Although excess lipid accumulation in non-adipose tissues is initially well tolerated, this metabolic excess ultimately causes cell dysfunction and cell death that is linked to the pathogenesis of complications of diabetes and obesity. Using a genetic screen, we discovered that RNASET2, a T2 endoribonuclease, is a critical mediator of oxidative stress damage and cell death in response to lipotoxicity. This study will elucidate the mechanism of action of RNASET2, by identifying the RNAs that this enzyme degrades, by elucidating the pathways through which RNA substrates are delivered to RNASET2, and by examining the contributions of RNASET2 to the pathogenesis of cardiac lipotoxicity in a mouse model. The results of these studies will provide new insights into the lipotoxic response to excess lipid accumulation in cardiovascular complications of metabolic diseases.