Apolipoprotein M Attenuates Anthracycline Cardiotoxicity and Lysosomal Injury

[Display omitted] •Circulating ApoM is inversely associated with mortality in human anthracycline-induced cardiomyopathy.•Anthracycline treatment reduces circulating ApoM in humans and mice.•Increasing ApoM attenuates doxorubicin cardiotoxicity and lysosomal injury and preserves myocardial autophagic flux, but it does not affect doxorubicin antineoplastic efficacy.•Autophagic impairment is characteristic of human anthracycline cardiomyopathy. Apolipoprotein M (ApoM) binds sphingosine-1-phosphate (S1P) and is inversely associated with mortality in human heart failure (HF). Here, we show that anthracyclines such as doxorubicin (Dox) reduce circulating ApoM in mice and humans, that ApoM is inversely associated with mortality in patients with anthracycline-induced heart failure, and ApoM heterozygosity in mice increases Dox-induced mortality. In the setting of Dox stress, our studies suggest ApoM can help sustain myocardial autophagic flux in a post-transcriptional manner, attenuate Dox cardiotoxicity, and prevent lysosomal injury.