Combinations of HDAC inhibitor and PPAR agonist induce ferroptosis of leukemia stem and progenitor cells in acute myeloid leukemia

Abstract Leukemia stem cells (LSCs) are responsible for leukemia initiation, relapse, and therapeutic resistance. Therefore, the development of novel therapeutic approaches targeting LSCs is urgently needed for patients with AML. Here, we report that the histone deacetylase inhibitor chidamide (CS055), in combination with peroxisome proliferator-activated receptor (PPAR) pan agonist (chiglitazar), synergistically targets leukemia stem-like cells from leukemia cell lines and patient samples, while sparing normal hematopoietic progenitor cells. Mechanistically, chiglitazar enhances the inhibitory effect of CS055 on HDAC3 and induces ferroptosis in leukemia stem-like cells by down-regulating the expression of ferroptosis suppressor SLC7A11 . In fact, the inhibition of HDAC3 increases H3K27AC levels in the promoter region of activating transcription factor 3 (ATF3), a transcriptional repressor of the SLC7A11 gene, and upregulates the expression of ATF3. In contrast, ATF4, a SLC7A11 activator, is suppressed by HDAC3 inhibition. Thus, our findings suggest that treatment with CS055 combined with chiglitazar, will target LSCs by inducing ferroptosis and may confer an effective approach for the treatment of AML.