DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin

Abstract Dihydroartemisinin (DHA) has been shown to be capable of inhibiting cancer growth, whereas it remains largely elusive that the underlying molecular mechanism of DHA induced acute myeloid leukemia (AML) cell death. In the present study, we examined the effects of DHA on the proliferation and ferroptosis of AML cells as well as to elucidate the underlying molecular mechanisms. We found that DHA strongly inhibited the viability of AML cell lines and arrest cell cycle at G0/G1 phase. Further studies found that DHA effectively induced AML cells ferroptosis, which was iron-dependent and accompanied by mitochondrial dysfunction. Mechanistically, DHA induced autophagy by regulating the activity of AMPK/mTOR/p70S6k signaling pathway, which accelerated the degradation of ferritin, increased the labile iron pool, promoted the accumulation of cellular ROS and eventually led to ferroptotic cell death. Over expression of ISCU (Iron-sulfur cluster assembly enzyme, a mitochondrial protein) significantly attenuated DHA induced ferroptosis by regulating iron metabolism, rescuing the mitochondrial function and increasing the level of GSH. Meanwhile, FTH reconstituted AML cells also exhibited the reduced lipid peroxides content and restored the DHA-induced ferroptosis. In summary, these results provide experimental evidences on the detailed mechanism of DHA-induced ferroptosis and reveal that DHA might represent a promising therapeutic agent to preferentially target AML cells.