TRIM28 Is an E3 Ligase of IRP2 Suppressing Ischemia/Reperfusion–Induced Myocardial Ferroptosis
Authors' conclusion
Our study identifies TRIM28 as an essential E3 ubiquitin ligase of IRP2 and delineates that TRIM28-mediated inhibition of myocardial ferroptosis by targeting IRP2-TFR1 signaling protects the heart against I/R injury
Study context
- Population
- Mouse I/R hearts, neonatal rat ventricular myocytes and human heart samples from patients with ischemic heart disease
- Comparison
- TRIM28 overexpression vs deficiency in myocardial I/R-induced ferroptosis
Methodological detailsmouse I/R model, neonatal rat ventricular myocytes hypoxia/reoxygenation model, AAV9 cardiomyocyte-specific overexpression, tamoxifen-inducible cardiomyocyte-specific knockout, human heart samples
- Mouse I/R model
- Neonatal rat ventricular myocytes hypoxia/reoxygenation model
- AAV9 cardiomyocyte-specific overexpression
- Tamoxifen-inducible cardiomyocyte-specific knockout
- Human heart samples
Main finding
As reported in the abstract
- TRIM28 downregulated in ferroptosis inducer-treated and hypoxia/reoxygenation-injured cardiomyocytes and in I/R-injured mouse hearts
- Cardiomyocyte-specific TRIM28 overexpression protected against I/R-induced ferroptosis; deficiency exacerbated ferroptotic injury
- TRIM28 is an E3 ubiquitin ligase binding IRP2, promoting K48-linked ubiquitination at K877, downregulating IRP2 and TFR1, suppressing iron uptake and attenuating ferroptosis
- p55γ interacted with and upregulated TRIM28, mitigating I/R-induced ferroptosis
- Human ischemic heart disease samples: TRIM28 and p55γ decreased, IRP2 and TFR1 increased
- Perhexiline inhibited I/R-induced ferroptosis by upregulating p55γ and TRIM28
Original publication
TRIM28 Is an E3 Ligase of IRP2 Suppressing Ischemia/Reperfusion–Induced Myocardial Ferroptosis. Circulation. Published 9 March 2026. doi:10.
Summarised from the published abstract; every number is checked against it