Abstract
<jats:p>Doxorubicin (DOX) is an effective anthracycline chemotherapeutic agent, but its use is limited by cardiotoxicity that can progress to cardiomyopathy and heart failure. Cellular senescence contributes to DOX-induced cardiac injury, yet the upstream signals that initiate and propagate senescence in the injured heart remain unclear. Here, we identify Wnt5a, a non-canonical Wnt ligand, as a mediator of anthracycline cardiomyopathy. WNT5A was increased in serum from cancer patients receiving anthracycline therapy and in a pathologic human cardiomyocyte population in the context of DOX-induced cardiomyopathy. In mouse hearts, DOX induced early cardiomyocyte-enriched Wnt5a expression before overt cardiac dysfunction. Cardiomyocyte-specific Wnt5a deletion attenuated DOX-induced cardiac dysfunction, fibrosis and senescence marker induction, whereas recombinant Wnt5a and cardiomyocyte-targeted Wnt5a overexpression were sufficient to promote cardiomyocyte senescence and cardiac dysfunction. Mechanistically, DOX activated a Wnt5a-Fzd2 feed-forward axis that amplified Wnt5a expression in cardiomyocytes and propagated senescence to neighboring fibroblasts. Genetic disruption of this pathway in cardiomyocytes, fibroblasts or senescent cells reduced DOX-induced cardiomyopathy. Pharmacological inhibition of Wnt5a signaling with secreted frizzled-related protein 5 suppressed DOX-induced cardiac injury without compromising the anticancer efficacy of DOX. These findings identify Wnt5a-Fzd2 signaling as a senescence-amplifying mechanism in anthracycline cardiomyopathy and suggest a therapeutic strategy to mitigate DOX cardiotoxicity.</jats:p>