Drug Dev Res. 2026 Aug;87(5):e70340. doi: 10.1002/ddr.70340.
ABSTRACT
This article explored the role of TRIM38 in ferroptosis in heart failure (HF) and its underlying mechanisms. Methodologically, serum TRIM38, IRAK1 and TRAF6 proteins from HF patients were detected by Western blot. In an in vitro study, an HF cell model was established by inducing H9c2 cells with doxorubicin. Through a series of logical experiments, the effects of TRIM38 and IRAK1 on oxidative stress and ferroptosis in the HF cell model, and the underlying mechanisms, were researched. Notably, serum TRIM38 was decreased in HF patients, while IRAK1 and TRAF6 were increased. In the HF cell model, TRIM38 silencing enhanced oxidative stress and ferroptosis, which were reversed by ferrostatin-1, a ferroptosis inhibitor. TRIM38 caused ubiquitination degradation of IRAK1 protein. TRIM38 overexpression suppressed oxidative stress, ferroptosis, and the TRAF6-p38 MAPK pathway activity in the HF cell model, but this suppression was abrogated by IRAK1 overexpression. TRAF6 could activate p38 MAPK in the HF cell model. TRAF6 silencing or inhibiting p38 MAPK reversed the promotion of TRIM38 silencing on oxidative stress and ferroptosis in the HF cell model. Overall, TRIM38 might alleviate ferroptosis in HF by inactivating the TRAF6-p38 MAPK pathway via ubiquitinating IRAK1, suggesting TRIM38 as a potential therapeutic target for HF.
PMID:42418246 | DOI:10.1002/ddr.70340