Depletion of SASP senescent cardiomyocytes with senolytic drugs confers therapeutic effects in doxorubicin‐related cardiotoxicity

Doxorubicin (Dox), an anthracycline antibiotic, is widely used in cancer treatment. Although its antitumor efficacy appears significant, its clinical use is greatly restricted by its induction of cardiotoxicity. Cardiac senescence drives the Dox-induced cardiotoxicity, but whether diminishing these senescent cardiomyocytes could alleviate the cardiotoxicity remains unclear. Here, we assessed whether senescent cardiomyocytes have a senescence-associated secretory phenotype (SASP) that affects healthy non-senescent cardiomyocytes, rendering them senescent via the delivery of exosomes. Additionally, we explored whether targeting SASP senescent cardiomyocytes using a Bcl-2 inhibitor could alleviate cardiotoxicity. Cardiac damage was induced in a mouse model of continuous Dox treatment in vivo, and cardiomyocytes in vitro. Immunofluorescence of the senescence markers of Cdkn2a, Cdkn1a and γ-H