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<p>During chronic liver injury, hepatocytes promote liver fibrosis by interacting with hepatic stellate cells (HSCs). However, the key intracellular factors that regulate intercellular communication in hepatocytes remain poorly understood. Although cluster of differentiation 146 (CD146) is predominantly recognized as an endothelial cell marker, our study found that CD146 is substantially upregulated in hepatocytes under fibrotic stress and may play an independent role in transcellular signaling. This study aimed to elucidate the functions and underlying mechanisms of hepatocyte CD146 in liver fibrosis. We evaluated CD146 expression in liver tissues and serum soluble CD146 (sCD146) levels in patients with liver fibrosis and mouse models. Hepatocyte-specific CD146-overexpressing mice (AAV8-CD146) were generated and fed either a normal chow diet (NCD) or a high-fat diet (HFD); hepatocyte-specific CD146 knockout mice (CD146<sup>Alb−Cre</sup>) were subjected to carbon tetrachloride (CCl₄)-induced fibrosis. Comprehensive molecular, biochemical, and histological analyses were performed to systematically assess the role of CD146 in the initiation and progression of liver fibrosis. A co-culture system of hepatocytes and HSCs was also established to investigate the paracrine regulatory effects of CD146 on HSCs. The levels of sCD146 were positively correlated with the progression and severity of chronic liver disease. A diagnostic model incorporating sCD146 and other serological markers showed improved diagnostic performance for decompensated cirrhosis. Compared with healthy controls, hepatocyte CD146 expression was markedly upregulated in liver tissues from patients with cirrhosis and fibrotic mice. Under HFD conditions, hepatocyte-specific CD146 overexpression exacerbated hepatic inflammation and fibrosis in mice, whereas hepatocyte-specific CD146 deletion significantly attenuated CCl₄-induced liver fibrosis. Transforming growth factor-β1 (TGF-β1) induced CD146 upregulation in hepatocytes and increased the release of sCD146. Released sCD146 bound to integrin αvβ1 on the surface of HSCs, activated the p38 mitogen-activated protein kinase (p38 MAPK) pathway, and promoted HSC activation and type I collagen production. These findings identify hepatocyte-derived CD146/sCD146 as a TGF-β1-inducible mediator of hepatocyte–HSC communication that promotes liver fibrosis through the CD146/sCD146–integrin αvβ1–p38 MAPK signaling axis. They also support serum sCD146 as a potential non-invasive biomarker for advanced chronic liver disease.</p> Graphical Abstract <p></p>

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Hepatocyte CD146 and soluble CD146 promote hepatic stellate cell activation via the integrin αvβ1–p38 MAPK signaling axis to drive liver fibrosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Bingqing Yang,
  • Chenxue Hou,
  • Rongcai Ye,
  • Jingya Yin,
  • Yixue Shu,
  • Xiaoyan Cheng,
  • Lei Sun,
  • Kun Yang,
  • Quan Sun,
  • Yue Li,
  • Wen Xie,
  • Qi Wang

摘要

During chronic liver injury, hepatocytes promote liver fibrosis by interacting with hepatic stellate cells (HSCs). However, the key intracellular factors that regulate intercellular communication in hepatocytes remain poorly understood. Although cluster of differentiation 146 (CD146) is predominantly recognized as an endothelial cell marker, our study found that CD146 is substantially upregulated in hepatocytes under fibrotic stress and may play an independent role in transcellular signaling. This study aimed to elucidate the functions and underlying mechanisms of hepatocyte CD146 in liver fibrosis. We evaluated CD146 expression in liver tissues and serum soluble CD146 (sCD146) levels in patients with liver fibrosis and mouse models. Hepatocyte-specific CD146-overexpressing mice (AAV8-CD146) were generated and fed either a normal chow diet (NCD) or a high-fat diet (HFD); hepatocyte-specific CD146 knockout mice (CD146Alb−Cre) were subjected to carbon tetrachloride (CCl₄)-induced fibrosis. Comprehensive molecular, biochemical, and histological analyses were performed to systematically assess the role of CD146 in the initiation and progression of liver fibrosis. A co-culture system of hepatocytes and HSCs was also established to investigate the paracrine regulatory effects of CD146 on HSCs. The levels of sCD146 were positively correlated with the progression and severity of chronic liver disease. A diagnostic model incorporating sCD146 and other serological markers showed improved diagnostic performance for decompensated cirrhosis. Compared with healthy controls, hepatocyte CD146 expression was markedly upregulated in liver tissues from patients with cirrhosis and fibrotic mice. Under HFD conditions, hepatocyte-specific CD146 overexpression exacerbated hepatic inflammation and fibrosis in mice, whereas hepatocyte-specific CD146 deletion significantly attenuated CCl₄-induced liver fibrosis. Transforming growth factor-β1 (TGF-β1) induced CD146 upregulation in hepatocytes and increased the release of sCD146. Released sCD146 bound to integrin αvβ1 on the surface of HSCs, activated the p38 mitogen-activated protein kinase (p38 MAPK) pathway, and promoted HSC activation and type I collagen production. These findings identify hepatocyte-derived CD146/sCD146 as a TGF-β1-inducible mediator of hepatocyte–HSC communication that promotes liver fibrosis through the CD146/sCD146–integrin αvβ1–p38 MAPK signaling axis. They also support serum sCD146 as a potential non-invasive biomarker for advanced chronic liver disease.

Graphical Abstract