TRIM28 is a key cardiomyocyte ferroptosis suppressor via TRIM28-IRP2-TFR1 signaling

Transcriptome RNA-seq was conducted to comprehensively understand the alterations in gene expression profiles associated with cardiomyocyte ferroptosis. We isolated neonatal rat ventricular cardiomyocytes (NRVMs) and treated them with erastin for RNA-Seq. Transcriptomic correlation analysis of cardiomyocyte ferroptosis revealed that TRIM28 had the strongest correlation with ferroptosis and was downregulated in cardiomyocyte ferroptosis.

Mechanically, we identified TRIM28 as the new E3 ubiquitin ligase that mediated the degradation of IRP2 via promoting the K48 polyubiquitin chain at the K877 site of IRP2, thereby inhibiting TFR1 expression and cardiomyocyte ferroptosis. Human plasma targeted eicosanoid lipidomes data revealed that the eicosanoid metabolite 8-iso-PGF2α accumulated specifically in patients after percutaneous coronary intervention and was positively correlated with plasma levels of creatine kinase MB/cardiac troponin I. TRIM28 overexpression alleviated I/R-induced cardiac ferroptosis and 8-iso-PGF2α accumulation.

Furthermore, we found that p55γ, an upstream regulator of TRIM28, interacted with TRIM28 to degrade IRP2 and downregulate TFR1, thereby suppressing ferroptosis. We demonstrated that perhexiline dually activated TRIM28 and p55γ, effectively preventing I/R-induced ferroptosis. Our results demonstrate that TRIM28 is a key suppressor of cardiomyocyte ferroptosis.

The TRIM28-IRP2-TFR1 axis-mediated cardiomyocyte ferroptosis plays a crucial role in I/R injury. Collectively, these findings indicate that targeting TRIM28 represents a promising therapeutic strategy for inhibiting cardiomyocyte ferroptosis and protecting against cardiac injury.