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BRD9 recognizes lactate-induced H3K18 lactylation to drive oncogenic chromatin remodeling in hepatocellular carcinoma

Cell Death & Differentiation (2026)Cite this article

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Abstract

Histone lactylation couples glycolytic metabolism to oncogenic transcription, but its mechanistic readers remain poorly defined. Here, we identify bromodomain-containing protein 9 (BRD9) as a lactyl-lysine reader that links lactate-driven H3K18 lactylation (H3K18la) to chromatin remodeling in hepatocellular carcinoma (HCC). Clinically, elevated H3K18la levels correlate with poor HCC prognosis. Structural (NMR) and biophysical analyses demonstrate that BRD9’s bromodomain engages H3K18la with weak, transient affinity through its conserved acetyl-lysine pocket, distinct from its stable H3K18ac binding. This enables BRD9 to function as a metabolic-epigenetic sensor, dynamically recruited to chromatin in response to glycolytic flux. Multi-omics profiling reveals that H3K18la recruits BRD9 and the non-canonical BRG1-associated factor (ncBAF) chromatin remodeling complex to active enhancers and promoters, promoting chromatin accessibility and driving oncogenic transcription (SPARC, TMEM64, ANGEL1, SCARB1). Glycolytic inhibition or BRD9 targeting displaces BRD9 from chromatin, suppresses oncogenes, and impairs HCC proliferation. Modulating the lactylation vis p300 or HDAC inhibition attenuates transcription and reduces tumor viability. In vivo, glycolytic inhibition suppresses tumor growth. Our findings establish a feedforward loop wherein glycolytic flux promotes H3K18la-dependent BRD9-ncBAF recruitment to remodel chromatin and sustain oncogenic transcription, defining BRD9 as a critical metabolic-epigenetic mediator and a promising therapeutic target in HCC.

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Fig. 1: Elevated histone lactylation correlates with cell proliferation and tumorigenesis in HCC.
Fig. 2: H3K8la interacts with BRD9 bromodomain.
Fig. 3: H3K18la co-localizes with BRD9 at active enhancers and promoters.
Fig. 4: H3K18la and BRD9 recruit ncBAF and increase chromatin accessibility.
Fig. 5: H3K18la and BRD9 are essential for gene transcription and cell survival.
Fig. 6: 2-DG treatment alleviates tumor growth in HepG2 xenograft mice.

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Data availability

The data that support this study are available from the corresponding authors upon reasonable request. All protocols used in this study are available in the Methods section. RNA-seq, ChIP-seq, and ATAC-seq data generated in this study have been deposited in the NCBI SRA database under BioProject accession code (GSE314155). The structure coordinates for the BRD9 bromodomain in complex with the H3K18la peptide have been deposited in the Protein Data Bank under PDB accession codes (21GE, 21HJ). NMR data are available in the Biological Magnetic Resonance Data Bank (BMRB code: 36816, 36817). Source data are provided with this paper. Supplementary Information is available in the online version of the paper.

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Acknowledgements

We thank the biobank at the First Hospital of Jilin University (Changchun, China) for liver samples from HCC patients. We acknowledge the BGI Group for generating RNA-seq data and Seqhealth Technology Co., Ltd. for ChIP-seq data and ATAC-seq data. We thank Di Liu for the assistance with ITC and NMR experiments, and Naicui Zhai for Mass spectrometric analysis, both conducted in the core facility of the First Hospital of Jilin University. This work was supported in part by the research fund from the First Hospital of Jilin University (Changchun, China), International Center of Future Science of Jilin University, and National Natural Science Foundation of China (82372736; LZ).

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Authors and Affiliations

  1. Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China

    Enwei Wei, Donglei Ji, Yanjie Jia, Chunfeng Gao, Miaomiao Yu, Guanglei Shang, Linying Xie, Wenju Zhang, Yameng Li, Yingying Liang & Lei Zeng

  2. International Center of Future Science, Jilin University, Changchun, China

    Enwei Wei, Chunfeng Gao, Miaomiao Yu, Guanglei Shang, Linying Xie, Wenju Zhang, Yameng Li, Yingying Liang & Lei Zeng

  3. Department of Cell Fate and Diseases, Jilin Provincial Key Laboratory of Women’s Reproductive Health, Jilin Provincial Clinical Research Center for Birth Defect and Rare Disease, The First Hospital of Jilin University, Changchun, China

    Ze Sun & Yanzhu Yue

  4. Pennsylvania State University College of Medicine, Hershey, PA, USA

    Caroline Zeng

  5. State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, Jilin, China

    Chunyu Wang

  6. Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Changchun, China

    Bai Ji & Yahui Liu

  7. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Ming-Ming Zhou

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Contributions

LZ, M-MZ and YL conceived the project. EW designed and performed experiments. EW, WZ, YL, YL and LX performed transfection in cells and qRT-PCR, EW, YJ and DJ for cellular experiments. EW, CG and BJ worked on HCC patient tissue experiments, and EW, MY and GS performed ChIP experiments. CW and CZ worked on NMR experiments. ZS and YY analyzed sequencing data. LZ and M-MZ wrote the manuscript with input from all co-authors.

Corresponding authors

Correspondence to Yahui Liu, Ming-Ming Zhou or Lei Zeng.

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The authors declare no competing interests.

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Written informed consent was obtained from all patients, and all procedures were approved by the Institute Research Ethics Committee of the First Hospital of Jilin University (No.: 2025-591). All animal experiments were approved by the Animal Ethics Committee of the College of Basic Medical Sciences of Jilin University (No.: 2025-591) and were conducted in compliance with the Guiding Principles established by the Laboratory Animal Management Committee of the College of Basic Medical Sciences of Jilin University.

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Wei, E., Ji, D., Jia, Y. et al. BRD9 recognizes lactate-induced H3K18 lactylation to drive oncogenic chromatin remodeling in hepatocellular carcinoma. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01698-6

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