BET-induced metabolic reprogramming fuels inflammation at the vascular-fat interface in mice and patients with cardiometabolic disease

  • Cell Rep. 2026 Jun 23;45(6):117365. doi: 10.1016/j.celrep.2026.117365.
Alessandro Mengozzi  1 ,  Sarah Costantino  2 ,  Alessia Mongelli  3 ,  Emiliano Duranti  4 ,  Shafeeq A Mohammed  3 ,  Era Gorica  3 ,  Federica Cappelli  4 ,  Marialucia Telesca  3 ,  Silvia Armenia  5 ,  Thorsten Hornemann  6 ,  Andreas Hulsmeier  6 ,  Carolina de Ciuceis  7 ,  Claudia Agabiti-Rosei  7 ,  Chiara Ippolito  4 ,  Rosario Bellini  8 ,  Nicola Riccardo Pugliese  4 ,  Christian M Matter  2 ,  Omer Dzemali  2 ,  Stefano Masi  9 ,  Stefano Taddei  4 ,  Frank Ruschitzka  2 ,  Agostino Virdis  10 ,  Francesco Paneni  11
Affiliations
  • 1. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Health Science Interdisciplinary Center, Sant'Anna School of Advanced Studies, Pisa, Italy. Electronic address: [email protected].
  • 2. Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Department of Cardiology, University Hospital Zurich, Zurich, Switzerland.
  • 3. Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
  • 4. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
  • 5. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Health Science Interdisciplinary Center, Sant'Anna School of Advanced Studies, Pisa, Italy.
  • 6. Institute for Clinical Chemistry, University Hospital and University of Zürich, Zürich, Switzerland.
  • 7. Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
  • 8. Unit of Bariatric Surgery, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
  • 9. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Institute of Cardiovascular Science, University College London, London, UK.
  • 10. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; Geriatric Unit, Azienda Ospedaliero-Universitario Pisa, Pisa, Italy.
  • 11. Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland; Department of Cardiology, University Hospital Zurich, Zurich, Switzerland. Electronic address: [email protected].
PMID: 42228564 DOI: 10.1016/j.celrep.2026.117365
Abstract

Epigenetic reading of histone marks by BET proteins is emerging as a pivotal mechanism governing gene transcription and may be implicated in cardiometabolic disease (CMD). Using vessels from mice and patients with CMD, we show that pharmacological inhibition of BET proteins by RVX-208 prevents the maladaptive crosstalk between perivascular adipose tissue (PVAT) and blood vessels. The effect of the BET inhibitor on endothelial function was more pronounced in the presence of PVAT. In mouse and human PVAT, RVX-208 rescued maladaptive transcriptional programs with a marked downregulation of hexokinase-2 (HK2). This was associated with reduced glycolysis, lipid accumulation, and secretion of pro-inflammatory cytokines. In human adipocytes, HK2 overexpression induced a pro-inflammatory phenotype fostering endothelial damage. Pharmacological inhibition of HK2 in vessels from cardiometabolic patients restored endothelial-dependent vasorelaxation. This unveiling of a BET/HK2-dependent crosstalk between PVAT and blood vessels highlights the potential of therapeutic strategies to prevent vascular damage in cardiometabolic patients.

Keywords
BRD4; CP: metabolism; CP: molecular biology; Cardiometabolic; glycolytic; hexokinase-2; inflammation; perivascular adipose tissue; vascular.
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