p16INK4a promotes myocardial ischemia-reperfusion injury by regulating bile acid transport via Slco1a4

  • Tingting Yang
  • , Qiulian Zhou
  • , Yihua Bei
  • , Danni Meng
  • , Songwei Ai
  • , Yuhui Zhang
  • , Jian Zhang
  • , Li Liu
  • , Hongjian Chen
  • , Xue Pan
  • , Xiaohang Yin
  • , Michail Spanos
  • , Guoping Li
  • , Dragos Cretoiu
  • , Joost P G Sluijter
  • , Anthony Rosenzweig*
  • , Junjie Xiao*
  • *Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Myocardial ischemia-reperfusion (I/R) injury remains a significant challenge in cardiovascular medicine, with its molecular mechanisms still not fully understood. Screening the GEO and Comparative Toxicogenomics Database as well as spatial multi-omics data, we identify Cdkn2a, encoding p16INK4a, as a determinant in I/R injury. Cdkn2a expression is elevated in the myocardium of ischemic cardiomyopathy patients and p16INK4a protein is enriched in cardiomyocytes within ischemic zones of myocardial infarction tissues. We find that p16INK4a is consistently upregulated in both in vivo and in vitro I/R models, promoting apoptosis in neonatal rat cardiomyocytes (NRCMs) and human embryonic stem cell-derived cardiomyocytes (hESC-CMs) exposed to oxygen-glucose deprivation/reperfusion (OGD/R). p16INK4a inhibition confers cellular protection, an effect also observed in in vivo I/R injury models. Mechanistically, p16INK4a promotes binding of the RNA-binding protein CUGBP1 to the GRE sequence of Npas2 mRNA reducing its stability and translation, likely by inhibiting CDK4. This regulation impairs transcription of the Nasp2 target Slco1a4 and consequently bile acid transport, resulting in accumulation of intracellular bile acids and apoptosis. These findings identify p16INK4a-regulated bile acid transport as a driver of cardiac I/R injury.

Original languageEnglish
Pages (from-to)1023-1056
Number of pages34
JournalEMBO Reports
Volume27
Issue number4
Early online date12 Jan 2026
DOIs
Publication statusPublished - 25 Feb 2026

Keywords

  • Cardiac Ischemia/Reperfusion Injury
  • Npas2 mRNA Stability and Translation
  • Slco1a4
  • p16

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