Liraglutide attenuates doxorubicin-induced cardiomyocyte ferroptosis via DHHC7-mediated STAT3 palmitoylation

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences Pub Date : 2025-08-15 DOI:10.1016/j.lfs.2025.123912

Ge Gao , Cheng Shen , Manman Wang , Cuiling Ji , Fang Fang , Yu Jiang , Lihong Shi , Wenqiang Chen , Jinguo Zhang

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Abstract

Aims

This study aimed to investigate liraglutide's protective effects against doxorubicin (DOX)-induced cardiotoxicity and ferroptosis, and to elucidate the underlying mechanisms involving signal transducer and activator of transcription 3 (STAT3) signaling and its post-translational palmitoylation.

Materials and methods

In vivo models of chronic DOX-induced cardiotoxicity were established in male C57BL/6 J mice. Cardiac function was assessed via echocardiography. Ferroptosis markers such as malondialdehyde (MDA), glutathione (GSH), iron (Fe²⁺), reactive oxygen species (ROS), mitochondrial ultrastructure) were evaluated in myocardial tissue and H9c2 cardiomyocytes. Bioinformatics analysis of the GSE193861 dataset identified ferroptosis-related differentially expressed genes. STAT3 and DHHC7 were modulated using short hairpin RNA (shRNA) knockdown and cardiomyocyte-specific adeno-associated virus 9 (AAV9)-mediated overexpression. Molecular interactions were assessed via co-immunoprecipitation, acyl-biotin exchange assays, and western blotting.

Key findings

Liraglutide administration significantly attenuated DOX-induced cardiac dysfunction and cardiomyocyte ferroptosis. Bioinformatics identified STAT3 as a central regulator, with liraglutide restoring DOX-impaired STAT3 phosphorylation and nuclear translocation, thereby enhancing transcription of the anti-ferroptotic enzyme glutathione peroxidase 4 (GPX4). STAT3 knockdown abolished liraglutide's protection. Mechanistically, liraglutide upregulated the palmitoyltransferase DHHC7, rescuing DOX-suppressed STAT3 palmitoylation. DHHC7 knockdown and palmitoylation inhibition abrogated liraglutide-mediated STAT3 phosphorylation and anti-ferroptotic effects. Crucially, cardiomyocyte-specific DHHC7 overexpression replicated liraglutide's cardioprotection, mitigating DOX-induced ferroptosis and dysfunction.

Significance

We demonstrate a novel cardioprotective axis wherein liraglutide enhances DHHC7-dependent STAT3 palmitoylation, facilitating its phosphorylation, nuclear translocation, and transcriptional activation of GPX4 to suppress ferroptosis. This study provides the first evidence that DHHC7-mediated STAT3 palmitoylation is essential for liraglutide's efficacy, identifying a promising therapeutic target for DOX cardiotoxicity.

Abstract Image

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利拉鲁肽通过dhhc7介导的STAT3棕榈酰化减轻阿霉素诱导的心肌细胞铁下垂

目的研究利拉鲁肽对多柔比星（DOX）诱导的心脏毒性和铁死亡的保护作用，并阐明信号转导和转录3激活因子（STAT3）信号及其翻译后棕榈酰化的潜在机制。材料与方法建立雄性C57BL/ 6j小鼠慢性dox致心脏毒性体内模型。通过超声心动图评估心功能。检测心肌组织和H9c2心肌细胞中丙二醛（MDA）、谷胱甘肽（GSH）、铁（Fe2+）、活性氧（ROS）、线粒体超微结构等凋亡标志物。对GSE193861数据集进行生物信息学分析，鉴定出与铁枯病相关的差异表达基因。STAT3和DHHC7通过短发夹RNA （shRNA）敲低和心肌细胞特异性腺相关病毒9 （AAV9）介导的过表达进行调节。分子相互作用通过免疫共沉淀、酰基生物素交换测定和免疫印迹法进行评估。利拉鲁肽可显著减轻dox诱导的心功能障碍和心肌细胞下垂。生物信息学鉴定出STAT3是一个中心调节因子，利拉鲁肽恢复dox损伤的STAT3磷酸化和核易位，从而增强抗铁溶酶谷胱甘肽过氧化物酶4 （GPX4）的转录。STAT3敲低可消除利拉鲁肽的保护作用。在机制上，利拉鲁肽上调棕榈酰转移酶DHHC7，挽救dox抑制的STAT3棕榈酰化。DHHC7的敲除和棕榈酰化抑制消除了利拉鲁肽介导的STAT3磷酸化和抗铁沉作用。至关重要的是，心肌细胞特异性DHHC7过表达复制利拉鲁肽的心脏保护作用，减轻dox诱导的铁下沉和功能障碍。我们证明了一种新的心脏保护轴，其中利拉鲁肽增强dhhc7依赖性STAT3棕榈酰化，促进其磷酸化，核易位和GPX4的转录激活，以抑制铁凋亡。这项研究首次证明dhhc7介导的STAT3棕榈酰化对利拉鲁肽的疗效至关重要，并确定了一个有希望的治疗DOX心脏毒性的靶点。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.