BPGM as an intrinsic brake to constrain metastasis through phospho-epigenetic-mediated carnitine biosynthesis suppression

  • Neoplasia. 2026 May:75:101299. doi: 10.1016/j.neo.2026.101299.
Meng-Zhi Wu  1 ,  Dou Feng  2 ,  Wu-Ping Liu  1 ,  Wei-Lun Huang  2 ,  Qiang Wu  2 ,  Tian-Sheng Chou  1 ,  Wen-Hao Xiao  2 ,  Zhou-Zhou Yao  2 ,  Zhen-Jiang Li  2 ,  Ting-Ting Xie  3 ,  Chang-Han Chen  1 ,  Zhi-Yu Yang  1 ,  Rui-Wen Mao  1 ,  Ci-Chun Wu  4 ,  Jun-Cheng Wang  2 ,  Yu-Jin Zhang  1 ,  Rodney E Kellems  5 ,  Yang Xia  6
Affiliations
  • 1. National Medical Metabolomics International Collaborative Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 2. National Medical Metabolomics International Collaborative Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China; Depatment of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 3. National Medical Metabolomics International Collaborative Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Family Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 4. National Medical Metabolomics International Collaborative Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 5. Department of Biochemistry and Molecular Biology, The University of Texas McGovern Medical School at Houston, Houston, TX, USA.
  • 6. National Medical Metabolomics International Collaborative Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China; Depatment of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China. Electronic address: [email protected].
PMID: 41875824 DOI: 10.1016/j.neo.2026.101299
Abstract

Metabolic adaptations that fuel metastatic dissemination are increasingly mapped, yet the existence of intrinsic metabolic "brakes" that actively restrain metastatic progression remains enigmatic. Here, we unveil bisphosphoglycerate mutase (BPGM) as a previously unrecognized metastasis suppressor that orchestrates a phospho-epigenetic relay linking glycolytic flux to carnitine-dependent fatty acid oxidation. Through high-resolution metabolomics, we discover that BPGM and its catalytic product 2,3-bisphosphoglycerate (2,3-BPG) constitute a metabolic checkpoint whose disruption predicts metastatic virulence in multiple cancers. Mechanistically, BPGM suppresses metastasis by triggering CDK1-T14 phosphorylation-dependent assembly of an EZH2-H3K27me3 repressor complex that silences γ-butyrobetaine hydroxylase (BBOX1), the rate-limiting enzyme in carnitine biosynthesis. This phospho-switch mechanism converts glycolytic 2,3-BPG levels into epigenetic orchestrator, thereby starving metastatic cells of carnitine-required fatty acid oxidation. Hypoxia-mediated KDM4A-H3K9me3 cascade emerges as the upstream inactivator of this metabolic-epigenetic checkpoint, explaining how tumor microenvironmental stress liberates metastatic potential. Therapeutically, pharmacological BBOX1 inhibition with Meldonium recapitulates BPGM-mediated metastasis suppression in orthotopic models, reducing metastatic burden. These findings reveal BPGM as a metabolic gatekeeper that integrates bioenergetic sensing with chromatin remodeling to constrain metastatic competence, while hypoxia-mediated checkpoint failure unleashes carnitine-fueled metastatic progression. Targeting the hypoxia-BPGM-BBOX1 axis represents an innovative approach for metastasis-preventive therapy.

Keywords
Bisphosphoglycerate mutase; Carnitine biosynthesis; Histone methylation; Tumor metastasis; γ-butyrobetaine hydroxylase (BBOX1).
Products