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

Miyesaier Abudureyimu1, Guizhen Wang2,3, Xing Qin4

  • 1Cardiovascular Department, Shanghai Xuhui Central Hospital, Fudan University, Shanghai 200031, China.

Acta Pharmaceutica Sinica. B
|May 25, 2026
PubMed

Insights

Cluster of differentiation 74 (CD74) exacerbates doxorubicin-induced cardiotoxicity by impairing cellular repair and promoting cell death. Inhibiting CD74 with Amifostine shows therapeutic potential for treating this condition.

Area of Science:

  • Cardiology
  • Oncology
  • Immunology

Background:

  • Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a significant clinical limitation.
  • Mechanisms underlying DIC, including mitochondrial dysfunction, oxidative stress, and ferroptosis, are not fully understood.

Purpose of the Study:

  • To investigate the role of cluster of differentiation 74 (CD74) in DIC.
  • To elucidate the molecular mechanisms by which CD74 contributes to DOX-induced cardiac damage.

Main Methods:

  • Analysis of CD74 levels in DOX-exposed patients and mice.
  • Assessment of cardiac function and pathology in CD74-deleted or wild-type mice challenged with DOX.
  • Investigation of CD74's interaction with ribonucleotide reductase M2 (RRM2) and the RRM2/p53 pathway.
  • Evaluation of Amifostine, a CD74 inhibitor, in a DIC mouse model.
  • Co-culture studies using macrophages and cardiomyocytes to assess CD74's role in intercellular communication.

Main Results:

  • Elevated CD74 levels were observed in DOX-exposed subjects.
  • CD74 deletion significantly protected against DOX-induced cardiac remodeling, dysfunction, apoptosis, and ferroptosis.
  • CD74 interacts with RRM2, promoting its relocation to the plasma membrane, impairing repair, and activating the RRM2/p53 cascade.
  • A specific CD74 mutant (aa 220-250) did not aggravate DOX-induced cardiac dysfunction.
  • Amifostine treatment ameliorated cardiac damage and functional impairment in a DIC mouse model.
  • CD74 knockdown in macrophages reduced DOX-induced cardiomyocyte dysfunction.

Conclusions:

  • CD74 plays a critical role in mediating DOX-induced cardiotoxicity.
  • CD74 promotes cardiac damage by regulating RRM2 localization, impairing repair, and exacerbating mitochondrial injury, apoptosis, and ferroptosis via the RRM2/p53 pathway.
  • CD74 inhibition, particularly with Amifostine, represents a promising therapeutic strategy for managing DIC.
Keywords:
AmifostineCD74CardiotoxicityDoxorubicinFerroptosisMitochondrial integrityOxidative stress

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