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Background <p>Doxorubicin (DOX)-induced cardiotoxicity (DIC) injury primarily contributes to anthracycline-associated end-stage cardiovascular mortality. Ligustrazine (LIG), a natural compound extracted from <i>Ligusticum chuanxiong</i>, a medicinal plant, has cardioprotective effects. However, therapeutic applications of LIG are limited owing to its poor water solubility, rapid degradation, and low bioavailability. These limitations can be overcome by encapsulating LIG into nanocarriers. We highlight the therapeutic potential of LIG drug delivery technology (LIG–Na) for DIC by integrating bioinformatics, single-cell sequencing, spatial transcriptomics, and transgenic animal models, and investigate the mechanisms underlying mitochondrial homeostasis (MQH).</p> Methods <p>We used bioinformatics to predict DIC-related mechanisms and established DOX-induced models using SIRT5/DUSP1/PHB2<sup>CKO</sup> mice and DUSP1 transgenic mice (SIRT5/DUSP1/PHB2<sup>TG</sup>). The pathological mechanisms of LIG-Na-mediated alleviation of cardiac injury were examined using echocardiography, WB, TEM, and fluorescence staining. In addition, mitochondrial functional and morphological changes were evaluated using qPCR, ELISA, and confocal laser scanning microscopy following si/adRNA-mediated silencing of SIRT5/DUSP1/PHB2 in cardiomyocytes to further assess the targeted therapeutic effects of LIG–Na.</p> Results <p>DOX treatment induced severe mitochondrial dysfunction, which was effectively normalized by LIG–Na. Although these protective effects were completely abolished in SIRT5/DUSP1/PHB2<sup>CKO</sup> mice, these remained unaffected in SIRT5/DUSP1/PHB2<sup>TG</sup> mice.</p> Conclusion <p>LIG-Na ameliorated DOX-mediated cardiac dysfunction and MQH dysregulation through the SIRT5/DUSP1-PHB2S91 phosphorylation axis, thereby effectively suppressing mitochondrial dysfunction and mitigating DIC in mice.</p> Graphical abstract <p></p>

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A novel ligustrazine-based nanodelivery system protects against doxorubicin-induced cardiotoxicity by targeting the SIRT5–DUSP1 axis for mitochondrial repair

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月15日

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  • Hongshuo Shi,
  • Boxian Pang,
  • Fenglei Zhang,
  • Zhijiang Guo,
  • Wenshi Xu,
  • Man Zheng,
  • Yang You,
  • Guobin Liu,
  • Yifeng Nie,
  • Jianxiao Liang,
  • Xing Chang

摘要

Background

Doxorubicin (DOX)-induced cardiotoxicity (DIC) injury primarily contributes to anthracycline-associated end-stage cardiovascular mortality. Ligustrazine (LIG), a natural compound extracted from Ligusticum chuanxiong, a medicinal plant, has cardioprotective effects. However, therapeutic applications of LIG are limited owing to its poor water solubility, rapid degradation, and low bioavailability. These limitations can be overcome by encapsulating LIG into nanocarriers. We highlight the therapeutic potential of LIG drug delivery technology (LIG–Na) for DIC by integrating bioinformatics, single-cell sequencing, spatial transcriptomics, and transgenic animal models, and investigate the mechanisms underlying mitochondrial homeostasis (MQH).

Methods

We used bioinformatics to predict DIC-related mechanisms and established DOX-induced models using SIRT5/DUSP1/PHB2CKO mice and DUSP1 transgenic mice (SIRT5/DUSP1/PHB2TG). The pathological mechanisms of LIG-Na-mediated alleviation of cardiac injury were examined using echocardiography, WB, TEM, and fluorescence staining. In addition, mitochondrial functional and morphological changes were evaluated using qPCR, ELISA, and confocal laser scanning microscopy following si/adRNA-mediated silencing of SIRT5/DUSP1/PHB2 in cardiomyocytes to further assess the targeted therapeutic effects of LIG–Na.

Results

DOX treatment induced severe mitochondrial dysfunction, which was effectively normalized by LIG–Na. Although these protective effects were completely abolished in SIRT5/DUSP1/PHB2CKO mice, these remained unaffected in SIRT5/DUSP1/PHB2TG mice.

Conclusion

LIG-Na ameliorated DOX-mediated cardiac dysfunction and MQH dysregulation through the SIRT5/DUSP1-PHB2S91 phosphorylation axis, thereby effectively suppressing mitochondrial dysfunction and mitigating DIC in mice.

Graphical abstract