Ligustrazine nano-drug delivery system ameliorates doxorubicin-mediated myocardial injury via piezo-type mechanosensitive ion channel component 1-prohibitin 2-mediated mitochondrial quality surveillance
Abstract Background Doxorubicin (DOX) demonstrates significant therapeutic and anticancer efficacy. Nevertheless, it demonstrates significant cardiotoxicity, resulting in permanent cardiac damage. Ligustrazine (LIG) is a bioactive alkaloid derived from the rhizome of the medicinal plant Ligusticum c...
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BMC
2025-05-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-025-03420-z |
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| author | Junyan Wang Haowen Zhuang Chun Li Ruiqi Cai Hongshuo Shi Boxian Pang Zhijiang Guo Sang-Bing Ong Yifeng Nie Yingzhen Du Hao Zhou Xing Chang |
| author_facet | Junyan Wang Haowen Zhuang Chun Li Ruiqi Cai Hongshuo Shi Boxian Pang Zhijiang Guo Sang-Bing Ong Yifeng Nie Yingzhen Du Hao Zhou Xing Chang |
| author_sort | Junyan Wang |
| collection | DOAJ |
| description | Abstract Background Doxorubicin (DOX) demonstrates significant therapeutic and anticancer efficacy. Nevertheless, it demonstrates significant cardiotoxicity, resulting in permanent cardiac damage. Ligustrazine (LIG) is a bioactive alkaloid derived from the rhizome of the medicinal plant Ligusticum chuanxiong Hort. The alkaloid has exhibited cardioprotective properties. The therapeutic application of LIG is constrained by inadequate water solubility, fast breakdown, and low bioavailability. Nanoparticle drug delivery technologies effectively address these constraints by encapsulating LIG into nanocarriers, significantly enhancing its solubility and bioavailability, hence maximizing its therapeutic efficacy. Consequently, this study employed tetrahedral backbone nucleic acid molecules as LIG carriers. Furthermore, animal models and single-cell sequencing analyses were employed to forecast the mechanisms and targets of pertinent studies. A mouse model genetically modified for the piezo type mechanosensitive ion channel component 1 (PIEZO1), transmembrane BAX inhibitor motif containing 6 (TMBIM6), and prohibitin 2 (PHB2), along with an in vivo and in vitro model of DOX-induced cardiomyopathy (DIC), was established, and a gene-modified cellular system comprising upstream genes and downstream effector targets was constructed. The mechanism of LIG was validated by molecular biology and integrated pharmacology with the implementation of the LIG nano-drug loading method. Results LIG nano-delivery enhanced DOX-induced cardiac dysfunction and mitochondrial impairment by modulating the PHB2Ser91/Ser176 phosphorylation axis through PIEZO1-TMBIM6, and significantly suppressed cardiomyocyte pyroptosis resulting from mitochondrial homeostasis dysregulation. The findings indicate that LIG nano-delivery is a promising therapeutic approach for addressing DIC. Conclusion The PHB2Ser91/Ser176 phosphorylation axis regulated by PIEZO1-TMBIM6 is an important target for LIG nano-drug delivery systems to improve mitochondrial damage in DIC. Graphical abstract |
| format | Article |
| id | doaj-art-51118c0b00da4c62903b4c13e7ba7aa3 |
| institution | DOAJ |
| issn | 1477-3155 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-51118c0b00da4c62903b4c13e7ba7aa32025-08-20T03:16:32ZengBMCJournal of Nanobiotechnology1477-31552025-05-0123112410.1186/s12951-025-03420-zLigustrazine nano-drug delivery system ameliorates doxorubicin-mediated myocardial injury via piezo-type mechanosensitive ion channel component 1-prohibitin 2-mediated mitochondrial quality surveillanceJunyan Wang0Haowen Zhuang1Chun Li2Ruiqi Cai3Hongshuo Shi4Boxian Pang5Zhijiang Guo6Sang-Bing Ong7Yifeng Nie8Yingzhen Du9Hao Zhou10Xing Chang11State Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese MedicineState Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese MedicineState Key Laboratory of Traditional Chinese Medicine Syndrome, School of Pharmaceutical Sciences, Guangzhou University of Chinese MedicineLiaoning University of Traditional Chinese MedicineShuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineCAS Center for Excellence in Nanoscience, National Center for Nanoscience and TechnologyDepartment of Medicine & Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong (CUHK)Department of Medicine & Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong (CUHK)CAS Center for Excellence in Nanoscience, National Center for Nanoscience and TechnologyThe Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Medical School of Chinese PLASenior Department of Cardiology, The Sixth Medical Center of People’s Liberation Army General HospitalGuang’anmen Hospital, China Academy of Chinese Medical SciencesAbstract Background Doxorubicin (DOX) demonstrates significant therapeutic and anticancer efficacy. Nevertheless, it demonstrates significant cardiotoxicity, resulting in permanent cardiac damage. Ligustrazine (LIG) is a bioactive alkaloid derived from the rhizome of the medicinal plant Ligusticum chuanxiong Hort. The alkaloid has exhibited cardioprotective properties. The therapeutic application of LIG is constrained by inadequate water solubility, fast breakdown, and low bioavailability. Nanoparticle drug delivery technologies effectively address these constraints by encapsulating LIG into nanocarriers, significantly enhancing its solubility and bioavailability, hence maximizing its therapeutic efficacy. Consequently, this study employed tetrahedral backbone nucleic acid molecules as LIG carriers. Furthermore, animal models and single-cell sequencing analyses were employed to forecast the mechanisms and targets of pertinent studies. A mouse model genetically modified for the piezo type mechanosensitive ion channel component 1 (PIEZO1), transmembrane BAX inhibitor motif containing 6 (TMBIM6), and prohibitin 2 (PHB2), along with an in vivo and in vitro model of DOX-induced cardiomyopathy (DIC), was established, and a gene-modified cellular system comprising upstream genes and downstream effector targets was constructed. The mechanism of LIG was validated by molecular biology and integrated pharmacology with the implementation of the LIG nano-drug loading method. Results LIG nano-delivery enhanced DOX-induced cardiac dysfunction and mitochondrial impairment by modulating the PHB2Ser91/Ser176 phosphorylation axis through PIEZO1-TMBIM6, and significantly suppressed cardiomyocyte pyroptosis resulting from mitochondrial homeostasis dysregulation. The findings indicate that LIG nano-delivery is a promising therapeutic approach for addressing DIC. Conclusion The PHB2Ser91/Ser176 phosphorylation axis regulated by PIEZO1-TMBIM6 is an important target for LIG nano-drug delivery systems to improve mitochondrial damage in DIC. Graphical abstracthttps://doi.org/10.1186/s12951-025-03420-zLigustrazineNano-carrier drug deliveryDoxorubicin-induced myocardial injuryPiezo-type mechanosensitive ion channel component 1Prohibitin 2Mitochondrial quality control |
| spellingShingle | Junyan Wang Haowen Zhuang Chun Li Ruiqi Cai Hongshuo Shi Boxian Pang Zhijiang Guo Sang-Bing Ong Yifeng Nie Yingzhen Du Hao Zhou Xing Chang Ligustrazine nano-drug delivery system ameliorates doxorubicin-mediated myocardial injury via piezo-type mechanosensitive ion channel component 1-prohibitin 2-mediated mitochondrial quality surveillance Journal of Nanobiotechnology Ligustrazine Nano-carrier drug delivery Doxorubicin-induced myocardial injury Piezo-type mechanosensitive ion channel component 1 Prohibitin 2 Mitochondrial quality control |
| title | Ligustrazine nano-drug delivery system ameliorates doxorubicin-mediated myocardial injury via piezo-type mechanosensitive ion channel component 1-prohibitin 2-mediated mitochondrial quality surveillance |
| title_full | Ligustrazine nano-drug delivery system ameliorates doxorubicin-mediated myocardial injury via piezo-type mechanosensitive ion channel component 1-prohibitin 2-mediated mitochondrial quality surveillance |
| title_fullStr | Ligustrazine nano-drug delivery system ameliorates doxorubicin-mediated myocardial injury via piezo-type mechanosensitive ion channel component 1-prohibitin 2-mediated mitochondrial quality surveillance |
| title_full_unstemmed | Ligustrazine nano-drug delivery system ameliorates doxorubicin-mediated myocardial injury via piezo-type mechanosensitive ion channel component 1-prohibitin 2-mediated mitochondrial quality surveillance |
| title_short | Ligustrazine nano-drug delivery system ameliorates doxorubicin-mediated myocardial injury via piezo-type mechanosensitive ion channel component 1-prohibitin 2-mediated mitochondrial quality surveillance |
| title_sort | ligustrazine nano drug delivery system ameliorates doxorubicin mediated myocardial injury via piezo type mechanosensitive ion channel component 1 prohibitin 2 mediated mitochondrial quality surveillance |
| topic | Ligustrazine Nano-carrier drug delivery Doxorubicin-induced myocardial injury Piezo-type mechanosensitive ion channel component 1 Prohibitin 2 Mitochondrial quality control |
| url | https://doi.org/10.1186/s12951-025-03420-z |
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