Nanotuner targeting mitochondrial redox and iron homeostasis imbalance for the treatment of acute liver injury.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-16 eCollection Date: 2025-01-01 DOI:10.7150/thno.119357
Minghao Li, Qiwei Yang, Jie Gao, Xudong Liu, Jihua Shi, Wenzhi Guo, Yi Zhang, Qiwen Yu, Xinzhi Sun, Shuijun Zhang
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引用次数: 0

Abstract

Background: Acute liver injury (ALI), a highly perilous clinical condition triggered by diverse etiological factors, frequently progresses to acute liver failure with life-threatening consequences. However, due to the limited intervention time window for ALF, donor shortages, challenges in utilizing marginal grafts, surgical complexity and risks, and the high economic burden, developing novel therapeutic strategies targeting ALI-induced ALF has become imperative. Methods: Through transcriptome analysis, we determined that ferroptosis is a key driver in the pathogenesis of ALI. To combat hepatocyte ferroptosis, we designed a novel mitochondria-targeted nanotuner (CPTD) for regulating mitochondrial oxidative stress and iron homeostasis imbalance during ALI. This nanotuner features a cerium oxide (CeO₂) nanozyme core with a polydopamine (PDA) coating, functionalized with triphenylphosphonium (TPP) for mitochondrial targeting and deferoxamine (DFO) for iron chelation. In vitro and in vivo experiments evaluated CPTD's ability to target mitochondria and the labile iron pool (LIP). Results: The nanotuner demonstrates dual regulatory capacity by effectively accumulating in hepatic mitochondria to concurrently scavenge reactive oxygen species (ROS) and sequester labile iron ions, thereby rectifying mitochondrial oxidative stress and iron dyshomeostasis. Comprehensive evaluations across multiple ALI models, mainly including hepatic ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity, revealed that CPTD robustly inhibits ferroptosis, mitigates oxidative damage, attenuates inflammatory responses, and preserves hepatic function. Conclusions: Our findings establish this dual-targeting nanotuner as a promising therapeutic strategy for ALI, providing novel insights into mitochondrial redox and iron homeostasis modulation.

靶向线粒体氧化还原和铁稳态失衡的纳米调谐器治疗急性肝损伤。
背景:急性肝损伤(ALI)是一种由多种病因引起的高度危险的临床疾病,经常发展为急性肝衰竭,并导致危及生命的后果。然而,由于ALF的干预时间窗口有限,供体短缺,利用边缘移植物的挑战,手术的复杂性和风险,以及高昂的经济负担,开发针对ali诱导的ALF的新治疗策略已势在必行。方法:通过转录组分析,我们确定铁下垂是ALI发病的关键驱动因素。为了对抗肝细胞铁凋亡,我们设计了一种新的线粒体靶向纳米调谐器(CPTD)来调节ALI期间线粒体氧化应激和铁稳态失衡。该纳米调谐器具有氧化铈(ceo2)纳米酶核心和聚多巴胺(PDA)涂层,三苯基膦(TPP)功能化用于线粒体靶向和去铁胺(DFO)功能化用于铁螯合。体外和体内实验评估了CPTD靶向线粒体和不稳定铁池(LIP)的能力。结果:纳米调谐器具有双重调节能力,通过有效积聚在肝脏线粒体中,同时清除活性氧(ROS)和隔离不稳定的铁离子,从而纠正线粒体氧化应激和铁平衡失调。多种ALI模型的综合评价,主要包括肝缺血再灌注损伤和对乙酰氨基酚引起的肝毒性,显示CPTD强有力地抑制铁下沉,减轻氧化损伤,减轻炎症反应,并保持肝功能。结论:我们的研究结果表明,这种双靶向纳米调谐器是一种很有前景的ALI治疗策略,为线粒体氧化还原和铁稳态调节提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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