Macrophage-derived CCL1 targets CCR8 receptor in hepatic stellate cells to promote liver fibrosis through JAk/STAT pathway

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY Biochemical pharmacology Pub Date : 2025-07-01 Epub Date: 2025-03-21 DOI:10.1016/j.bcp.2025.116884

Shaoxi Diao , Liangyun Li , Jintong Zhang , Minglu Ji , Lijiao Sun , Wenwen Shen , Shuai Wu , Zixiang Chen , Cheng Huang , Jun Li

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Abstract

Liver fibrosis is caused by liver injury resulting from the wound healing response. According to recent research, the primary factor responsible for liver fibrosis is the activation of hepatic stellate cells (HSCs). C-C motif chemokine ligand 1 (CCL1) is one of several chemokine genes clustered on chromosome 17, which is involved in immune regulation and inflammatory processes. However, the role of CCL1 in liver fibrosis has not been reported. We found that CCL1 secreted by macrophages can target and activate the receptor protein C-C motif chemokine receptor 8 (CCR8) of HSCs, accelerating liver fibrosis progression by activating the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway. This suggested that the CCL1-mediated regulation of CCR8 is an important event in liver fibrosis progression. In conclusion, this study identified a novel signalling axis, the CCL1/CCR8/JAK/STAT pathway, which regulates the activation and apoptosis of HSCs, thus providing a novel therapeutic strategy for liver fibrosis.

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巨噬细胞源性CCL1靶向肝星状细胞CCR8受体，通过JAk/STAT通路促进肝纤维化。

肝纤维化是由肝损伤引起的伤口愈合反应。根据最近的研究，导致肝纤维化的主要因素是肝星状细胞（hsc）的活化。C-C基序趋化因子配体1 （CCL1）是聚集在17号染色体上的几个趋化因子基因之一，参与免疫调节和炎症过程。然而，CCL1在肝纤维化中的作用尚未见报道。我们发现巨噬细胞分泌的CCL1可以靶向并激活hsc的受体蛋白C-C基序列趋化因子受体8 (CCR8)，通过激活Janus激酶(JAK)/信号换能器和转录激活因子（STAT）信号通路加速肝纤维化进程。这表明ccl1介导的CCR8调控是肝纤维化进展中的一个重要事件。综上所述，本研究发现了一种新的信号轴CCL1/CCR8/JAK/STAT通路，该通路调节hsc的活化和凋亡，从而为肝纤维化提供了一种新的治疗策略。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.