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<p>Hepatitis B virus (HBV) infection remains a leading etiological driver of hepatocellular carcinoma (HCC). Cuproptosis is a recently defined copper-dependent form of regulated cell death that selectively eliminates mitochondria-dependent cells; whether HBV rewires this vulnerability remains unknown. Here we unveil a novel HBV X protein (HBx)-driven mechanism of cuproptosis evasion. Integrative analysis of clinical specimens, HBx-transgenic (HBx-Tg) mice, and multi-omics datasets revealed marked downregulation of STEAP4 (six-transmembrane epithelial antigen of prostate 4), a metalloreductase essential for cuproptosis sensitivity, in HBV-positive HCC. Mechanistically, HBx attenuates sirtuin 3 (SIRT3), impairing deacetylation of STEAP4 at lysine 404 and abolishing its mitochondrial targeting. Consequently, cells switch from the tricarboxylic acid (TCA) cycle respiration to glycolysis, reducing sensitivity to the copper ionophore elesclomol (ES). Restoring STEAP4 expression or pharmacological activation of SIRT3 with honokiol (HKL) re-instated mitochondrial STEAP4 localization and re-sensitized HBV-related HCC cells to cuproptosis; combination with ES produced synergistic tumor suppression in vitro and in orthotopic models. Collectively, our findings establish the SIRT3–STEAP4 axis as a novel regulator of cuproptosis resistance in HBV-related HCC. HBx-mediated repression of SIRT3 disrupts STEAP4 deacetylation and mitochondrial targeting, fostering metabolic reprogramming and evasion of copper-induced cell death. The results provide a pre-clinical rationale for copper-directed combination strategies in HBV-associated HCC.</p><p></p>

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SIRT3 deacetylates STEAP4 to modulate cuproptosis sensitivity via mitochondrial metabolic reprogramming in HBV-related HCC

  • 期刊论文

  • 发表日期：

    2026年3月16日

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  • Ze-Bang Du,
  • Xin-Mou Wu,
  • Jia-Ming Lei,
  • Yu-Xin Cai,
  • Jie He,
  • Bo Qian,
  • Xin-Xin He,
  • Wen-Hao Han,
  • Yuan Lu,
  • Xiao-Gang Xia,
  • Han-Ying Zheng,
  • Dong-Bei Guo,
  • You-Liang Yao,
  • Wen-Gang Li,
  • Yu-Chun Lin,
  • Zhong-Ning Lin

摘要

Hepatitis B virus (HBV) infection remains a leading etiological driver of hepatocellular carcinoma (HCC). Cuproptosis is a recently defined copper-dependent form of regulated cell death that selectively eliminates mitochondria-dependent cells; whether HBV rewires this vulnerability remains unknown. Here we unveil a novel HBV X protein (HBx)-driven mechanism of cuproptosis evasion. Integrative analysis of clinical specimens, HBx-transgenic (HBx-Tg) mice, and multi-omics datasets revealed marked downregulation of STEAP4 (six-transmembrane epithelial antigen of prostate 4), a metalloreductase essential for cuproptosis sensitivity, in HBV-positive HCC. Mechanistically, HBx attenuates sirtuin 3 (SIRT3), impairing deacetylation of STEAP4 at lysine 404 and abolishing its mitochondrial targeting. Consequently, cells switch from the tricarboxylic acid (TCA) cycle respiration to glycolysis, reducing sensitivity to the copper ionophore elesclomol (ES). Restoring STEAP4 expression or pharmacological activation of SIRT3 with honokiol (HKL) re-instated mitochondrial STEAP4 localization and re-sensitized HBV-related HCC cells to cuproptosis; combination with ES produced synergistic tumor suppression in vitro and in orthotopic models. Collectively, our findings establish the SIRT3–STEAP4 axis as a novel regulator of cuproptosis resistance in HBV-related HCC. HBx-mediated repression of SIRT3 disrupts STEAP4 deacetylation and mitochondrial targeting, fostering metabolic reprogramming and evasion of copper-induced cell death. The results provide a pre-clinical rationale for copper-directed combination strategies in HBV-associated HCC.