Research progress and prospect of histone lactylation in digestive system tumors

doi:10.19401/j.cnki.1007-3639.2025.04.011

Abstract

Abstract:

Histone lactylation is a novel type of post-translational modification, where a lactate molecule covalently binds to the lysine residues of histones. This modification plays a key role in cellular metabolic reprogramming, particularly in digestive system tumorigenesis and progression. In recent years, the role of histone lactylation in various malignancies has been increasingly recognized, highlighting its broad impact on tumor biology and clinical potential. This article focused on the research progress of histone lactylation in digestive system cancers, specifically analyzing its mechanisms in major gastrointestinal cancers such as gastric cancer, liver cancer, and colon cancer. Studies have shown that lactylation modifies histone lysine residues directly, regulating tumor cell gene expression and chromatin conformation, thereby promoting tumor proliferation, invasion, and metastasis. Lactylation affects histone-DNA interactions, altering chromatin openness and enhancing the transcriptional activity of oncogenes. In addition, targeted therapies that modulate lactation levels or inhibit lactation-related enzymes, such as lactate dehydrogenase inhibitors, lactate production inhibitors, and specific histone lactonases, are effective in inhibiting tumorigenesis and progression and have demonstrated potential therapeutic efficacy in preclinical models. This article systematically summarized the mechanisms of histone lactylation in various types of gastrointestinal cancers, offering new research directions and theoretical support for targeted therapeutic strategies based on lactylation modification.

Key words: Histone lactylation, Lactate, Post-translational modification, Tumor

ZENG Dandan, LUO Wenfeng, YE Jiazhou, LIN Yan, LIANG Rong. Research progress and prospect of histone lactylation in digestive system tumors[J]. China Oncology, 2025, 35(4): 424-430.

Figures/Tables 1

Tab. 1

Overview of histone lactylation in relation to tumors of the digestive system"

Type of disease	Cells type	Lactylation sites	Relevant molecule or pathway	Downstream effect	Reference
Gastric cancer	Tumor cell	Not mentioned	GLUT3, LDHA	Promoting proliferation, migration, and invasion of tumor cells	[11]
	Tumor cell	Not mentioned	AARS, YAP	Inhibition of apoptotic signaling and accelerates tumor cell growth	[12]
Liver cancer	Tumor stem cell, tumor cell	H3K9, H3K56, H3K14	Demethylzeylasteral, RJA, glycolysis/glycolysis-related cellular pathways	Inhibition of proliferation of hepatocellular carcinoma stem cells, tumor cells	[19-20]
	Tumur cell	H3K124	CENPA/YY1 complex, CCND1, NRP2, YY1	Promoting tumor growth	[21]
	Tumur cell	Not mentioned	ESM1, GP73	Promoting angiogenesis in the tumor microenvironment for hepatocellular carcinoma growth and metastasis	[22-23]
	Macrophage	H3K18	SRSF, MYB, GLUT1, LDHA, HK-1	Promoting polarization of M2-type macrophages to create an immunosuppressive microenvironment	[24]
	Tumor infiltrating lymphocytes	Pantothenoylation	NR6A1, OSBP2, UNC119B; WNT, MAPK, MTOR, NOTCH signaling pathway	Promotion of immunosuppressive TME	[25]
Pancreatic cancer	Tumor cell	Not mentioned	P53, KRAS, SLC16, Raf/MEK/ERK signaling pathway	Promoting tumor cell proliferation, invasion metastasis	[28-31]
	Tumor cell, immune cell	Not mentioned	NUSAP1, c-Myc, HIF-1α, LDHA	Promotion of tumor cell proliferation and metastasis, immune escape	[32-33]
	Tumor cell	H4K12	Nectin-2	Enhancement of immune escape of tumor cells	[34]
	Tumor cell	H3K18	TTK, BUB1B, AMPK pathway	Promoting tumor proliferation and inhibition of apoptosis	[35-36]
Colorectal cancer	Not mentioned	Not mentioned	SMC4, PGAM1, HK2, PFKL, ALDOC, ABC transporter proteins	Tumor growth promotion, angiogenesis and immune escape, immunosuppressive TME	[39]
	Neutrophil	H3K18	GPR37, CXCL1, CXCL5; Hippo corridor	Promoting TME neutrophil recruitment	[40]
	Tumor cell	Not mentioned	LINC00152, YY1, IL-8, TNF-α; NF-κB passage	Promoting migration and invasion of tumor cells	[41]
	Macrophage	H3K18	RARγ, TRAF6, TNF-α, IL-6; NF-κB, STAT3 pathway	Promoting tumor growth	[42]
	Tumor cell	H3K18	NOP2/NSUN2, ENO1	Promoting proliferation and metastasis of tumor cells	[43]
	Tumor cell	Not mentioned	KAT8, eEF1A2	Promoting proliferation and metastasis of tumor cells	[44]
	Tumor cell	Not mentioned	circATXN7, NF-κB	Promoting immune escape of tumor cells	[45]
	Tumor cell	Not mentioned	RUBCNL, BECN1, PtdIns3K complexes	Promoting maturation and function of autophagosomes	[46]

Tab. 1

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