The Nrf Family and Its Cardioprotective Potential: Mechanisms, Functions, and Therapeutic Perspectives.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL

Drug Design, Development and Therapy Pub Date : 2025-09-15 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S547848

Chao Cui, Hui Song, Yifeng Guo, Jingfei Shi, Biao Geng, Gang Wang

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引用次数: 0

Abstract

This review systematically elucidates the molecular mechanisms and therapeutic potential of nuclear factor erythroid 2-related factor (Nrf) family members in the cardiovascular system. As critical components of the CNC-bZIP transcription factor family, the Nrf family (including Nrf-2/NFE2L2, Nrf-1/NFE2L1, and Nrf-3/NFE2L3) orchestrates antioxidant response element (ARE)-dependent gene expression networks, playing pivotal roles in maintaining redox homeostasis, modulating inflammatory responses, improving mitochondrial function, and regulating programmed cell death (apoptosis, autophagy, and pyroptosis). Clinical data have demonstrated that in patients with myocardial infarction, the expression of Nrf-3 gene is significantly upregulated in myocardial cells within the infarcted area. Its high expression is associated with increased in-hospital mortality during the acute phase and accelerated progression of ventricular remodeling. Knockout of the Nrf-3 gene can reduce the acute-phase mortality of myocardial infarction, improve ventricular remodeling, and enhance cardiac function. Additionally, a crossover trial involving 19 participants showed that after 2 months of administration of olive oil by-product pâté tablets, the plasma Nrf-2 level in the subjects increased by 88.9% with concurrent improvement in cardiovascular risk factors. Collectively, these findings confirm the impact of the Nrf family on cardiovascular prognosis and its potential for intervention. Furthermore, we comprehensively analyze the regulatory functions of Nrf members in major cardiovascular pathologies, including myocardial ischemia-reperfusion injury, atherosclerotic plaque formation/stabilization, and heart failure progression. Based on recent advances, we also discuss innovative therapeutic strategies targeting the Nrf pathway, encompassing pharmacological activators, gene/epigenetic therapies, combinatorial approaches, and lifestyle interventions, thereby providing a theoretical framework and novel perspectives for the precision medicine of cardiovascular diseases.

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Nrf家族及其心脏保护潜能：机制、功能和治疗前景。

本文综述了核因子-红系2相关因子（Nrf）家族成员在心血管系统中的分子机制及其治疗潜力。作为nc - bzip转录因子家族的关键组成部分，Nrf家族（包括Nrf-2/NFE2L2、Nrf-1/NFE2L1和Nrf-3/NFE2L3）协调抗氧化反应元件（ARE）依赖的基因表达网络，在维持氧化还原稳态、调节炎症反应、改善线粒体功能和调节程序性细胞死亡（凋亡、自噬和焦亡）方面发挥关键作用。临床资料表明，在心肌梗死患者中，梗死区心肌细胞中Nrf-3基因表达显著上调。它的高表达与急性期住院死亡率增加和心室重构的加速进展有关。敲除Nrf-3基因可降低心肌梗死急性期死亡率，改善心室重构，增强心功能。此外，一项涉及19名参与者的交叉试验显示，在服用橄榄油副产品p糖片2个月后，受试者的血浆Nrf-2水平增加了88.9%，同时心血管危险因素得到改善。总的来说，这些发现证实了Nrf家族对心血管预后的影响及其干预的潜力。此外，我们全面分析了Nrf成员在主要心血管疾病中的调节功能，包括心肌缺血-再灌注损伤、动脉粥样硬化斑块形成/稳定和心力衰竭进展。基于最新进展，我们还讨论了针对Nrf通路的创新治疗策略，包括药物激活剂，基因/表观遗传疗法，组合方法和生活方式干预，从而为心血管疾病的精准医学提供理论框架和新视角。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.