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<p>Hepatocellular carcinoma (HCC) is a highly lethal malignancy, with epithelial-mesenchymal transition (EMT)-driven metastasis a key factor for poor prognosis. The C5a/C5a receptor (C5aR) pathway significantly facilitates HCC cell EMT, yet no approved anti-cancer drugs specifically target C5aR. LukS-PV, a component of <i>Staphylococcus</i> <i>aureus</i>-secreted Panton-Valentine leukocidin (PVL), specifically targets C5aR and exerts anti-tumor effects in hematological and solid tumors. However, its impact on HCC EMT and mechanisms remains unknown. Our study showed LukS-PV targets C5aR to inhibit HCC cell EMT, migration, invasion, and in vivo lung metastasis. Mechanistically, LukS-PV downregulates B-cell lymphoma 6 (BCL6), reducing histone deacetylase 6 (HDAC6) expression. Decreased HDAC6 increases heat shock protein 60 (HSPD1) acetylation, promoting its ubiquitin-mediated degradation and EMT inhibition. This study demonstrates LukS-PV targets C5aR to inhibit HCC EMT via the BCL6/HDAC6/HSPD1 axis, highlighting its potential as an HCC therapeutic agent. These findings provide valuable EMT regulatory insights and identify potential HCC therapeutic targets.</p>

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LukS-PV targeting C5aR inhibits EMT in hepatocellular carcinoma via the BCL6/HDAC6/HSPD1 axis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月30日

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  • Pengsheng Ding,
  • Lan Shi,
  • Xuexue Xu,
  • Bing Lu,
  • Gan Liu,
  • Yangyan Wang,
  • Zhengchao Nie,
  • Xiaofang Wang,
  • Wenjiao Chang,
  • Yuanyuan Dai,
  • Xiaoling Ma,
  • Shanshan Zhang

摘要

Hepatocellular carcinoma (HCC) is a highly lethal malignancy, with epithelial-mesenchymal transition (EMT)-driven metastasis a key factor for poor prognosis. The C5a/C5a receptor (C5aR) pathway significantly facilitates HCC cell EMT, yet no approved anti-cancer drugs specifically target C5aR. LukS-PV, a component of Staphylococcus aureus-secreted Panton-Valentine leukocidin (PVL), specifically targets C5aR and exerts anti-tumor effects in hematological and solid tumors. However, its impact on HCC EMT and mechanisms remains unknown. Our study showed LukS-PV targets C5aR to inhibit HCC cell EMT, migration, invasion, and in vivo lung metastasis. Mechanistically, LukS-PV downregulates B-cell lymphoma 6 (BCL6), reducing histone deacetylase 6 (HDAC6) expression. Decreased HDAC6 increases heat shock protein 60 (HSPD1) acetylation, promoting its ubiquitin-mediated degradation and EMT inhibition. This study demonstrates LukS-PV targets C5aR to inhibit HCC EMT via the BCL6/HDAC6/HSPD1 axis, highlighting its potential as an HCC therapeutic agent. These findings provide valuable EMT regulatory insights and identify potential HCC therapeutic targets.