Ganoderma lucidum polysaccharides alleviate doxorubicin-induced cardiotoxicity by inhibiting ferroptosis through modulation of the Nrf2/SLC7A11/GPX4 signaling pathway

  • Int J Biol Macromol. 2026 Jun:367:152584. doi: 10.1016/j.ijbiomac.2026.152584.
Shangbo Zhang  1 ,  Rongrong Li  2 ,  Kaixin Wu  3 ,  Hui Zhao  3 ,  Jianxi Song  4 ,  Yang Zhang  3 ,  Yuyang Chen  5 ,  Junlei He  4 ,  Fanli Kong  6 ,  Yongchao Liu  7
Affiliations
  • 1. Medical Technology College, Beihua University, Jilin, 132013, China. Electronic address: [email protected].
  • 2. Key Laboratory for the Structure and Function of Polysaccharides in Traditional Chinese Medicine (Administration of Traditonal Chinese Medicine of Jilin Province), Beihua University, Jilin, 132013, China. Electronic address: [email protected].
  • 3. Medical Technology College, Beihua University, Jilin, 132013, China.
  • 4. Key Laboratory for the Structure and Function of Polysaccharides in Traditional Chinese Medicine (Administration of Traditonal Chinese Medicine of Jilin Province), Beihua University, Jilin, 132013, China.
  • 5. School of Pharmacy, Beihua University, Jilin, 132013, China.
  • 6. Medical Technology College, Beihua University, Jilin, 132013, China. Electronic address: [email protected].
  • 7. Medical Technology College, Beihua University, Jilin, 132013, China. Electronic address: [email protected].
PMID: 42155741 DOI: 10.1016/j.ijbiomac.2026.152584
Abstract

Doxorubicin (Dox) is a chemotherapeutic agent widely used in clinical oncology; however, its application is limited by dose-dependent cardiotoxicity, in which Ferroptosis has been identified as a key mechanism of myocardial injury. In recent years, growing attention has been paid to strategies aimed at mitigating the adverse effects of Dox. Ganoderma lucidum Polysaccharides (GLPs), major bioactive components derived from the fruiting body of Ganoderma lucidum, a traditional Chinese medicinal fungus, have been clinically applied with proven safety and reliability. In this study, GLPs were extracted and investigated for their potential cardioprotective effects against Dox-induced injury through the inhibition of Ferroptosis. A rat model of doxorubicin-induced cardiotoxicity (DIC) was established via multiple intraperitoneal injections of Dox at a cumulative dose of 20 mg/kg over a 15-day period. In parallel, H9c2 rat cardiomyocytes were cultured to construct an in vitro DIC cell model. Both the in vivo and in vitro models were treated with extracted GLPs, and alterations in relevant indicators were systematically analyzed to evaluate the cardioprotective effects of GLPs. The results demonstrated that GLPs alleviated DIC, reduced oxidative stress, and mitigated iron overload. Moreover, GLPs significantly upregulated the mRNA and protein expression levels of Nuclear factor erythroid 2-related factor 2 (Nrf2), Glutathione Peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11), all of which are crucial regulators of Ferroptosis and downstream targets of Nrf2. Importantly, knockdown of Nrf2 markedly weakened the protective effects of GLPs. These findings suggest that GLPs protect against Dox-induced myocardial injury by inhibiting Ferroptosis through the modulation of the Nrf2/SLC7A11/GPX4 signaling pathway.

Keywords
Doxorubicin; Doxorubicin-induced cardiotoxicity; Ferroptosis; Ganoderma lucidum polysaccharides; Myocardial injury.
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