TRIM38 ubiquitinates IRAK1, inactivating TRAF6-p38 MAPK pathway to alleviate ferroptosis in heart failure.

Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, is increasingly recognized as a critical contributor to the pathogenesis of heart failure (HF). Despite its emerging importance, the precise molecular mechanisms regulating ferroptosis in HF remain incompletely understood, limiting targeted therapeutic strategies. Current HF treatments primarily focus on hemodynamic management and neurohormonal modulation, often failing to address specific cell death pathways like ferroptosis. Investigating novel regulators, such as the E3 ubiquitin ligase TRIM38, could uncover new avenues for intervention by modulating key signaling cascades involved in cellular stress and death.

Researchers investigated TRIM38's role in heart failure (HF) by analyzing serum TRIM38, IRAK1, and TRAF6 protein levels in HF patients using Western blot. For in vitro studies, an HF cell model was established by inducing H9c2 cardiomyocytes with doxorubicin. They then performed a series of experiments involving TRIM38 silencing and overexpression, IRAK1 overexpression, TRAF6 silencing, and inhibition of p38 MAPK activity. The effects on oxidative stress, ferroptosis, and the TRAF6-p38 MAPK pathway were assessed, including the use of ferrostatin-1, a ferroptosis inhibitor, as a control.

In heart failure (HF) patients, serum TRIM38 protein levels were found to be decreased, while IRAK1 and TRAF6 proteins were increased. In the doxorubicin-induced H9c2 cell model of HF, TRIM38 silencing significantly enhanced oxidative stress and ferroptosis. This enhancement was subsequently reversed by treatment with the ferroptosis inhibitor ferrostatin-1. Mechanistically, TRIM38 was shown to induce the ubiquitination degradation of IRAK1 protein. Overexpression of TRIM38 effectively suppressed oxidative stress, ferroptosis, and the activity of the TRAF6-p38 MAPK pathway in the HF cell model. However, this protective effect of TRIM38 overexpression was abrogated when IRAK1 was also overexpressed. Further experiments revealed that TRAF6 could activate p38 MAPK in the HF cell model. > Silencing TRAF6 or inhibiting p38 MAPK activity successfully reversed the promotion of oxidative stress and ferroptosis caused by TRIM38 silencing in the HF cell model, confirming the pathway's involvement.