ROS-ATM-CBP axis-mediated PARP1 lactylation aggravates doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is a potent antineoplastic agent, but its clinical application is limited by the life-threatening cardiotoxic effects. Poly(ADP-ribose) polymerase 1 (PARP1) transfers ADP-ribose groups from donor NAD+ molecules onto target substrates upon oxidative stress, which may promote apoptosis and myocardial injury. The detailed molecular pathways of PARP1 activation, however, remain unclear. Here, we found that reactive oxygen species (ROS) function as signalling molecules to promote CBP-mediated PARP1 lactylation in an ATM-dependent manner, which induces PARP1 PARylation and ultimate cell apoptosis. We identified CBP and SIRT1 as specific lactyltransferase and delactylase of PARP1, respectively. Besides, the lactylation of PARP1 depends on the LDHA activity and lactate production. Moreover, Myocardium-specific CBP knockout mice decrease PARP1 lactylation and prevent doxorubicin-induced cardiac dysfunction. Our findings unravelled that excessive oxidative stress-induced ROS accumulation activates the ATM-CBP-PARP1 signalling pathway via a lactylation-PARylation cascade to promote apoptosis and myocardial injury.