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Background <p>Cardiovascular aging critically increases myocardial susceptibility to ischemia/reperfusion (I/R) injury. Selenoprotein T (SELENOT) has emerged as a novel modulator of cardiomyocyte differentiation and protection. However, its involvement in chronic age-associated cardiac dysfunction is unknown.</p> Methods <p>Using a D-galactose ageing model in which cardiac impairment was worsened by I/R injury, combined with histological, cellular, and molecular analyses, we investigated the cardioprotective potential of a small SELENOT mimetic peptide (PSELT).</p> Results <p>PSELT improved basal and post-ischemic left and right ventricular (LV and RV) hemodynamics, preserved myocardial architecture, and attenuated fibrosis and myofibrillar disorganization. Consistent with its ability to lower baseline RV workload, PSELT diminished pulmonary inflammation and fibrosis. Cardioprotection was further supported by decreased coronary LDH leakage and infarct size. Mechanistically, PSELT downregulated senescence markers (p21, p16), preserved desmin and SERCA2a expression, and attenuated inflammation by reducing NLRP3, caspase-1, and NF-κB nuclear translocation in aged LV and RV. PSELT counteracted cardiac ferroptosis by preserving GPX4 levels, limiting ACSL4 expression, and reducing lipid peroxidation and Fe<sup>2+</sup> levels, while mitigating ferroptotic death in RSL3-stimulated senescent cardiomyocytes. Additionally, PSELT normalized mitochondrial dynamics restoring DRP1, mitofusin-2 and OPA1 expression in cardiac mitochondria, while reducing Ca²⁺-induced mitochondrial swelling and mPTP opening. In human senescent cardiomyocytes, PSELT decreased p21 and p16, lowered SA-β-gal activity, improved mitochondrial membrane potential, enhanced respiration, and increased OCR and ECAR, while mitigating aging-related SELENOT overexpression.</p> Conclusions <p>PSELT enhances LV and RV resistance to I/R injury in aged hearts through the ferroptosis-mitochondrial axis and supports its potential as a therapeutic strategy against age-associated cardiac dysfunction.</p>

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Harnessing the novel safeguarding role of Selenoprotein T in age-related myocardial left and right decline through the ferroptosis-mitochondrial axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Anna De Bartolo,
  • Naomi Romeo,
  • Lidia Urlandini,
  • Vittoria Rago,
  • Francesco Conforti,
  • Rita Liparoti,
  • Alessandra Mercuri,
  • Marika De Cicco,
  • Maria Concetta Granieri,
  • Marco Fiorillo,
  • Eugenia Nicol Manti,
  • Nicola Amodio,
  • Rosa Mazza,
  • Maria Carmela Cerra,
  • Youssef Anouar,
  • Pasquale Pagliaro,
  • Tommaso Angelone,
  • Carmine Rocca

摘要

Background

Cardiovascular aging critically increases myocardial susceptibility to ischemia/reperfusion (I/R) injury. Selenoprotein T (SELENOT) has emerged as a novel modulator of cardiomyocyte differentiation and protection. However, its involvement in chronic age-associated cardiac dysfunction is unknown.

Methods

Using a D-galactose ageing model in which cardiac impairment was worsened by I/R injury, combined with histological, cellular, and molecular analyses, we investigated the cardioprotective potential of a small SELENOT mimetic peptide (PSELT).

Results

PSELT improved basal and post-ischemic left and right ventricular (LV and RV) hemodynamics, preserved myocardial architecture, and attenuated fibrosis and myofibrillar disorganization. Consistent with its ability to lower baseline RV workload, PSELT diminished pulmonary inflammation and fibrosis. Cardioprotection was further supported by decreased coronary LDH leakage and infarct size. Mechanistically, PSELT downregulated senescence markers (p21, p16), preserved desmin and SERCA2a expression, and attenuated inflammation by reducing NLRP3, caspase-1, and NF-κB nuclear translocation in aged LV and RV. PSELT counteracted cardiac ferroptosis by preserving GPX4 levels, limiting ACSL4 expression, and reducing lipid peroxidation and Fe2+ levels, while mitigating ferroptotic death in RSL3-stimulated senescent cardiomyocytes. Additionally, PSELT normalized mitochondrial dynamics restoring DRP1, mitofusin-2 and OPA1 expression in cardiac mitochondria, while reducing Ca²⁺-induced mitochondrial swelling and mPTP opening. In human senescent cardiomyocytes, PSELT decreased p21 and p16, lowered SA-β-gal activity, improved mitochondrial membrane potential, enhanced respiration, and increased OCR and ECAR, while mitigating aging-related SELENOT overexpression.

Conclusions

PSELT enhances LV and RV resistance to I/R injury in aged hearts through the ferroptosis-mitochondrial axis and supports its potential as a therapeutic strategy against age-associated cardiac dysfunction.