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  3. Multi-omics analysis of the HMGB2+ tumor epithelial cells in lactylation subgroups in colorectal cancer

Multi-omics analysis of the HMGB2+ tumor epithelial cells in lactylation subgroups in colorectal cancer

  • Cell Biosci. 2025 Nov 19;15(1):158. doi: 10.1186/s13578-025-01491-x.
Shangshang Hu 1 2,  Jinwei Lou 3,  Muzi Ding 3,  Yuhan Chen 3,  Jian Qin 1,  Zixuan Liu 3,  Yue Li 3,  QianNi Xiao 3,  Mu Xu 2,  Huiling Sun 2 4,  Yuqin Pan 5 6,  Shukui Wang 7 8 9
Affiliations

Affiliations

  • 1 General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China.
  • 2 School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China.
  • 3 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211122, Jiangsu, China.
  • 4 Jiangsu Collaborative Innovation Center on Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211100, Jiangsu, China.
  • 5 General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China. [email protected].
  • 6 Jiangsu Collaborative Innovation Center on Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211100, Jiangsu, China. [email protected].
  • 7 General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu, China. [email protected].
  • 8 School of Medicine, Southeast University, Nanjing, 210009, Jiangsu, China. [email protected].
  • 9 Jiangsu Collaborative Innovation Center on Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211100, Jiangsu, China. [email protected].
PMID: 41261427 DOI: 10.1186/s13578-025-01491-x
Abstract

Colorectal Cancer (CRC) is a prevalent malignancy, yet the role of lactylation in its progression remains unclear. This study investigates High Mobility Group Box 2 positive tumor epithelial cells (HMGB2+Epi), a lactylation-associated subpopulation. By integrating multi-omics data, including proteomics, single-cell, spatial, and bulk transcriptomics, we explored the function of HMGB2+Epi in CRC. Elevated lactylation levels in CRC tissues were correlated with poor prognosis. Single-cell analysis identified HMGB2+Epi as a central lactylation-enriched subpopulation. Functionally, HMGB2 enhanced the Warburg effect, promoting CRC cell proliferation, migration, and invasion. HMGB2 knockout reduced lactylation levels and inhibited tumor progression. Mechanistically, NFYB directly bound to the HMGB2 promoter, forming the NFYB-HMGB2 axis that drives lactylation and metabolic reprogramming. Cell-cell communication analysis revealed enhanced interactions between HMGB2+Epi and fibroblasts, endothelial cells, and T/NK cells. Molecular dynamics and in-vitro assays suggest that BI-2536 downregulates HMGB2 and lactylation in CRC cells. A risk model based on HMGB2+Epi outperformed 125 previously published models in independent cohorts. In summary, HMGB2+Epi represents a key lactylation-enriched subgroup, with the NFYB-HMGB2 axis driving CRC progression via lactylation. BI-2536 as a tool compound implicating the HMGB2-lactylation axis, and the HMGB2+Epi-based risk model provides a novel target for precision CRC therapy.

Keywords

Colorectal cancer; HMGB2; Lactylation; Multi-omics.

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