MFN1 Mediates Doxorubicin-Induced Cytotoxicity through Oxidative Stress-Induced Ferroptosis
TL;DR
DOX-induced cardiotoxicity reveals MFN1 as a key regulatory factor in DIC and provides a novel theoretical basis for its potential as a therapeutic target and inhibition of MFN1 significantly alleviates DIC injury.
Abstract
Doxorubicin (DOX)-induced cardiotoxicity (DIC) limits clinical application of DOX, and the mechanism is linked to ferroptosis. Mitofusin 1 (MFN1) has been reported to be involved in regulating cell death and mitochondrial dysfunction, yet its role in DIC remains unclear. In an in vitro DIC model using H9c2 cells, DOX treatment significantly up-regulated MFN1 expression, accompanied by mitochondrial dysfunction—increased reactive oxygen species, decreased mitochondrial membrane potential, and structural damage—and activation of ferroptosis markers, including depleted GSH, elevated MDA and Fe 2+ , down-regulated GPX4, and up-regulated SLC38A1/SLC1A5. Knockdown of MFN1 effectively reversed these effects, partially restored cell viability, improved mitochondrial function, and suppressed alterations in ferroptosis markers. The protective effect of MFN1 knockdown was further enhanced by the antioxidant N-Acetyl-cysteine. In summary, MFN1 regulates cardiomyocyte ferroptosis in DIC by promoting oxidative stress and mitochondrial dysfunction. Inhibition of MFN1 significantly alleviates DIC injury. This study reveals MFN1 as a key regulatory factor in DIC and provides a novel theoretical basis for its potential as a therapeutic target.