Deltex E3 ubiquitin ligase 2 prevents sepsis-induced myocardial injury through degrading TfR1 via promoting K27-linked ubiquitination.

Sepsis, a life-threatening systemic inflammatory condition, frequently leads to myocardial injury-a complication for which current therapeutic strategies demonstrate limited efficacy. Here, we explored the potential role and therapeutic implications of Deltex E3 ubiquitin ligase 2 (DTX2) in sepsis-induced myocardial injury. Our results demonstrated that DTX2 expression was significantly upregulated in septic patients, mice models, and lipopolysaccharide (LPS)-stimulated cardiomyocytes. Notably, Dtx2 deficiency markedly aggravated sepsis-induced myocardial hypertrophy, fibrosis, ferroptosis, and mitochondrial dysfunction. In contrast, cardiac-specific overexpression of Dtx2 improved cardiac function in vivo, highlighting its protective role in septic cardiomyopathy. Mechanistically, DTX2 was found to directly interact with transferrin receptor 1 (TfR1) through its DTC domain, mediating K27-linked ubiquitination at lysine 39, which facilitated TfR1 degradation and regulated iron metabolism. Importantly, pharmacological inhibition of ferroptosis counteracted the detrimental effects of Dtx2 deficiency in both LPS-challenged cells and mice. Moreover, genetic silencing of TfR1 considerably suppressed ferroptosis and ameliorated myocardial injury in Dtx2 knockout septic mice. The findings indicate that DTX2 exerts protective effects against abnormal iron accumulation and ferroptosis, thereby alleviating myocardial injury induced by sepsis. These insights could have therapeutic implications for patients with reduced DTX2 expression.