Nuclear OXCT1 attenuates histone β-hydroxybutyrylation-mediated MHC-I transcription PMID: 42204309

ADC Targets in Oncology

2026-04-10

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

Nat Chem Biol. 2026 May 27. doi: 10.1038/s41589-026-02229-7.

Zhiqiang Hu ^# ¹ ² , Wei Lv ^# ³ , Ting Wen ^# ¹ ² , Junyi Sun ^# ⁴ , Guimei Ji ^# ¹ ² , Shuo Ru ¹ ² , Xue Sun ⁵ , Zheng Wang ¹ ² , He Ren ⁵ , Yudi Zhang ¹ ² , Pengkun Chen ¹ ² ⁶ , Linlin Zhou ⁵ , Shiqi Wu ¹ ² , Xiaoqian Jia ¹ ² , Shanshuo Liu ⁴ , Zheng Zhu ¹ ² , Jiawei Xu ¹ ² , Tong Liu ⁵ ⁷ , Yuxiong Feng ¹ ² , Gaopeng Li ⁸ , Yuan Ding ⁹ , Yuhao Wang ¹ ² , Yang Luo ¹⁰ , Chang Liu ¹¹ , Zhimin Lu ¹ ² , Zhigang Ren ¹² , Sheng-Zhong Duan ¹³ , Daqian Xu ¹⁴ ¹⁵ ¹⁶

Affiliations

1. Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
2. Cancer Center, Zhejiang University, Hangzhou, China.
3. HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
4. Department of Infectious Diseases, State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
5. Department of Oncology Surgery, Harbin Medical University Cancer Hospital, Harbin, China.
6. Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China.
7. NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China.
8. Department of Colorectal Surgery and Oncology of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
9. Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangu, China.
10. Department of Laboratory Medicine, Chongqing General Hospital, School of Medicine, Chongqing University, Chongqing, China.
11. Institute of Modern Biology, Nanjing University, Nanjing, China.
12. Department of Infectious Diseases, State Key Laboratory of Antiviral Drugs, Pingyuan Laboratory, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [email protected].
13. Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China. [email protected].
14. Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China. [email protected].
15. Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
16. NHC Key Laboratory of Cell Transplantation, Harbin Medical University, Harbin, China. [email protected].
# Contributed equally.

Abstract

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.