Pathophysiology of Doxorubicin-Mediated Cardiotoxicity
Abstract
1. Introduction
2. Major Pathogenetic Mechanisms of DIC
2.1. DNA Instability and Topoisomerase Inhibition
2.2. Oxidative Stress
2.3. Autophagy
2.4. Inflammation
2.5. Apoptosis and Ferroptosis
3. Role of Sirtuins in DIC
4. Role of Natural Products in DIC
Therapeutic Attempts to Reduce DIC
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
CATI | Catalase |
DICJ | Doxorubicin-induced cardiotoxicity |
DOX | Doxorubicin |
ER | Endoplasmic reticulum |
GPx4 | Glutathione peroxidase 4 |
IL | Interleukin |
MnSOD | Manganese superoxide dismutase |
NLRP3 | Nod-like receptor thermal protein domain-associated protein 3 |
NO | Nitric oxide |
NOX | NADH oxidase |
RBP | RNA-binding protein |
RES | Resveratrol |
ROS | Reactive oxygen species |
SIRT | Sirtuins |
TLR | Toll-like receptor |
YAP | Yes-associated protein |
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Oxidative Stress | Interaction with mitochondrial DNA, and inhibition of the respiratory chain [31]; |
Generation of ROS, alteration of the phospholipids of cell membranes, mitochondria, and ER, with myocardial damage [32]; | |
Reduction of glutathione and CAT levels, with increase in oxidative stress [33]; DIC-mediated endothelial dysfunction with increased levels of endothelin-1, activation of type A and type B receptors, vasoconstriction, and release of NO, adrenomedullin, and prostacyclin [37] | |
Autophagy | DOX-mediated increase in Beclin-1, p62, and microtubule-associated protein 1A/1B light chain 3 (LC3)-II/LC3-I levels, with damaged mitochondria removed by mitophagy [43]; |
DOX-mediated abrogation of lysosome biosynthesis and catepsin activity, with autophagolysosomal accumulation, and impairment of autophagy [45]; DOX-induced inhibition of the fusion between autophagosomes and liposomes [46]; DOX-mediated enhancement of TLR9, and suppression of AMPK activation [47] | |
Inflammation | DIC-induced release of pro-inflammatory cytokines through activation of TLR-4, NF-kB, and NLRP3 inflammasome [48,49,50]; |
DOX-mediated transformation of smooth cardiac muscle cells into macrophage-like cells, with vascular wall low-grade inflammation and impairment of sarcoplasmic reticulum [55,56]; | |
DOX-induced apoptosis of cardiomyocytes via release of catecholamines by infiltrating macrophages [57] | |
Apoptosis/Ferroptosis | Decrease in the anti-apoptotic protein, Bcl-2, and increase in Bcl-2-associated X expression in DOX-treated cardiomyocytes, with increased mitochondrial permeability, cytochrome c release and caspase-3, thus leading to cardiomyocyte apoptosis [60]; |
DOX-induced ferroptosis of cardiomyocytes by inactivation of GPx4 [62,63,64]; Overexpression of methyltransferase-like 14 with upregulation of transferrin receptors, and uptake of iron [65]; DOX-mediated ferroptosis by impairment of Forkhead Box O4 transcription, and high mobility group Box 1 nuclear translocation [66] |
SIRT 1 | ROS generation and FOXO 1 deacetylation inhibition, with decrease in cardiac oxidative stress [71] |
SIRT 1-mediated inhibition of NF-kB through deacetylation of the peroxisome proliferator-activated receptor gamma coactivator 1 alpha; SIRT 1/Liver kinase B1/AMPK pathway activation; inhibition of miR-200a 3p, respectively [72,75,79] | |
Natural product (jaceosidin, calycosin, and dihydromyrecitin)-mediated activation of SIRT 1, with inhibition of NF-kB [76,77,94]; p53 protein acetylation decrease by resveratrol-activated SIRT 1, with attenuation of myocardial cell apoptosis [78]; SIRT 1-mediated activation of the Nrf2/Kelch-like associated protein, with reduction of ferroptosis, and DIC [79] | |
SIRT 2 | FOXO3a and AMPK SIRT 2-mediated activation, respectively, with reduced release of ROS and mitigation of DIC [81,108] |
SIRT 2 activation and improvement of DOX-mediated cardiac aging [65]; miR-140-5p inhibition with activation of the SIRT2/NRF2 antioxidant pathway [82] | |
SIRT 3 | Natural product (RES, daidzein, tubeimoside, berberine, Qishen granules) and dichloroacetic acid-mediated upregulation of SIRT3, with improvement of DOX-induced mitochondrial dysfunction, ROS generation, and apoptosis [70,84,85,86,87,109] |
miR-34-5p SIRT 3-mediated inhibition, with autophagic activity regulation, and protection from DIC [88] | |
SIRT 3-induced inhibition of NLRP3 inflammasome, with autophagy regulation, and pyroptosis decrease [83] | |
SIRT 4 | SIRT 4-mediated inhibition of fatty acid oxidation in muscles, with reduction of mitochondrial function [89] |
Overexpression of SIRT 4 and interaction with optic atrophin 1, with regulation of autophagy and ROS generation; SIRT 4-mediated inhibition of DIC, with activation of the akt/mTOR pathway [92] | |
SIRT 5 | Coenzyme Q 10-mediated overexpression of SIRT 5 and protection from DIC [93] |
SIRT 6 | SIRT 6 overexpression by targeting miR-330-5p, with inhibition of ROS generation, apoptosis, and necrosis during DIC [80,95] |
Enhancement of autophagy by SIRT 6-mediated acetylation and inhibition of SKG1 [110] | |
SIRT 7 | SIRT 7-induced reduction of myocardial stress via deacetylation of p53 and GATA4; regulation of |
autophagy and inhibition of miR-148-3p, respectively [83,98,100,101,102] |
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Arrigoni, R.; Jirillo, E.; Caiati, C. Pathophysiology of Doxorubicin-Mediated Cardiotoxicity. Toxics 2025, 13, 277. https://doi.org/10.3390/toxics13040277
Arrigoni R, Jirillo E, Caiati C. Pathophysiology of Doxorubicin-Mediated Cardiotoxicity. Toxics. 2025; 13(4):277. https://doi.org/10.3390/toxics13040277
Chicago/Turabian StyleArrigoni, Roberto, Emilio Jirillo, and Carlo Caiati. 2025. "Pathophysiology of Doxorubicin-Mediated Cardiotoxicity" Toxics 13, no. 4: 277. https://doi.org/10.3390/toxics13040277
APA StyleArrigoni, R., Jirillo, E., & Caiati, C. (2025). Pathophysiology of Doxorubicin-Mediated Cardiotoxicity. Toxics, 13(4), 277. https://doi.org/10.3390/toxics13040277