In summary, our data revealed that chemotherapy induces SIRT3 de-SUMOylation, which confers AML chemoresistance possibly through down-regulation of HES1-dependent FAO and targeting of SIRT3 de-SUMOylation synergize with chemotherapeutic agent Ara-C in vitro and in vivo, may be a promising regimen to overcome chemoresistance and improve the clinical outcome in AML (Figure S5). Here, HES1 is linked to acute myeloid leukemia.