Journal Article

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

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

2025

Overview

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/PHB2 CKO mice and DUSP1 transgenic mice (SIRT5/DUSP1/PHB2 TG ). 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/PHB2 CKO mice, these remained unaffected in SIRT5/DUSP1/PHB2 TG 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

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adverse and side effects / Alkaloids / Animal models / Animals / Anthracycline / Autophagy / Bioavailability / Bioinformatics / Biotechnology / Cancer therapies / Cardiomyocytes / Cardiotonic Agents - pharmacology / Cardiotoxicity / Cardiotoxicity - drug therapy / Cardiotoxicity - metabolism / Cardiotoxicity - prevention & control / Cardiovascular diseases / Cell death / Chemistry / Chemistry and Materials Science / Chemotherapy / Complications and side effects / Confocal microscopy / Data analysis / Datasets / Doxorubicin / Doxorubicin - adverse effects / Doxorubicin - toxicity / Doxorubicin-induced cardiotoxicity / Drug delivery / Drug Delivery Systems / Drugs / DUSP1 / Echocardiography / Health aspects / Heart diseases / Heart failure / Herbal medicine / Homeostasis / Laboratory animals / Ligustrazine drug delivery technology / Male / Medicinal plants / Metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / Mitochondrial DNA / Mitochondrial quality homeostasis / Molecular Medicine / Morphology / Myocytes, Cardiac - drug effects / Myocytes, Cardiac - metabolism / Nanoparticles / Nanoparticles - chemistry / Nanotechnology / Pharmaceutical research / Phosphorylation / Prevention / Pyrazines - chemistry / Pyrazines - pharmacology / Scanning microscopy / SIRT5 / Sirtuins - genetics / Sirtuins - metabolism / Therapeutic applications / Transcriptomics / Transgenic animals / Transgenic mice / Vehicles