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Background <p>Doxorubicin (DOX) clinical use is limited by cardiotoxicity, mainly driven by ferroptosis and oxidative stress. Tiron, an antioxidant and iron chelator, may deliver cardioprotective effects by inhibiting these pathways. Thus, the present study aimed to examine the mechanistic effects of Tiron on ferroptosis and apoptosis in DOX-induced cardiotoxicity.</p> Methods <p>H9c2 cardiomyocytes were pretreated with Tiron (0.1, 0.2, 0.5, and 1&#xa0;mM) for 24&#xa0;h prior to exposure to doxorubicin (1&#xa0;µM) for an additional 24&#xa0;h. Cell viability, DNA damage (comet assay), mitochondrial membrane potential (MMP), and membrane damage (lactate dehydrogenase [LDH] release) were assessed. Oxidative stress and ferroptosis markers, including GSH, ROS, SOD, MDA, GPX, and GPX4, were measured. Apoptosis was examined via caspase-3/7 activity and TUNEL assays.</p> Results <p>Tiron significantly improved viability, reduced LDH release, and lowered DNA fragmentation. It decreased MDA and ROS levels while restoring SOD, GPX, and GSH. Crucially, Tiron (1&#xa0;mM) significantly restored cellular GPX4 levels suppressed by DOX. Tiron preserved MMP, indicating protection against mitochondrial dysfunction. Moreover, it attenuated caspase-3/7 activation and reduced apoptosis in the TUNEL assay.</p> Conclusion <p>Tiron mitigates DOX-induced cardiotoxicity by modulating pathways associated with ferroptosis, apoptosis, and oxidative stress. Tiron demonstrates strong potential as a cardioprotective agent against anthracycline-induced injury by preserving mitochondrial function.</p>

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Dual blockade of ferroptosis and apoptosis: Tiron attenuates doxorubicin cardiotoxicity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Farzaneh Motafeghi,
  • Parham Rahmani,
  • Ehsan Ghassemi Barghi,
  • Jafar Gholami Gharab,
  • Parham Mortazavi,
  • Milad Dehpanah,
  • Nasrin Ghassemi Barghi

摘要

Background

Doxorubicin (DOX) clinical use is limited by cardiotoxicity, mainly driven by ferroptosis and oxidative stress. Tiron, an antioxidant and iron chelator, may deliver cardioprotective effects by inhibiting these pathways. Thus, the present study aimed to examine the mechanistic effects of Tiron on ferroptosis and apoptosis in DOX-induced cardiotoxicity.

Methods

H9c2 cardiomyocytes were pretreated with Tiron (0.1, 0.2, 0.5, and 1 mM) for 24 h prior to exposure to doxorubicin (1 µM) for an additional 24 h. Cell viability, DNA damage (comet assay), mitochondrial membrane potential (MMP), and membrane damage (lactate dehydrogenase [LDH] release) were assessed. Oxidative stress and ferroptosis markers, including GSH, ROS, SOD, MDA, GPX, and GPX4, were measured. Apoptosis was examined via caspase-3/7 activity and TUNEL assays.

Results

Tiron significantly improved viability, reduced LDH release, and lowered DNA fragmentation. It decreased MDA and ROS levels while restoring SOD, GPX, and GSH. Crucially, Tiron (1 mM) significantly restored cellular GPX4 levels suppressed by DOX. Tiron preserved MMP, indicating protection against mitochondrial dysfunction. Moreover, it attenuated caspase-3/7 activation and reduced apoptosis in the TUNEL assay.

Conclusion

Tiron mitigates DOX-induced cardiotoxicity by modulating pathways associated with ferroptosis, apoptosis, and oxidative stress. Tiron demonstrates strong potential as a cardioprotective agent against anthracycline-induced injury by preserving mitochondrial function.