, Russia.
⁶ College of Bioinformatics Science and Technology, Harbin Medical University, China.
⁷ NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, China; Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, China; Department of Hematology, The First Affiliated Hospital of Harbin Medical University, China. Electronic address: huitaofan@hrbmu.edu.cn.
⁸ Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China; Heilongjiang Provincial Key Laboratory of Panvascular Disease, China. Electronic address: tianjinwei@hrbmu.edu.cn.
⁹ Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China; State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China. Electronic address: yubo@hrbmu.edu.cn.
¹⁰ State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China; Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, China; Heilongjiang Province Key Laboratory of Research on Molecular Targeted Antitumor Drugs, China. Electronic address: shuijie.li@hrbmu.edu.cn.
¹¹ Department of Cardiology, Department of Pathophysiology, Key Laboratory of Myocardial Ischemia, Ministry of Education, Second Affiliated Hospital of Harbin Medical University, China; Heilongjiang Provincial Key Laboratory of Panvascular Disease, China. Electronic address: zhangweihua@hrbmu.edu.cn.

PMID: 40580755
DOI: 10.1016/j.redox.2025.103736

Abstract

Diabetic angiopathy, a major complication of type 2 diabetes mellitus (T2DM), is driven by vascular dysfunction, metabolic reprogramming, and oxidative stress. NAD⁺-dependent deacetylase SIRT6, located in the nucleus, is recognized for its role in modulating cardiovascular and metabolic homeostasis through histone deacetylation. However, the functions and mechanisms of accumulation of cytoplasmic SIRT6 in T2DM remain to be elucidated. Herein, a previously unrecognized cytoplasmic role for SIRT6 is identified in promoting pathological glycolysis during diabetic vascular remodeling. Vascular smooth muscle cell (VSMC) proliferation is observed, which is correlated with protein deacetylation, especially SIRT6, which translocated to the cytoplasm mediated by Importin 13 (IPO13). Furthermore, the accumulation of cytoplasmic SIRT6 facilitates its interaction with enolase 3 (ENO3), a newly discovered downstream target. This interaction promotes ENO3 deacetylation, enhances downstream phosphoenolpyruvic acid (PEP) levels, and thereby drives glycolysis reprogramming, ultimately leading to the pathological changes associated with diabetic angiopathy. Notably, exogenous hydrogen sulfide (H₂S) restores S-sulfhydration of SIRT6 at cysteine 141, counteracting the SIRT6-ENO3 interaction, suppressing glycolysis, and mitigating VSMC hyperproliferation. This study provides novel insights into the SIRT6-ENO3 pathway through regulating vascular glycolysis reprogramming, highlighting the therapeutic potential of targeting SIRT6 in the management of diabetic angiopathy.

Keywords: Cell proliferation; Glycolysis; Hydrogen sulfide (H(2)S); Sirtuin 6 (SIRT6); Type 2 diabetes (T2D).