Cardiomyocyte-derived Wnt5a drives doxorubicin-induced cardiomyopathy by amplifying cellular senescence

Sung, E.-A.; Zhai, P.; Ikeda, S.; Matsushita, M.; Takayama, K.; Takada, T.; Fefelova, N.; Xie, L.; Yehia, G.; Romanienko, P.; Gadiyar, V.; Birge, R.; Vecchio, D.; Forte, M.; Valenti, V.; Sciarretta, S.; Sadoshima, J.

doi:10.64898/2026.08.05.742723

bioRxiv · 10.64898/2026.08.05.742723

Cardiomyocyte-derived Wnt5a drives doxorubicin-induced cardiomyopathy by amplifying cellular senescence

Sung, E.-A.·Zhai, P.·Ikeda, S.·Matsushita, M.·Takayama, K.·Takada, T.·Fefelova, N.·Xie, L.·Yehia, G.·Romanienko, P.·Gadiyar, V.·Birge, R.·Vecchio, D.·Forte, M.·Valenti, V.·Sciarretta, S.·Sadoshima, J.

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Abstract

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.

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Sung, E.-A., Zhai, P., Ikeda, S., Matsushita, M., Takayama, K., Takada, T., Fefelova, N., Xie, L., Yehia, G., Romanienko, P., Gadiyar, V., Birge, R., Vecchio, D., Forte, M., Valenti, V., Sciarretta, S., Sadoshima, J.. 2026-08-06. Cardiomyocyte-derived Wnt5a drives doxorubicin-induced cardiomyopathy by amplifying cellular senescence. https://doi.org/10.64898/2026.08.05.742723

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