P2Y12-AMPKα2 signaling contributes to cardiomyocyte senescence in doxorubicin-induced heart failure

Doxorubicin(DOX)-induced cardiotoxicity is increasingly associated with cardiomyocyte senescence, yet the upstream regulatory mechanisms remain unclear. Here, we show that DOX promotes cardiomyocyte senescence in vivo and in vitro, accompanied by increased P2Y12 expression, reduced AMPKα2 activity, and activation of the ASK1-MEK3 signaling cascade. Disruption of AMPKα2 altered ASK1-MEK3 signaling without affecting P2Y12 expression, suggesting a potential hierarchical relationship between P2Y12 and AMPKα2. Floralozone attenuated DOX-induced cardiac dysfunction and reduced senescence-associated changes, coinciding with modulation of the P2Y12-AMPKα2 axis. These findings support an association between P2Y12-AMPKα2 signaling and cardiomyocyte senescence in DOX-induced heart failure.