2. Academic Validation
  3. Unveiling Selenoprotein T as a novel regulator of cardiomyocyte senescence: pivotal role of the CD36 receptor in AC16 human cardiomyocytes

Unveiling Selenoprotein T as a novel regulator of cardiomyocyte senescence: pivotal role of the CD36 receptor in AC16 human cardiomyocytes

  • Geroscience. 2025 Jul 1. doi: 10.1007/s11357-025-01759-7.
Anna De Bartolo 1,  Vittoria Rago 2,  Naomi Romeo 1,  Marika De Cicco 1,  Benjamin Lefranc 3 4,  Jérôme Leprince 3 4,  Giuseppe Passarino 5,  Pasquale Pagliaro 6 7,  Youssef Anouar 3,  Carmine Rocca # 8 9,  Tommaso Angelone # 10 11
Affiliations

Affiliations

  • 1 Cellular and Molecular Cardiovascular Physiology and Pathophysiology Laboratory, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Rende, CS, Italy.
  • 2 Human Anatomy Laboratory, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, CS, Italy.
  • 3 UNIROUEN, Inserm U1239, Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Rouen Normandie University, Mont-Saint-Aignan, France.
  • 4 Cell Imaging Platform of Normandy, Institute for Research and Innovation in Biomedicine (IRIB), UNIROUEN, UMS-UAR HERACLES, PRIMACEN, Rouen, France.
  • 5 Genetics Laboratory, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Rende, CS, Italy.
  • 6 Department of Clinical and Biological Sciences, University of Torino, Turin, Italy.
  • 7 National Institute of Cardiovascular Research (INRC), Bologna, Italy.
  • 8 Cellular and Molecular Cardiovascular Physiology and Pathophysiology Laboratory, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Rende, CS, Italy. carmine.rocca@unical.it.
  • 9 National Institute of Cardiovascular Research (INRC), Bologna, Italy. carmine.rocca@unical.it.
  • 10 Cellular and Molecular Cardiovascular Physiology and Pathophysiology Laboratory, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, Rende, CS, Italy. tommaso.angelone@unical.it.
  • 11 National Institute of Cardiovascular Research (INRC), Bologna, Italy. tommaso.angelone@unical.it.
  • # Contributed equally.
PMID: 40593378 DOI: 10.1007/s11357-025-01759-7
Abstract

Cellular senescence is a key driver of heart disease, yet its regulation in cardiomyocytes remains poorly understood. Selenoprotein T (SELENOT) plays a crucial role in cardiomyocyte differentiation and protection, but its role in cardiomyocyte senescence remains unknown. Here, we explore the novel role of SELENOT in preserving cardiomyocyte viability and genomic integrity during doxorubicin-induced senescence. Senescent differentiated cardiomyocytes exhibit hallmarks of cellular senescence, including increased β-galactosidase activity and elevated p53 and p21 levels, and upregulation of senescence-associated secretory phenotype (SASP) markers (i.e. MMP3, IL6, and TNFα). Additionally, senescent cells displayed disrupted cytosolic and mitochondrial redox homeostasis, which were mitigated by PSELT (a small peptide that mimics SELENOT activity). Notably, PSELT positively influenced DNA damage markers (p-γH2AX and lamin B1) and prevented ER stress regulating BIP, calnexin, IRE1α, and ERO1α expression. Intriguingly, SELENOT expression was upregulated in response to senescence, suggesting a stress-sensing redoxin function. Loss-of-function studies revealed that SELENOT deficiency led to cardiomyocyte death and DNA damage, which were only partially rescued by PSELT, supporting the existence of cross-regulatory mechanisms within the SELENOT/PSELT axis. Mechanistically, similar to SSO, an irreversible inhibitor of CD36, PSELT mitigated the senescence-induced upregulation of CD36, a key player in cardiac aging. Co-immunoprecipitation analysis demonstrated that SELENOT interacts with CD36 in both normal and senescent human cardiomyocytes. Overall, these findings underscore the essential role of SELENOT in preserving the viability and genomic integrity of senescent human cardiomyocytes and suggest that PSELT-mediated inhibition of CD36 may represent a promising therapeutic strategy for treating age-related cardiac dysfunction.

Keywords

Antioxidants; CD36; Cellular aging; Human cardiomyocytes; Peptides; Selenoproteins.

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