Juglone promotes spinal cord injury recovery by suppressing pyroptosis and necroptosis through FOS/USP53/ubiquitination

IF 8.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-09-27 DOI:10.1016/j.phymed.2025.157341

Lu Chen , Yong Chang , Shiji Zhang , Zihang Wang , Haoran Liu , Hongliang Wang , Lusen Shi , Na Li , Shiqing Feng

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引用次数: 0

Abstract

Background

Spinal cord injury (SCI) is a central nervous system (CNS) disorder, and it often results in severe neuronal damage. However, there are still no effective treatments for SCI, so it is important to explore and identify effective therapeutic strategies. As a natural compound extracted from walnuts, juglone has been previously reported to exhibit various biological activities, including anti-tumor and anti-inflammatory effects, but the effects on central nerve system are still blank.

Purpose

This study aims to evaluate the therapeutic effects of juglone in spinal cord injury and elucidate its molecular mechanisms in neuroprotection.

Study design

In vitro neuronal OGD/R experiments and in vivo spinal cord injury model experiments were employed to investigate the neuroprotective effects of juglone on neurons.

Methods

Neuronal OGD/R models and spinal cord injury models were used to detect the neuroprotective effect of juglone. Immunofluorescence, Western Blot and ELISA were employed to investigate the effects of juglone on necroptosis and pyroptosis of neurons. RNA-Seq analysis, immunoprecipitation, Western Blot, qRT-PCR, immunofluorescence and ChIP-qPCR were utilized to elucidate the molecular mechanism of its neuroprotective effect.

Results

Juglone can inhibit necroptosis and pyroptosis both in vivo and in vitro, thereby exerting neuroprotective effects. Mechanistically, we identify a novel FOS/USP53 signaling axis, in which juglone suppresses the expression of FOS that directly regulates the deubiquitinating enzyme USP53. Reduced FOS expression leads to the downregulation of USP53, thereby promoting the ubiquitination and degradation of MLKL and GSDMD. This cascade ultimately alleviates necroptosis and pyroptosis in injured neurons.

Conclusion

Juglone is a potential neuroprotective drug that exerts its effect by inhibiting necroptosis and pyroptosis through the FOS/USP53/ubiquitination signaling axis. These findings provide a novel potential drug target for the treatment of spinal cord injury.

Abstract Image

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Juglone通过FOS/USP53/泛素化抑制焦亡和坏死，促进脊髓损伤恢复

脊髓损伤（SCI）是一种中枢神经系统（CNS）疾病，常导致严重的神经元损伤。然而，目前仍没有有效的治疗脊髓损伤的方法，因此探索和确定有效的治疗策略是很重要的。核桃酚作为一种从核桃中提取的天然化合物，具有抗肿瘤、抗炎等多种生物活性，但对中枢神经系统的作用仍是空白。目的评价核桃醌对脊髓损伤的治疗作用，探讨其神经保护的分子机制。研究设计采用体外神经元OGD/R实验和体内脊髓损伤模型实验研究核桃醌对神经元的神经保护作用。方法采用神经OGD/R模型和脊髓损伤模型检测核桃酮的神经保护作用。采用免疫荧光法、Western Blot法和ELISA法观察核桃醌对大鼠神经元坏死和焦亡的影响。利用RNA-Seq分析、免疫沉淀、Western Blot、qRT-PCR、免疫荧光和ChIP-qPCR等方法对其神经保护作用的分子机制进行了研究。结果核桃酮在体内和体外均能抑制坏死性下垂和焦下垂，从而发挥神经保护作用。在机制上，我们发现了一个新的FOS/USP53信号轴，其中核桃酮抑制直接调节去泛素化酶USP53的FOS的表达。FOS表达降低导致USP53下调，从而促进MLKL和GSDMD的泛素化和降解。这种级联最终减轻了损伤神经元的坏死和焦亡。结论核桃酮是一种潜在的神经保护药物，通过FOS/USP53/泛素化信号轴发挥其抑制坏死性和焦亡的作用。这些发现为脊髓损伤的治疗提供了一个新的潜在药物靶点。

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

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.