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<p>Liver cirrhosis is a major manifestation of end-stage liver disease, and its pathogenesis and therapeutic strategies are key areas of research in hepatology. The limitations of traditional treatments have prompted researchers to turn their attention to immune regulatory mechanisms, among which macrophage polarization regulation has become the most promising therapeutic target. In this paper, the central role of macrophages in the development of cirrhosis and their regulatory network are described, with a focus on the critical role of M1/M2 polarization balance in the process of liver fibrosis. The dynamic polarization process of macrophages in the hepatic microenvironment is finely regulated: the M1 type activates hepatic stellate cells through proinflammatory factors, such as TNF-α and IL-1β, and promotes ECM deposition, whereas the M2 type participates in tissue repair and fibrosis reversal through the secretion of anti-inflammatory factors, such as IL-10 and TGF-β, and MMPs. On the basis of this mechanism, three main classes of intervention strategies have been developed: first, immunomodulatory therapies, including CCR2/CCR5 antagonists and cytokine modulation; second, small molecule-targeted drugs, such as JNK inhibitors and natural active ingredients; and third, cutting-edge biotherapeutic technologies, including genetically engineered macrophage and stem cell combination therapies. Importantly, the modulation of macrophage polarization through the targeted delivery of siRNA via nanocarriers or the induction of M2-type polarization using mesenchymal stem cells can significantly reduce the degree of fibrosis. However, these strategies still face challenges in translational applications, such as dynamic changes in the polarization state and insufficient target specificity. In the future, we need to analyse the heterogeneity of macrophages with the help of new technologies such as single-cell sequencing, develop spatiotemporal specific regulation schemes, and explore multitarget synergistic therapeutic strategies. The breakthroughs in this field will not only revolutionize the treatment mode of liver cirrhosis but also provide important reference information for the treatment of fibrotic diseases in other organs, marking the shift in liver disease treatment from traditional symptomatic treatment to a new era of precise immunomodulation. In conclusion, the targeted regulation of macrophage polarization has demonstrated significant therapeutic potential for liver cirrhosis, with its clinical application poised to revolutionize the treatment paradigm for liver diseases. Future studies should focus on leveraging single-cell technologies to elucidate macrophage heterogeneity and develop precision delivery strategies targeting macrophages, thereby advancing the clinical translation of personalized combination therapies based on macrophage modulation.</p>

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New perspectives in the treatment of liver cirrhosis: targeting macrophage regulatory mechanisms

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月31日

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  • Shihao Zheng,
  • Size Li,
  • Qiuyue Wang,
  • Xiaobin Zao,
  • Xiaoke Li,
  • Wenying Qi,
  • Fane Cheng,
  • Yuexiao Geng,
  • Peng Zhang,
  • Xinyue Shi,
  • Yongan Ye

摘要

Liver cirrhosis is a major manifestation of end-stage liver disease, and its pathogenesis and therapeutic strategies are key areas of research in hepatology. The limitations of traditional treatments have prompted researchers to turn their attention to immune regulatory mechanisms, among which macrophage polarization regulation has become the most promising therapeutic target. In this paper, the central role of macrophages in the development of cirrhosis and their regulatory network are described, with a focus on the critical role of M1/M2 polarization balance in the process of liver fibrosis. The dynamic polarization process of macrophages in the hepatic microenvironment is finely regulated: the M1 type activates hepatic stellate cells through proinflammatory factors, such as TNF-α and IL-1β, and promotes ECM deposition, whereas the M2 type participates in tissue repair and fibrosis reversal through the secretion of anti-inflammatory factors, such as IL-10 and TGF-β, and MMPs. On the basis of this mechanism, three main classes of intervention strategies have been developed: first, immunomodulatory therapies, including CCR2/CCR5 antagonists and cytokine modulation; second, small molecule-targeted drugs, such as JNK inhibitors and natural active ingredients; and third, cutting-edge biotherapeutic technologies, including genetically engineered macrophage and stem cell combination therapies. Importantly, the modulation of macrophage polarization through the targeted delivery of siRNA via nanocarriers or the induction of M2-type polarization using mesenchymal stem cells can significantly reduce the degree of fibrosis. However, these strategies still face challenges in translational applications, such as dynamic changes in the polarization state and insufficient target specificity. In the future, we need to analyse the heterogeneity of macrophages with the help of new technologies such as single-cell sequencing, develop spatiotemporal specific regulation schemes, and explore multitarget synergistic therapeutic strategies. The breakthroughs in this field will not only revolutionize the treatment mode of liver cirrhosis but also provide important reference information for the treatment of fibrotic diseases in other organs, marking the shift in liver disease treatment from traditional symptomatic treatment to a new era of precise immunomodulation. In conclusion, the targeted regulation of macrophage polarization has demonstrated significant therapeutic potential for liver cirrhosis, with its clinical application poised to revolutionize the treatment paradigm for liver diseases. Future studies should focus on leveraging single-cell technologies to elucidate macrophage heterogeneity and develop precision delivery strategies targeting macrophages, thereby advancing the clinical translation of personalized combination therapies based on macrophage modulation.