A Critical Role for Neutral Sphingomyelinase-2 in Doxorubicin-induced Cardiotoxicity

Cardiotoxicity is a major side effect of Doxorubicin (Dox) that has hampered its clinical utility, and strategies to mitigate this cardiotoxicity are limited. Sphingolipids (SL) are central to the chemotherapy response in cancer but their role in normal tissue is less clear. Here, we identified the SL enzyme neutral sphingomyelinase-2 (nSMase2) as a critical mediator of chronic Dox-induced cardiotoxicity, establishing nSMase2 as a key downstream effector of Dox in cardiomyocytes (CM) and showing that in vivo loss of nSMase2 activity is protecting against chronic Dox-induced cardiac damage and dysfunction. Biologically, these studies link nSMase2 with Dox-induced CM senescence both in vitro and in vivo and identify the dual specificity phosphatase DUSP4 as a novel effector of nSMase2 in the Dox response. In addition to cementing a role for SL metabolism in Dox effects in normal tissue, this study advances nSMase2 as a target of interest for cardioprotection.