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 language | English |
|---|---|
| Pages (from-to) | 1023-1056 |
| Number of pages | 34 |
| Journal | EMBO Reports |
| Volume | 27 |
| Issue number | 4 |
| Early online date | 12 Jan 2026 |
| DOIs | |
| Publication status | Published - 25 Feb 2026 |
Keywords
- Cardiac Ischemia/Reperfusion Injury
- Npas2 mRNA Stability and Translation
- Slco1a4
- p16
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