The histone lysine-specific demethylase inhibitor JIB-04 sensitizes AML cells to venetoclax by inducing ferroptosis.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with various molecular and cytogenetic subtypes. Treatment options for elderly patients are limited due to high toxicity of conventional chemotherapy. The BCL-2 inhibitor venetoclax is effective in combination with hypomethylating agents or low-dose cytarabine, but about 30% of patients don’t respond to the initial combination treatment. Thus, alternative combinations are needed to sensitize AML cells to venetoclax and overcome resistance mechanisms. Here, we report that targeting histone lysine-specific demethylases (KDMs) induces ferroptosis in various AML subtypes. In both patient samples and cell lines, JIB04 increases the level of reactive oxygen species (ROS), ferrous iron, and lipid peroxidation, all signs of ferroptosis. The combination of JIB04 and venetoclax proved to be highly synergistic and was dependent on ferroptosis induction. Blocking ferroptosis by using the antioxidant N-Acetyl-L-cysteine (NAC) reverses the synergistic killing. On the molecular level, the ferroptosis inducers HMOX1, SAT1, and PTGS2 were found to be upregulated by JIB04. Collectively, these findings identify JIB04 as a new ferroptosis inducer in AML and highlight the potential of ferroptosis induction as a valuable strategy in combination with venetoclax to treat AML.