Endothelial RRM2B-dependent mitochondrial DNA signalling drives doxorubicin-cardiotoxicity
Pontarin, G.; Graziani, S.; Bonello, A.; Branas Casas, R.; Risato, G.; Tiso, N.; Argenton, F.; Rampazzo, C.; Shinjo, S.; Zamberlan, M.; Facchinello, N.; Scorrano, L.
Show abstract
Doxorubicin remains a mainstay of cancer therapy, yet its clinical use is constrained by severe cardiotoxicity, classically attributed to cardiomyocyte death. Here, we identify endothelial inflammation driven by mitochondrial DNA (mtDNA) turnover and release as a critical mediator of doxorubicin-induced cardiac injury. In vivo, a standard doxorubicin regimen activates the cGAS-STING innate immune pathway in endothelial cells before cardiomyocyte dysfunction or death occurs. Mechanistically, doxorubicin recruits the stress-inducible ribonucleotide reductase subunit RRM2B (p53R2) that normally sustains the mitochondrial deoxyribonucleotide pool, to promote aberrant mtDNA turnover and release, fuelling sterile inflammation. The FDA-approved BAX inhibitor Eltrombopag suppresses mtDNA release, attenuates endothelial inflammation, and prevents doxorubicin cardiotoxicity in vivo without compromising anticancer efficacy. These findings reveal an unrecognized proinflammatory role of RRM2B and establish endothelial inflammation as a central driver of chemotherapy-related cardiac injury, identifying the cardiac endothelium as a tractable target for cardioprotection during cancer treatment.
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