Chemoresistance contributes to poor survival and high relapse risk in acute myeloid leukemia (AML). As a pro-inflammatory cytokine, interleukin-6 (IL-6) plays a vital role in the chemoresistance of malignancies. However, the underlying mechanisms of chemoresistance in AML have not been widely studied. Lipid metabolism, which contributes to chemoresistance in AML, is enhanced by IL-6 in skeletal muscle cells. We hypothesized that IL-6 promotes the chemoresistance of AML by promoting lipid metabolism. Based on the positive correlation between IL-6 receptor expression and the cellular response to exogenous IL-6, we performed Gene Ontology analysis of a dataset consisting the information of 151 AML patients from The Cancer Genome Atlas. We found that lipid transport-associated genes were upregulated in the high IL-6 receptor expression group. Additionally, IL-6 promoted fatty acid (FA) uptake in both AML cell lines and primary AML cells. Inhibition of FA uptake by sulfo-N-succinimidyl oleate repressed IL-6-induced chemoresistance. Western blotting, quantitative polymerase chain reaction, and chromatin immunoprecipitation assays indicated that IL-6 promoted CD36 expression at both the mRNA and protein levels through stat3 signaling. Knockout of CD36 or stat3 repressed IL-6-induced FA uptake and chemoresistance. Furthermore, in five human AML samples, we validated that compared to CD36−cells, CD36+ primary AML cells were less sensitive to cytosine arabinoside (Ara-c) and that blockade of CD36 re-sensitized CD36+ AML cells to Ara-c. Mice injected with CD36 knockout cells followed by treatment with Ara-c showed markedly decreased leukemia burden and prolonged survival in vivo. Finally, treatment with the CD36 antibody in combination with Ara-c exhibited synergistic effects in vivo. In conclusion, IL-6 promotes chemoresistance in AML through the stat3/CD36-mediated FA uptake. Blockade of CD36 improved the effect of Ara-c, representing a promising strategy for AML therapy.

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