2. Academic Validation
  3. SIRT6 alleviates ischemic injury via orchestrating the RREB1/Snail and STC1/Smad7 signaling pathways to regulate endothelial-mesenchymal transition

SIRT6 alleviates ischemic injury via orchestrating the RREB1/Snail and STC1/Smad7 signaling pathways to regulate endothelial-mesenchymal transition

  • Sci China Life Sci. 2026 Jul;69(7):2311-2327. doi: 10.1007/s11427-025-3198-0.
Zhentao Zhang # 1,  Zheyan Fang # 1,  Shuang Zhao # 2,  Mukaddas Abdurahman # 1,  Gang Zhao # 1,  Runyang Feng 1,  Zhenyang Guo 1,  Xueting Yu 1,  Hangnan Hong 1,  Jilong Geng 1,  Xiansu Nie 1,  Supuya Abuduwahapi 1,  Lingyun Lan 1,  Junbo Ge 3 4 5 6 7 8 9,  Hua Li 10
Affiliations

Affiliations

  • 1 Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, 200032, China.
  • 2 Department of Medical Examination, Shanghai Xuhui District Central Hospital, Shanghai, 200031, China.
  • 3 Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, 200032, China. [email protected].
  • 4 National Basic Science Center for Complex System of Panvascular Intervention, Shanghai, 200032, China. [email protected].
  • 5 National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China. [email protected].
  • 6 Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. [email protected].
  • 7 Shanghai Clinical Research Center for Interventional Medicine, Shanghai, 200032, China. [email protected].
  • 8 Key Laboratory of Viral Heart Diseases, National Health Commission, Shanghai, 200032, China. [email protected].
  • 9 Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, Shanghai, 200032, China. [email protected].
  • 10 Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan University, Shanghai, 200032, China. [email protected].
  • # Contributed equally.
PMID: 41882317 DOI: 10.1007/s11427-025-3198-0
Abstract

Endothelial-to-mesenchymal transition (EndMT) constitutes a transdifferentiation phenomenon during which endothelial cells (ECs) progressively acquire mesenchymal traits. Mounting evidence has established that EndMT holds a central and indispensable position in angiogenesis. Partial EndMT, an intermediate stage of ECs within the EndMT cascade, is intimately regulated by numerous Enzymes. Among them, Sirtuin 6 (SIRT6), a member of the Sirtuin family of NAD+-dependent deacetylases, has been reported to be involved in the repair of cardiovascular injury; however, the SIRT6-mediated molecular mechanism inpartial EndMT has hitherto remained largely unelucidated. In the present study, SIRT6 can regulate EndMT elicited by TGF-β and maintain a partial EndMT state. Subsequently, through conducting proteomic data analysis and performing verification using Molecular Biology techniques, we found that SIRT6 promoted EndMT via the upregulation of RREB1/Snail; simultaneously, SIRT6 directly targeted Sp1 to augment the expression of STC1 which in turn acetylated Smad7 to inhibit phosphorylation of SMAD2/3, decreasing the formation of phosphorylated SMAD2/3 and SMAD4 to curtail excessive EndMT. Finally, in the model of murine hindlimb ischemia, the overexpression of SIRT6 could increase capillary density and promote the recovery of blood flow, effects that were partially abrogated by siRREB1 or recombinant STC1. These results of in vivo animal experiments are consistent with the previous conclusions of in vitro cell experiments. Collectively, our findings demonstrated that SIRT6 orchestrated a beneficial balance of the EndMT response to promote angiogenesis and mitigate ischemic injury, thereby providing a potential therapeutic target related to EndMT for ischemic diseases.

Keywords

Sirt6; Smad; angiogenesis; ischemic injury; partial EndMT.

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