Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2026 Jan 9:e18180.
doi: 10.1002/advs.202518180. Online ahead of print.

Hepatocyte BPGM Induces RET Lactylation and Macrophage Reprogramming to Promote Tumorigenesis in Hepatocellular Carcinoma

Jiajia Zhang  1   2 , Lu Shi  2 , Liangliang Lin  1 , Yang Zhang  1 , Miao Zhang  1 , Lili Wu  3 , Yong Xia  4 , Yaqiong Zhang  5 , Peng Han  6 , Likun Zhuang  2 , Liang Shi  1
Affiliations

Hepatocyte BPGM Induces RET Lactylation and Macrophage Reprogramming to Promote Tumorigenesis in Hepatocellular Carcinoma

Jiajia Zhang et al. Adv Sci (Weinh). .

Abstract

Aerobic glycolysis is a hallmark of cancer, yet the role of the key glycolytic enzyme bisphosphoglycerate mutase (BPGM) in hepatocellular carcinoma (HCC) progression remains unclear. Here, clinical sample analyses revealed that BPGM expression was upregulated in HCC tissues and associated with poor prognosis. Hepatocyte-specific Bpgm knockout significantly attenuated DEN-induced HCC development in mice. Spatial transcriptomics and single-cell RNA sequencing revealed that hepatocyte-specific Bpgm knockout reduced the monocyte/macrophage infiltration and decreased M2 polarization of tumor-associated macrophages. Additionally, BPGM overexpression promoted the proliferation and migration of HCC cells and enhanced intracellular lactate accumulation. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified ret proto-oncogene (RET) as a downstream effector that mediated the effects of BPGM on HCC cells. BPGM promoted P300-mediated lactylation of RET at lysine 549 (K549), which competitively inhibited its ubiquitination, thereby preventing RET protein degradation and enhancing its stability. BPGM in HCC cells also induced both histone lactylation and M2 polarization of macrophages by lactate secretion. This study revealed that BPGM in hepatocytes could enhance RET expression via increasing its lactylation in malignant cells and promote M2 polarization of macrophages, both of which contributed to HCC progression. These findings established that BPGM could act as a potential therapeutic target for HCC.

Keywords: BPGM; HCC; RET; macrophage polarization; protein lactylation.

PubMed Disclaimer

References

    1. R. L. Siegel, A. N. Giaquinto, and A. Jemal, “Cancer Statistics,” CA: A Cancer Journal for Clinicians 74, no. 1 (2024): 12–49, https://doi.org/10.3322/caac.21820.
    1. J. Zheng, S. Wang, L. Xia, et al., “Hepatocellular Carcinoma: Signaling Pathways and Therapeutic Advances,” Signal Transduction and Targeted Therapy 10, no. 1 (2025): 35, https://doi.org/10.1038/s41392‐024‐02075‐w.
    1. K. Huang, Y. Han, Y. Chen, H. Shen, S. Zeng, and C. Cai, “Tumor Metabolic Regulators: Key Drivers of Metabolic Reprogramming and the Promising Targets in Cancer Therapy,” Molecular Cancer 24, no. 1 (2025): 7, https://doi.org/10.1186/s12943‐024‐02205‐6.
    1. J. Lin, D. Rao, M. Zhang, and Q. Gao, “Metabolic Reprogramming in the Tumor Microenvironment of Liver Cancer,” Journal of Hematology & Oncology 17, no. 1 (2024): 6, https://doi.org/10.1186/s13045‐024‐01527‐8.
    1. D. Zhang, Z. Tang, H. Huang, et al., “Metabolic Regulation of Gene Expression by Histone Lactylation,” Nature 574, no. 7779 (2019): 575–580, https://doi.org/10.1038/s41586‐019‐1678‐1.

LinkOut - more resources