Crotonoside induces ferroptosis and mitochondrial dysfunction in AML.

Crotonoside, an isomer of guanine, has demonstrated inhibitory activity against various acute myeloid leukemia (AML) cell lines. Transcriptome sequencing analyses indicate that the mechanism by which crotonoside inhibits AML cell activity is not singular. This study examines the impact of crotonoside on mitochondrial function and the induction of ferroptosis. By assessing mitochondrial respiration capacity, mitochondrial membrane potential, mitochondrial mass, and several ferroptosis-related parameters in both KG-1a and Molm-13 cell lines, we observed that crotonoside induces mitochondrial damage, leading to dysfunction and the accumulation of reactive oxygen species (ROS), which subsequently triggers ferroptosis in AML cells. Molecular docking simulations, informed by the structural characteristics of crotonoside, suggest that its mitochondrial damage is mediated through the inhibition of mitochondrial DNA polymerase γ. Furthermore, this ferroptosis is intricately linked to crotonoside's modulation of AML cell autophagy via the p62/KEAP1 signaling pathway. Nonetheless, the precise mechanisms underlying the inhibition of mitochondrial DNA polymerase γ and the subsequent induction of ferroptosis following crotonoside intervention remain to be fully elucidated.