CD74 deficiency protects against doxorubicin cardiotoxicity through RRM2-mediated regulation of ferroptosis

Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a major health threat that limits its clinical application. While mitochondrial dysfunction, oxidative stress and ferroptosis are implicated in DIC pathology, the precise mechanism remains elusive. This study evaluated the role of cluster of differentiation 74 (CD74), an immunoregulatory protein, in DIC. Our findings revealed elevated CD74 levels in blood samples from DOX-exposed patients and DOX-challenged mouse hearts. CD74 deletion mitigated DOX-indued cardiac remodeling, contractile anomaly, mitochondrial abnormalities, apoptosis, and ferroptosis. Mechanistically, CD74 bound to DNA synthesis molecule ribonucleotide reductase M2 (RRM2), redistributing it from cytoplasm to plasma membrane, impairing DOX-induced repair and exacerbating mitochondrial injury, apoptosis, and ferroptosis via activation of RRM2/p53 cascade. Notably, a CD74 mutant (aa 220–250) failed to aggravate DOX-induced cardiac dysfunction, unlike WT CD74. Moreover, the protective effects of CD74 inhibition in cardiomyocytes were negated by p53 activation, highlighting its role in DOX-induced damage. Treatment with CD74 inhibitor Amifostine in a DIC mouse model significantly alleviated cardiac remodeling and functional impairment by reducing oxidative stress and ferroptosis. Transwell study using the CD74-null Raw 264.7 macrophages and cardiomyocytes revealed that CD74 knockdown in macrophages overly attenuated DOX-instigated cardiomyocyte dysfunction. These findings establish CD74 as a potential therapeutic target for DIC, as its regulation of RRM2 cytomembrane diversion and ferroptosis ultimately drives cardiac remodeling and contractile anomalies in response to DOX challenge. Amifostine, a CD74 inhibitor, mitigates doxorubicin-induced cardiac (DIC) remodeling and dysfunction by attenuating oxidative stress and ferroptosis, thereby underscoring CD74 as a potential therapeutic target for DIC.