Endothelial RRM2B-dependent mitochondrial DNA signaling drives doxorubicin-cardiotoxicity

Doxorubicin remains a cornerstone of several anticancer regimens, yet its clinical use is limited by severe cardiotoxicity traditionally attributed to cardiomyocyte death. Here, we show that doxorubicin induces a mitochondrial DNA–dependent inflammatory program in endothelial cells that plays a central, unexpected role in driving cardiac dysfunction. Mechanistically, the stress-inducible ribonucleotide reductase subunit RRM2B (p53R2), which sustains the mitochondrial pool of deoxyribonucleotides for DNA synthesis and repair, drives aberrant mitochondrial DNA turnover and fuels activation of the cGAS–STING innate immune pathway in endothelial cells upon in vivo treatment with doxorubicin. Pharmacological intervention with the FDA-approved BAX inhibitor eltrombopag suppresses this sterile inflammatory response in the endothelium and protects against doxorubicin-induced cardiotoxicity in vivo, without limiting doxorubicin anticancer effects. Our findings uncover a previously unrecognized function of RRM2B in sterile inflammation and highlight endothelial inflammation as a key determinant of chemotherapy-related cardiac injury, establishing the heart endothelium as a tractable therapeutic target for cardioprotection in cancer treatment.