Elsevier Inc. Aco1 ---- iron response element Ireb2 ---- iron response element Ireb2 citrate ---> isocitrate iron response element p53 signaling pathway intrinsic apoptotic pathway doxorubicin pharmacokinetics pathway Aco1 doxorubicin ---- Fe3+ p53 signaling pathway --+> intrinsic apoptotic pathway ROS generation cardiolipin --+> intrinsic apoptotic pathway damage responses, inhibition of transcription, chromatin --+> p53 signaling pathway damage responses, inhibition of transcription, chromatin --+> intrinsic apoptotic pathway damage responses, inhibition of transcription, chromatin Top2b doxorubicin ---> damage responses, inhibition of transcription, chromatin DOX adducts doxorubicin ---| Ireb2 citrate Fe3+ ---> Fe2+ Fe3+ Fe2+ ---> ROS generation Fe2+ doxorubicin pharmacokinetics pathway ---> ROS generation isocitrate doxorubicin ---| Aco1 doxorubicin ---- iron response element doxorubicin ---> doxorubicin pharmacokinetics pathway cardiolipin ---- doxorubicin ROS generation ---> cardiolipin cardiolipin doxorubicin doxorubicin ---- Top2b