Inhibition of MALT1 reduces ferroptosis in rat hearts following ischemia/reperfusion via enhancing the Nrf2/SLC7A11 pathway

The dysregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and/or solute carrier family 7 member 11 (SLC7A11) is believed to contribute to ferroptosis in the hearts suffered ischemia/reperfusion (I/R), but the mechanisms behind the dysregulation of them are not fully elucidated. Mucosa associated lymphoid tissue lymphoma translocation gene 1 (MALT1) can function as a paracaspase to cleave specified substrates and it is predicted to interact with Nrf2. This study aims to explore whether targeting MALT1 can reduce I/R-induced ferroptosis via enhancing the Nrf2/SLC7A11 pathway. The SD rat hearts were subjected to 1h-ischemia plus 3h-reperfusion to establish the I/R injury model, which showed myocardial injuries (increase in infarct size and creatine kinase release) and up-regulation of MALT1 while downregulation of Nrf2 and SLC7A11 concomitant with the increased ferroptosis, reflecting by an increase in glutathione peroxidase 4 (GPX4) level while decreases in the levels of acyl-CoA synthetase long chain family member 4 (ACSL4), total iron, Fe2+ and lipid peroxidation (LPO); these phenomena were reversed in the presence of MI-2, a specific inhibitor of MALT1. Consistently, similar results were achieved in the cultured cardiomyocytes subjected to 8h-hypoxia plus 12h-reoxygenation. Furthermore, micafungin, an antifungal drug, could also exert beneficial effect on mitigating myocardial I/R injury via inhibition of MALT1. Based on these observations, we conclud that inhibition of MALT1 can reduce I/R-induced myocardial ferroptosis through enhancing the Nrf2/SLC7A11 pathway; and MALT1 may be used as a potential target to seek novel or existing drugs (such as micafungin) for treating myocardial infarction.

Comments:

This study investigated the role of MALT1 in regulating ferroptosis in ischemia/reperfusion (I/R)-induced myocardial injury. The results showed that MALT1 was up-regulated in the I/R injury model while Nrf2 and SLC7A11 were downregulated, and this was associated with increased ferroptosis. Treatment with MI-2, a specific inhibitor of MALT1, reversed these changes and reduced ferroptosis in both the I/R injury model and cultured cardiomyocytes subjected to hypoxia/reoxygenation. Micafungin, an antifungal drug, was also found to inhibit MALT1 and reduce myocardial I/R injury.

The study suggests that inhibition of MALT1 can reduce myocardial ferroptosis by enhancing the Nrf2/SLC7A11 pathway. MALT1 may be a potential therapeutic target for developing novel or existing drugs for treating myocardial infarction.