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Alteration of cardiac energetics and mitochondrial function in doxorubicin‑induced cardiotoxicity: Molecular mechanism and prospective implications (Review)

  • Authors:
    • Gong Qing
    • Chao Huang
    • Jixiang Pei
    • Bo Peng
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, The People's Hospital of Chongqing Liangping District, Chongqing 405299, P.R. China, State Key Laboratory of Frigid Zone Cardiovascular Disease, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110000, P.R. China, Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266100, P.R. China, Department of Anesthesiology, Chongqing Traditional Chinese Medicine Hospital, Chongqing 400021, P.R. China
    Copyright: © Qing et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 183
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    Published online on: September 3, 2025
       https://doi.org/10.3892/ijmm.2025.5624
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Abstract

Doxorubicin (DOX)‑induced cardiotoxicity (DIC) remains a critical challenge in cancer therapy, significantly limiting its use in clinical practice. The underlying mechanisms involve disruptions in cardiac metabolism and mitochondrial dysfunction. The heart relies on mitochondrial oxidative phosphorylation to produce ATP, which is essential for maintaining both contraction and relaxation. DOX disrupts glucose metabolism and fatty acid oxidation, resulting in energy shortages and excessive production of reactive oxygen species (ROS). These ROS contribute to mitochondrial damage, organelle malfunction and eventually cardiomyocyte death. This review describes the pathophysiological aspects of DIC, emphasising the molecular mechanisms underlying mitochondrial dysfunction and metabolic dysregulation in the heart during DIC progression. Additionally, the potential diagnostics, therapeutic interventions and drugs targeting metabolic pathways are summarised, focusing on metabolic modulation, combining non‑pharmacological therapies, such as exercise, fasting and mitochondrial transplantation, and approaches to enhance mitochondrial quality control, offering promising theoretical insights and practical strategies for DIC prevention and management.
View Figures

Figure 1

Simplified scheme of the molecular
mechanism of DIC. The figure was taken from a previous review by
our group (17). ATP, adenosine
triphosphate; AMPK, AMP-activated protein kinase; AKT, protein
kinase B; Ac-CoA, acetyl-coenzyme A; DIC, doxorubicin-induced
cardiotoxicity; DOX, doxorubicin; ETC, electron transport chain;
Foxo1, Forkhead box O1; ROS, reactive oxygen species; OXPHOS,
oxidative phosphorylation; PUFA, polyunsaturated fatty acids;
System Xc-, cystine-glutamate antiporter; TFEB, transcription
factor EB; TLR, toll-like receptors; TNF-α, tumor-necrosis factor
α; IL-6, interleukin-6; TOP IIβ, topoisomerase IIβ; NLRP3, NOD-like
receptor 3; ULK1, unc-51 like autophagy activating kinase 1; NADH,
nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine
dinucleotide phosphate.

Figure 2

Overview of energetic metabolism in
doxorubicin-induced cardiotoxicity. In DOX-induced cardiotoxicity,
both FA and glucose oxidation are impaired, primarily due to the
reduction in transcriptional signaling (PPARα, PGC1α) and the
downregulation of energy metabolism gene expression. Insulin
resistance limits glucose transport, primarily through GLUT4. KB
oxidation is increased, while BCAAs oxidation is decreased, leading
to the accumulation of BCAAs in the myocardium and mitochondria.
This accumulation promotes ROS generation and inhibits oxidative
phosphorylation. Additionally, DOX directly affects the ETC,
thereby impairing ATP production. ADP, adenosine diphosphate; ATP,
adenosine triphosphate; Arg2, arginase-2; CK, creatine kinase; TCA,
tricarboxylic acid; PDH, pyruvate dehydrogenase; PPARα, peroxisome
proliferator-activated receptors α; PGC1α, peroxisome
proliferator-activated receptor gamma co-activator-1α; CPT1/2,
carnitine O-palmitoyl transferase 1/2; GLUT1/4, glucose transporter
1/4; GSH, glutathione; GSR, glutathione reductase; G6PD, glucose 6
phosphatase dehydrogenase; PCr, phosphocreatine; β-OHB,
β-hydroxybutyrate; BCAAs, branched-chain amino acids; FAT, fatty
acid translocase; MPC, mitochondrial pyruvate carrier; PFK2,
ATP-dependent 6-phosphofructokinase 2; FA, fatty acid; KB, ketone
body; LDH, lactate dehydrogenase; ETC, electron transport
chain.

Figure 3

Crosstalk between AMPK and cardiac
energy metabolism in doxorubicin-induced cardiotoxicity. AMPK
regulates changes in cardiac energy metabolism via regulating key
enzymes or genes in glucose and FAs metabolism, while metformin,
EGCG and resveratrol affect glucose and fatty acid oxidation via
regulating AMPK. ACC2, acetyl-CoA carboxylase; ATP, adenosine
triphosphate; AMPK, AMP-activated protein kinase; GLUT4, glucose
transporter 4; CPT1, carnitine O-palmitoyl transferase 1; G6P,
glucose-6-phosphate; EGCG, epigallocatechin-3-gallate; PPARα,
peroxisome proliferator-activated receptors α; F6P, fructose 6
phosphate; PFK2, phosphofructokinase-2; DOX, doxorubicin; ROS,
reactive oxygen species; ULK1, unc-51 like autophagy activating
kinase 1; PDH, pyruvate dehydrogenase; TCA, tricarboxylic acid.

Figure 4

Overview of alteration of energetics
and mitochondrial function within the cardiomyocyte in the
pathogenesis DIC. DOX disrupts cardiac energetic metabolism, AMPK
signalling pathway and mitochondrial function, resulting in energy
shortages and excessive production of reactive oxygen species.
Those alterations aggravate DIC. Metformin, EGCG, oleuropein and
betaine may provide cardioprotection through regulating AMPK.
Empagliflozin may provide an alternative cardiac substrate of KB to
change cardiac energetics. Semaglutide, isoliquiritin and
liensinine may provide cardioprotection through improving
mitochondrial function. AAs, amino acids; ATP, adenosine
triphosphate; ADP, adenosine diphosphate; CPT1/2, carnitine
O-palmitoyl transferase 1/2; GLUT1/4, glucose transporter 1/4; G6P,
glucose-6-phosphate; GDH, glutamate dehydrogenase; KB, ketone
bodies; FAs, fatty acids; AMPK, AMP-activated protein kinase; EGCG,
epigallocatechin-3-gallate; DOX, doxorubicin; DIC,
doxorubicin-induced cardiotoxicity; EGCG,
epigallocatechin-3-gallate; FAT, fatty acid translocase; ROS,
reactive oxygen species; MCT1, monocarboxylate transporter 1;
Mfn1/2, mitochondrial protein mitofusin 1/2; DRP1, dynamin-related
protein 1; PPARα, peroxisome proliferator-activated receptors α;
PGC1α, peroxisome proliferator-activated receptor gamma
co-activator-1α; β-OHB, β-hydroxybutyrate; Fis1, fission protein
1.

Figure 5

Multiple therapeutic strategies in
doxorubicin-induced cardiotoxicity, including mitochondrial
transplantation, clinical drugs, strategies regulating AMPK
activity, targeting mitochondrial dynamics and exercise and
fasting. AMPK, AMP-activated protein kinase; EGCG,
epigallocatechin-3-gallate; FAO, fatty acid oxidation; GLUT4,
glucose transporter 4; DRP1, dynamin-related protein 1; PGC1α,
peroxisome proliferator-activated receptor gamma co-activator-1α;
ROS, reactive oxygen species; MFN2, mitochondrial protein mitofusin
2; SGLT2-I, sodium-glucose cotransporter 2 inhibitor.
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Copy and paste a formatted citation
Spandidos Publications style
Qing G, Huang C, Pei J and Peng B: Alteration of cardiac energetics and mitochondrial function in doxorubicin‑induced cardiotoxicity: Molecular mechanism and prospective implications (Review). Int J Mol Med 56: 183, 2025.
APA
Qing, G., Huang, C., Pei, J., & Peng, B. (2025). Alteration of cardiac energetics and mitochondrial function in doxorubicin‑induced cardiotoxicity: Molecular mechanism and prospective implications (Review). International Journal of Molecular Medicine, 56, 183. https://doi.org/10.3892/ijmm.2025.5624
MLA
Qing, G., Huang, C., Pei, J., Peng, B."Alteration of cardiac energetics and mitochondrial function in doxorubicin‑induced cardiotoxicity: Molecular mechanism and prospective implications (Review)". International Journal of Molecular Medicine 56.5 (2025): 183.
Chicago
Qing, G., Huang, C., Pei, J., Peng, B."Alteration of cardiac energetics and mitochondrial function in doxorubicin‑induced cardiotoxicity: Molecular mechanism and prospective implications (Review)". International Journal of Molecular Medicine 56, no. 5 (2025): 183. https://doi.org/10.3892/ijmm.2025.5624
Copy and paste a formatted citation
x
Spandidos Publications style
Qing G, Huang C, Pei J and Peng B: Alteration of cardiac energetics and mitochondrial function in doxorubicin‑induced cardiotoxicity: Molecular mechanism and prospective implications (Review). Int J Mol Med 56: 183, 2025.
APA
Qing, G., Huang, C., Pei, J., & Peng, B. (2025). Alteration of cardiac energetics and mitochondrial function in doxorubicin‑induced cardiotoxicity: Molecular mechanism and prospective implications (Review). International Journal of Molecular Medicine, 56, 183. https://doi.org/10.3892/ijmm.2025.5624
MLA
Qing, G., Huang, C., Pei, J., Peng, B."Alteration of cardiac energetics and mitochondrial function in doxorubicin‑induced cardiotoxicity: Molecular mechanism and prospective implications (Review)". International Journal of Molecular Medicine 56.5 (2025): 183.
Chicago
Qing, G., Huang, C., Pei, J., Peng, B."Alteration of cardiac energetics and mitochondrial function in doxorubicin‑induced cardiotoxicity: Molecular mechanism and prospective implications (Review)". International Journal of Molecular Medicine 56, no. 5 (2025): 183. https://doi.org/10.3892/ijmm.2025.5624
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