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Background: Apolipoprotein M (APOM) is a lipoprotein that binds sphingosine-1-phosphate (S1P) and high-density lipoprotein (HDL). APOM/S1P attenuate myocardial ischemia/reperfusion injury by reducing infarct size. We recently published that reduced APOM plasma protein levels are associated with mortality across the spectrum of human heart failure. With the goal of uncovering mechanisms by which APOM impacts heart failure mortality, we modeled doxorubicin cardiotoxicity in hepatocyte specific APOM overexpression (APOM TG ) and littermate controls. Results: Doxorubicin treatment acutely reduces APOM plasma protein levels in control mice. APOM TG mice exhibit ~3-5 fold increased APOM and ~2.5 fold increased S1P. In acute and chronic doxorubicin cardiotoxicity models, APOM TG mice were protected from mortality and reductions in left-ventricular mass and ejection fraction observed in littermate controls. In murine models of acute leukemia, doxorubicin effectively killed leukemic cells in control and APOM TG mice. In the myocardium, APOM TG mice and controls had similar levels of γ-H2AX foci after doxorubicin treatment, indicating similar levels of DNA damage, and electron microscopy indicated similar mitochondrial morphology. However, APOM TG mice exhibited enhanced autophagic flux, and APOM prevented doxorubicin-induced reductions in autophagic flux observed in littermate control mice (Figure). Mechanistically, treatment of neonatal rat cardiomyocytes with S1P mimetics attenuated doxorubicin-induced loss of lysosomal pH, suggesting that APOM may enhance lysosomal function via S1P. In the murine myocardium, doxorubicin reduced the nuclear protein content of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, in control mice but not APOM TG mice. Furthermore, adeno-associated virus mediated knockdown of TFEB completely reversed the beneficial effects of APOM on the myocardium, leading to cardiomyopathy and mortality in APOM TG mice. Conclusions: Our studies identify APOM and S1P as regulators of TFEB in the myocardium, hence providing a mechanistic link between HDL and the autophagy-lysosome pathway in the murine heart. The role of APOM in myocardial autophagy may explain our observed clinical associations between reduced APOM and mortality.