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<p>Understanding of the metabolic determinants influencing immunotherapy responsiveness remains limited. Here we performed a multiomics analysis of tumor biopsies from patients with hepatocellular carcinoma (HCC) treated with immune checkpoint blockade (ICB) and revealed that heightened expression of OXCT1, a rate-limiting enzyme in ketone body metabolism, was negatively correlated with ICB efficacy, whereas its metabolic substrate, β-hydroxybutyrate (BHB), displayed an opposite effect. Mechanistically, glucose deprivation in HCC cells promotes AMPK-mediated OXCT1 S113 phosphorylation, which exposes the nuclear localization sequence of OXCT1 to trigger its nuclear translocation. Nucleus-translocated OXCT1 associates with IRF1 to locally consume BHB and suppress histone H3K9 BHB at the major histocompatibility complex class I (MHC-I) and chemokine gene loci, leading to repressed transcription of these immune genes. Targeting the AMPK−OXCT1−IRF1 axis sensitizes tumor cells to ICB upon ketogenic diet. These findings reveal a mechanism by which a non-canonical function of nuclear OXCT1 coordinates the interplay between ketone body metabolic reprogramming and immunotherapy responsiveness.</p><p></p>

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Nuclear OXCT1 attenuates histone β-hydroxybutyrylation-mediated MHC-I transcription

  • 期刊论文

  • 发表日期：

    2026年5月27日

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  • Zhiqiang Hu,
  • Wei Lv,
  • Ting Wen,
  • Junyi Sun,
  • Guimei Ji,
  • Shuo Ru,
  • Xue Sun,
  • Zheng Wang,
  • He Ren,
  • Yudi Zhang,
  • Pengkun Chen,
  • Linlin Zhou,
  • Shiqi Wu,
  • Xiaoqian Jia,
  • Shanshuo Liu,
  • Zheng Zhu,
  • Jiawei Xu,
  • Tong Liu,
  • Yuxiong Feng,
  • Gaopeng Li,
  • Yuan Ding,
  • Yuhao Wang,
  • Yang Luo,
  • Chang Liu,
  • Zhimin Lu,
  • Zhigang Ren,
  • Sheng-Zhong Duan,
  • Daqian Xu

摘要

Understanding of the metabolic determinants influencing immunotherapy responsiveness remains limited. Here we performed a multiomics analysis of tumor biopsies from patients with hepatocellular carcinoma (HCC) treated with immune checkpoint blockade (ICB) and revealed that heightened expression of OXCT1, a rate-limiting enzyme in ketone body metabolism, was negatively correlated with ICB efficacy, whereas its metabolic substrate, β-hydroxybutyrate (BHB), displayed an opposite effect. Mechanistically, glucose deprivation in HCC cells promotes AMPK-mediated OXCT1 S113 phosphorylation, which exposes the nuclear localization sequence of OXCT1 to trigger its nuclear translocation. Nucleus-translocated OXCT1 associates with IRF1 to locally consume BHB and suppress histone H3K9 BHB at the major histocompatibility complex class I (MHC-I) and chemokine gene loci, leading to repressed transcription of these immune genes. Targeting the AMPK−OXCT1−IRF1 axis sensitizes tumor cells to ICB upon ketogenic diet. These findings reveal a mechanism by which a non-canonical function of nuclear OXCT1 coordinates the interplay between ketone body metabolic reprogramming and immunotherapy responsiveness.