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Background <p>The C-C motif chemokine ligand 2 (CCL2)–C-C chemokine receptor type 2 (CCR2) signaling axis is critically involved in angiogenesis and cellular invasion; however, the therapeutic potential of its targeted blockade on alveolar echinococcosis (AE) remains largely unexplored. This study aimed to determine whether RS504393, a selective CCR2 antagonist, can inhibit the progression of AE by blocking the CCL2–CCR2 axis and modulating its downstream pathogenic mechanisms.</p> Methods <p>In this study, bioinformatics analysis of the GSE124362 dataset was combined with molecular docking simulations. Liver tissues from patients with AE and from <i>Echinococcus multilocularis</i>-infected mice were examined through histopathological and immunohistochemical staining methods. Pathological alterations and parasitic load were assessed by Western blot and quantitative real-time PCR (RT-PCR). An in vitro co-culture model involving <i>Echinococcus multilocularis</i> protoscolex-stimulated endothelial progenitor cells (EPCs), JS1 hepatic stellate cells (JS1) and RAW264.7 macrophages was established to evaluate angiogenesis, fibrogenic activity and macrophage polarization.</p> Results <p>Integrated bioinformatics and molecular docking analyses revealed CCL2–CCR2 overexpression and high-affinity binding during AE progression. Treatment with RS504393 significantly attenuated hepatic fibrosis, suppressed phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) pathway activation and reduced M2 macrophage polarization in central lesion tissue of <i>E. multilocularis</i>-infected mice . In vitro, RS504393 inhibited angiogenesis driven by EPCs, induced apoptosis in JS1 cells, and redirected macrophage polarization from the M2 towards a more anti-parasitic phenotype.</p> Conclusions <p>CCR2 blockade with RS504393 attenuates AE progression by inhibiting PI3K-AKT signaling, suppressing angiogenesis and inducing stellate cell apoptosis, collectively reducing hepatic fibrosis and parasitic burden. Our findings provide a mechanistic rationale for repurposing CCR2 antagonists as a novel host-directed therapeutic strategy for echinococcosis.</p> Graphical abstract <p></p>

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Blockade of the CCL2–CCR2 axis attenuates fibrosis and parasite load in vesicular echinococcosis by inhibiting the PI3K-AKT pathway that regulates angiogenesis and hepatic stellate cell apoptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月29日

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  • Bin Fan,
  • Yuyu Ma,
  • Menggen Meng,
  • Jiahui Chen,
  • Xinwei Qi,
  • Yuqin Sun,
  • Xuan Zhou,
  • Haonan Wang,
  • Xiumin Ma,
  • Liang Wang

摘要

Background

The C-C motif chemokine ligand 2 (CCL2)–C-C chemokine receptor type 2 (CCR2) signaling axis is critically involved in angiogenesis and cellular invasion; however, the therapeutic potential of its targeted blockade on alveolar echinococcosis (AE) remains largely unexplored. This study aimed to determine whether RS504393, a selective CCR2 antagonist, can inhibit the progression of AE by blocking the CCL2–CCR2 axis and modulating its downstream pathogenic mechanisms.

Methods

In this study, bioinformatics analysis of the GSE124362 dataset was combined with molecular docking simulations. Liver tissues from patients with AE and from Echinococcus multilocularis-infected mice were examined through histopathological and immunohistochemical staining methods. Pathological alterations and parasitic load were assessed by Western blot and quantitative real-time PCR (RT-PCR). An in vitro co-culture model involving Echinococcus multilocularis protoscolex-stimulated endothelial progenitor cells (EPCs), JS1 hepatic stellate cells (JS1) and RAW264.7 macrophages was established to evaluate angiogenesis, fibrogenic activity and macrophage polarization.

Results

Integrated bioinformatics and molecular docking analyses revealed CCL2–CCR2 overexpression and high-affinity binding during AE progression. Treatment with RS504393 significantly attenuated hepatic fibrosis, suppressed phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) pathway activation and reduced M2 macrophage polarization in central lesion tissue of E. multilocularis-infected mice . In vitro, RS504393 inhibited angiogenesis driven by EPCs, induced apoptosis in JS1 cells, and redirected macrophage polarization from the M2 towards a more anti-parasitic phenotype.

Conclusions

CCR2 blockade with RS504393 attenuates AE progression by inhibiting PI3K-AKT signaling, suppressing angiogenesis and inducing stellate cell apoptosis, collectively reducing hepatic fibrosis and parasitic burden. Our findings provide a mechanistic rationale for repurposing CCR2 antagonists as a novel host-directed therapeutic strategy for echinococcosis.

Graphical abstract