Ligustrazine nano-drug delivery system ameliorates doxorubicin-mediated myocardial injury via piezo-type mechanosensitive ion channel component 1-prohibitin 2-mediated mitochondrial quality surveillance.

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.