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

Cell Death & Differentiation (2026)Cite this article

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Abstract

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.

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Fig. 1: STEAP4-directed copper metabolism and cuproptosis define a therapeutic vulnerability in HBV-related HCC.
Fig. 2: Anti-HBx sensitizes HBV-related HCC cells to ES-induced cuproptosis through STEAP4 up-regulation.
Fig. 3: TTM reverses STEAP4-mediated sensitization of ES-induced cuproptosis and tumor suppression in HBx-expressing HCC cells.
Fig. 4: STEAP4 orchestrates mitochondrial metabolic reprogramming to confer cuproptosis resistance in HBx-expressing HCC cells.
Fig. 5: ES and STEAP4 synergistically enhance cuproptosis sensitivity and suppress HBV-related HCC tumorigenesis in vivo.
Fig. 6: SIRT3-mediated deacetylation of STEAP4 governs its mitochondrial translocation in HBx-expressing HCC cells.
Fig. 7: STEAP4-K404 deacetylation licenses cuproptosis and potentiates ES efficacy in an orthotopic HCC model.
Fig. 8: Honokiol potentiates anti-tumor activity via SIRT3–STEAP4 dependent cuproptosis.

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Data availability

All data supporting the conclusions of this study are contained within the article and its supplementary files. Raw data and unique biological materials are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thanks all colleagues who provided reagents, technical support or intellectual input.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 82273667, 82272935, 82574139, 82573484), the Fujian Province Special Fund Project for Promoting High-Quality Development of Marine and Fishery Industries (FJHYF-L-2025-27), the Industry-University-Research Cooperation Project of Fujian Science and Technology Plan (No. 2022Y4009), the Fundamental Research Funds for the Central Universities (No. 20720250004), Natural Science Foundation of Xiamen, China (No. 3502Z202573032), and Scientific Research Foundation of State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory (2023XAKJ0101024).

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Author notes

  1. These authors contributed equally: Ze-Bang Du, Xin-Mou Wu, Jia-Ming Lei.

Authors and Affiliations

  1. State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiang’an Hospital of Xiamen University, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen, China

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

  2. Department of Hepatobiliary Surgery, Cancer Research Center, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China

    Xiao-Gang Xia & Wen-Gang Li

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Contributions

ZD, XW, ZL, and BQ conceived and designed the study and wrote the manuscript with comments from all authors; JL, YC, JH, XH, WH, and YL performed experiments. XX, HZ, DG, and YY acquired and analyzed the data; WL, Y-CL, and ZL provided reagents and technical assistance. ZD, and ZL wrote, reviewed, and edited the paper.

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Correspondence to Wen-Gang Li, Yu-Chun Lin or Zhong-Ning Lin.

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We confirm that all methods were performed in accordance with the relevant guidelines and regulations. Animal procedures were approved by the Animal Ethics Committee of Xiamen University (XMULAC20220282; 12 March 2022) and conducted in accordance with institutional guidelines.

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Du, ZB., Wu, XM., Lei, JM. et al. SIRT3 deacetylates STEAP4 to modulate cuproptosis sensitivity via mitochondrial metabolic reprogramming in HBV-related HCC. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01713-w

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