Sakuranetin Prevents Acetaminophen-Induced Liver Injury via Nrf2-Induced Inhibition of Hepatocyte Ferroptosis.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2025-01-10 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S497817

Zhida Long, Xiao Yu, Shijia Li, Nuo Cheng, Chenglong Huo, Xuewen Zhang, Shuai Wang

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Abstract

Introduction: Oxidative stress is an important cause of acetaminophen (APAP)-induced liver injury (AILI). Sakuranetin (Sak) is an antitoxin from the cherry flavonoid plant with good antioxidant effects. However, whether sakuranetine has a protective effect on APAP-induced liver injury is not clear.

Methods: Mouse and HepG2 cell models of APAP injury were used to investigate the effect of sakuranetin on AILI and its mechanism. Serum transaminase levels, histological changes, inflammatory mediators, oxidative stress, ferroptosis-related markers and Nrf2 signaling pathway proteins were analyzed.

Results: Sakuranetin significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as inflammatory factor; increased HepG2 activity and decreased cell death; inhibited ROS production, increased glutathione (GSH) content, expression of Glutathione Peroxidase 4 (GPX4) and Solute Carrier Family 7 Member 11 (SLC7A11), and decreased malondialdehyde and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) expression in mice and HepG2 cells after APAP treatment. Further analysis showed that sakuranetin induced the activation of the NFE2 Like BZIP Transcription Factor 2 (Nrf2) signaling pathway in liver tissue and HepG2 cells and promoted the nuclear translocation of Nrf2. Moreover, the hepatoprotective effect of sakuranetin and its inhibitory effect on ferroptosis were significantly attenuated by the Nrf2 inhibitor ML385.

Conclusion: Sakuranetin alleviates AILI by activating the Nrf2 signaling pathway and inhibiting ferroptosis, and sakuranetin may be a potential therapeutic agent for the treatment of AILI.

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樱素通过nrf2诱导的肝细胞凋亡抑制对乙酰氨基酚诱导的肝损伤。

氧化应激是对乙酰氨基酚（APAP）诱导的肝损伤（AILI）的重要原因。Sakuranetin （Sak）是从樱桃类黄酮植物中提取的一种抗毒素，具有良好的抗氧化作用。然而，樱碱是否对apap诱导的肝损伤具有保护作用尚不清楚。方法：采用APAP损伤小鼠模型和HepG2细胞模型，研究樱素对AILI的影响及其机制。分析血清转氨酶水平、组织学变化、炎症介质、氧化应激、铁中毒相关标志物和Nrf2信号通路蛋白。结果：樱素显著降低血清谷丙转氨酶（ALT）、天冬氨酸转氨酶（AST）及炎症因子；提高HepG2活性，降低细胞死亡；APAP抑制小鼠和HepG2细胞ROS生成，增加谷胱甘肽（GSH）含量，增加谷胱甘肽过氧化物酶4 （GPX4）和溶质载体家族7成员11 （SLC7A11）的表达，降低丙二醛和酰基辅酶a合成酶长链成员4 （ACSL4）的表达。进一步分析发现，樱素可激活肝组织和HepG2细胞中NFE2 Like BZIP Transcription Factor 2 （Nrf2）信号通路，促进Nrf2的核易位。此外，Nrf2抑制剂ML385显著减弱了樱花素的肝保护作用和对铁下垂的抑制作用。结论：樱素可通过激活Nrf2信号通路，抑制铁凋亡来缓解AILI，可能是治疗AILI的潜在药物。

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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索莱宝

MDA kit

索莱宝

GSH kit

阿拉丁

acetaminophen

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.