Fig. 7: Doxorubicin-induced regulated cell death pathways.
From: Regulated cell death pathways in doxorubicin-induced cardiotoxicity
Summary of regulated cell death pathways triggered by doxorubicin in the heart. Doxorubicin triggers ROS production by inducing initiation of autophagy and by blocking lysosomal proteolysis resulting in the accumulation of autophagosomes and autolysosomes. Doxorubicin undergoes both redox cycling forming dox-semiquinone moieties and Fenton reaction creating oxidative species. Excess iron and lipid peroxidation due to doxorubicin treatment results in ferroptosis. Doxorubicin activates NLRP inducing the release of Il-1β and Il-18 resulting in death due to pyroptosis. RIPK1 and RIPK3 activation due to doxorubicin treatment leads to phosphorylation of MLKL and necroptosis. Doxorubicin causes necroptosis through RIPK1 independent pathway by activating RIPK3 and CAMKII leading to mPTP and membrane potential loss. ROS trigger p53 activation and GATA4 downregulation stimulating the intrinsic apoptotic pathway. Doxorubicin treatment upregulates death receptors and together with the activation of NFAT and NF-κΒ the extrinsic apoptotic pathway is triggered. Pink color capsules represent apoptosis, brown color capsules represent necroptosis, blue color capsules represent ferroptosis and white capsules represent pyroptosis. DOX doxorubicin, ROS reactive oxygen species, Tf transferrin, TfR transferrin receptor, GPX4 glutathione peroxidase 4, mPTP mitochondria permeability transition pore, Lipid-OO lipid peroxides, NLRP3 NOD−, LRR−, and pyrin domain-containing protein 3, TINCR terminal differentiation-induced ncRNA, GSDM-N gasdermin, TNFα tumor necrosis factor-alpha, TRADD tumor necrosis factor receptor type 1 associated death domain protein, FADD Fas-associated protein with death domain, RIPK receptor-interacting serine/threonine-protein kinase, CAMKII calcium/calmodulin-dependent protein kinase II, NRF2 nuclear factor erythroid 2-related factor, TFEB Transcription factor EB, NF-κΒ nuclear factor-κB, NFAT4 nuclear factor of activated T-cells, ROS reactive oxygen species, SIRT sirtuin, GATA4 GATA-binding protein 4.
