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

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

Abstract

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.