Quercetin Antagonizes Doxorubicin-Induced Cardiotoxicity via HO-1/PGC-1α-ALOX5 Axis: Arachidonic Acid Metabolism-Ferroptosis Crosstalk as a Therapeutic Target

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Abstract
Myocardial injury caused by Doxorubicin has limited its clinical application. Our research has demonstrated that doxorubicin induces various forms of cell death, oxidative stress, and metabolic abnormalities. We have confirmed, through both in vitro and in vivo studies, that apoptosis, iron overload, inflammatory responses, and arachidonic acid metabolism contribute to doxorubicin's cardiotoxic effects. Treatment with quercetin effectively reduces iron accumulation and preserves mitochondrial structural integrity by inhibiting oxidative stress and inflammatory responses. Using molecular docking and surface plasmon resonance (SPR) techniques, our study suggests that quercetin activates the HO-1/PGC-1α pathway, which may involve downregulation of ALOX5 expression, thereby alleviating oxidative stress, inhibiting iron-dependent lipid peroxidation and ferroptosis-like changes, mitigating inflammatory responses, and modulating arachidonic acid metabolism. Additionally, quercetin enhances energy availability and supports mitochondrial function. We propose quercetin, a promising active compound derived from traditional Chinese medicine, as a potential mitigator of doxorubicin-induced cardiotoxicity.
Funding Information
  • Science and Technology Research Project of Jiangxi Provincial Department of Education (GJJ2403621)
  • the Nanchang Medical College University-level Scientific Research Project (NYXJ-2024-025)
  • Science and Technology Program of the Health Commission of Jiangxi Province (202610802)
  • the "Young Talent" Scientific Research Project of Jiangxi Provincial Children's Hospital (2024JXEYQM09)

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