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Background <p>Hepatocellular carcinoma (HCC) involves abnormal alterations in cellular homeostasis regulation and molecular crosstalk between hepatic stellate cells (HSCs) and hepatocytes, and the underlying mechanisms are highly complex. Recent evidence suggests that HSCs exhibit obvious plasticity, are activated by stress stimuli such as carcinogens, and participate in HCC occurrence and progression through crosstalk with hepatocytes. MARVELD1 is a newly reported regulator of genomic stability closely associated with malignant tumors. However, the relationship between MARVELD1-mediated hepatocyte homeostasis and the crosstalk axis from HSCs remains unclear.</p> Methods <p>Diethylnitrosamine (DEN)-induced HCC models were established using both systemic and hepatocyte-specific <i>MarvelD1</i> knockout mice. Micro-CT scans were employed to track liver lesions after DEN treatment. RNA sequencing was used to analyze the molecular features of early liver injury after DEN treatment. H&amp;E, immunohistochemistry, immunofluorescence, and qRT‒PCR were performed to evaluate HSC activation. Furthermore, an experimental procedure was used to obtain conditional medium (CM) from DEN-treated LX2 cells, and ELISA was used to determine the CCL5 concentration in CM. Antibody-blocking experiments were conducted to assess the interaction between CCL5 secreted by LX2 cells and CCR5 on hepatocytes during carcinogen-induced transformation of <i>MarvelD1</i>-deficient hepatocytes and its effect on cell proliferation and NF-κB pathway activation. CCK8 assays were used to evaluate the proliferation of MARVELD1-overexpressing HepG2 and MARVELD1-knockdown PLC/PRF/5 cells treated with CM from DEN-treated LX2 cells. Western blotting and qRT‒PCR were performed to evaluate the expression levels of the differentially expressed genes and proteins. Mouse primary HSCs and hepatocytes, either wild-type or <i>MarvelD1</i> deficient, were used to validate the above findings and the expression patterns after DEN treatment.</p> Results <p><i>MarvelD1-</i>deficient mice exhibited early-onset of HCC. In <i>MarvelD1</i>-deficient hepatocytes, metabolic, cancer and inflammatory response pathways, which represent early events, were upregulated in the context of early liver injury following DEN exposure. HSCs were activated early after DEN exposure and secreted active molecules that stimulate malignant proliferation of <i>MarvelD1</i>-deficient hepatocytes. The results of antibody-blocking experiments revealed that the interaction of CCL5 secreted by LX2 cells with CCR5 in hepatocytes is a crucial crosstalk axis for carcinogen-induced <i>MarvelD1</i>-deficient hepatocyte proliferation and canonical NF-κB signaling pathway activation. The expression patterns in HSCs and hepatocytes mediated by <i>MarvelD1</i> involved the CCL5/CCR5-initiated NF-κB pathway and cancer-related factors after DEN treatment.</p> Conclusion <p>The CCL5/CCR5 axis is involved in crucial crosstalk between activated hepatic stellate cells and <i>MarvelD1-</i>deficient hepatocytes during the early stages of DEN exposure. <i>MarvelD1</i> plays an important regulatory role in maintaining NF-κB signaling homeostasis in hepatocytes to inhibit cell proliferation.</p>

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MARVELD1 regulates hepatocyte transformation via maintaining NF-κB signaling homeostasis mediated by the CCL5/CCR5 axis between hepatic stellate cells and hepatocytes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Muhammad Luqman Akhtar,
  • Haoxiu Sun,
  • Liangyu Cao,
  • Xiaoyu Lin,
  • Bing Wang,
  • Depeng Yang,
  • Lijun Yang,
  • Wei Sun,
  • Jiahui Cheng,
  • Mengmeng Zhang,
  • Yaqi Zhao,
  • Lei Yue,
  • Yao Zhang,
  • Xinyue Shi,
  • Jingyu Zang,
  • Letian Li,
  • Yuehao Chen,
  • Qiuyu Ji,
  • Jianxin Lv,
  • Huan Nie,
  • Yu Li,
  • Fang Han

摘要

Background

Hepatocellular carcinoma (HCC) involves abnormal alterations in cellular homeostasis regulation and molecular crosstalk between hepatic stellate cells (HSCs) and hepatocytes, and the underlying mechanisms are highly complex. Recent evidence suggests that HSCs exhibit obvious plasticity, are activated by stress stimuli such as carcinogens, and participate in HCC occurrence and progression through crosstalk with hepatocytes. MARVELD1 is a newly reported regulator of genomic stability closely associated with malignant tumors. However, the relationship between MARVELD1-mediated hepatocyte homeostasis and the crosstalk axis from HSCs remains unclear.

Methods

Diethylnitrosamine (DEN)-induced HCC models were established using both systemic and hepatocyte-specific MarvelD1 knockout mice. Micro-CT scans were employed to track liver lesions after DEN treatment. RNA sequencing was used to analyze the molecular features of early liver injury after DEN treatment. H&E, immunohistochemistry, immunofluorescence, and qRT‒PCR were performed to evaluate HSC activation. Furthermore, an experimental procedure was used to obtain conditional medium (CM) from DEN-treated LX2 cells, and ELISA was used to determine the CCL5 concentration in CM. Antibody-blocking experiments were conducted to assess the interaction between CCL5 secreted by LX2 cells and CCR5 on hepatocytes during carcinogen-induced transformation of MarvelD1-deficient hepatocytes and its effect on cell proliferation and NF-κB pathway activation. CCK8 assays were used to evaluate the proliferation of MARVELD1-overexpressing HepG2 and MARVELD1-knockdown PLC/PRF/5 cells treated with CM from DEN-treated LX2 cells. Western blotting and qRT‒PCR were performed to evaluate the expression levels of the differentially expressed genes and proteins. Mouse primary HSCs and hepatocytes, either wild-type or MarvelD1 deficient, were used to validate the above findings and the expression patterns after DEN treatment.

Results

MarvelD1-deficient mice exhibited early-onset of HCC. In MarvelD1-deficient hepatocytes, metabolic, cancer and inflammatory response pathways, which represent early events, were upregulated in the context of early liver injury following DEN exposure. HSCs were activated early after DEN exposure and secreted active molecules that stimulate malignant proliferation of MarvelD1-deficient hepatocytes. The results of antibody-blocking experiments revealed that the interaction of CCL5 secreted by LX2 cells with CCR5 in hepatocytes is a crucial crosstalk axis for carcinogen-induced MarvelD1-deficient hepatocyte proliferation and canonical NF-κB signaling pathway activation. The expression patterns in HSCs and hepatocytes mediated by MarvelD1 involved the CCL5/CCR5-initiated NF-κB pathway and cancer-related factors after DEN treatment.

Conclusion

The CCL5/CCR5 axis is involved in crucial crosstalk between activated hepatic stellate cells and MarvelD1-deficient hepatocytes during the early stages of DEN exposure. MarvelD1 plays an important regulatory role in maintaining NF-κB signaling homeostasis in hepatocytes to inhibit cell proliferation.