化合物J27通过靶向JNK缓解高脂肪饮食诱导的代谢功能障碍相关的脂肪变性肝病

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-04-05 DOI:10.1016/j.intimp.2025.114570

Jiaxi Ye , Weiwei Zhu , Yaqian Cui , Qianhui Zhang , Yongqiang Xiong , Leiming Jin , Ao Wang , Mengsha Lin , Hui Dong , Guang Liang , Xiang Hu , Wu Luo

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引用次数: 0

摘要

背景：代谢功能障碍相关脂肪变性肝病（MASLD）是最典型的肝脏疾病。作为MAPK家族的成员，cjun - n-末端激酶（JNK）在MASLD的发病机制中起着至关重要的作用。一种小分子化合物J27已通过抑制JNK磷酸化显示出强大的抗炎作用，但其治疗MASLD的潜力尚不清楚。方法采用高脂饮食（HFD）诱导的MASLD小鼠模型，观察J27的作用。通过组织染色、生化分析和其他方法评估病理变化。在体外，在棕榈酸刺激下，J27对巨噬细胞、肝细胞和共培养系统的影响进行了测试。结果j27通过靶向JNK，在体内和体外均能显著降低hfd诱导的肝脂肪变性、肝损伤、胰岛素抵抗和炎症反应。一方面，J27阻断JNK活化，从而改善胰岛素信号通路，缓解肝细胞代谢功能障碍。另一方面，J27通过破坏JNK/NF-κB轴抑制巨噬细胞的炎症反应，通过细胞间通讯进一步减轻肝细胞损伤。结论sj27作为一种有效的JNK抑制剂，可显著降低hfd诱导的MASLD，提示sj27是一种有前景的治疗该病的候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Compound J27 alleviates high-fat diet-induced metabolic dysfunction-associated steatotic liver disease by targeting JNK

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Compound J27 alleviates high-fat diet-induced metabolic dysfunction-associated steatotic liver disease by targeting JNK

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most characteristic form of liver diseases. As the member of MAPK family, the cJun-N-terminal-kinase (JNK) plays a crucial role in the pathogenesis of MASLD. A small molecule compound, J27, has demonstrated strong anti-inflammatory effects by inhibiting JNK phosphorylation, but its therapeutic potential in MASLD remains unclear.

Methods

To evaluate the effect of J27, we used a high-fat diet (HFD)-induced MASLD mouse model with or without J27 treatment. Pathological changes were assessed through tissue staining, biochemical analysis, and other assays. In vitro, J27's effects were tested on macrophages, hepatocytes, and co-culture systems under palmitic acid stimulation.

Results

J27 significantly reduced HFD-induced hepatic steatosis, liver injury, insulin resistance, and inflammatory responses by targeting JNK both in vivo and in vitro. On one hand, J27 blocked JNK activation, thereby improving insulin signaling and alleviating metabolic dysfunction in hepatocytes. On the other hand, J27 inhibited the inflammatory response in macrophages by disrupting the JNK/NF-κB axis, which, through cell-cell communication, further reduced hepatocyte injury.

Conclusions

J27, as a potent JNK inhibitor, markedly reduced HFD-induced MASLD, suggesting it as a promising therapeutic candidate for this disease.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.