组蛋白乳酸化在消化系统肿瘤中的研究进展及展望

doi:10.19401/j.cnki.1007-3639.2025.04.011

摘要/Abstract

摘要：

组蛋白乳酸化修饰是一种新型的组蛋白翻译后修饰，通过乳酸分子与组蛋白赖氨酸残基的共价结合，在细胞代谢重编程中发挥关键作用，尤其在消化系统肿瘤的发生、发展中具有重要意义。近年来，组蛋白乳酸化在多种恶性肿瘤中的作用机制逐渐被揭示，显示其在肿瘤生物学中的广泛影响和临床潜力。本文重点梳理组蛋白乳酸化在消化系统肿瘤中的研究进展，具体分析其在胃癌、肝癌、结肠癌等主要消化道肿瘤中的作用机制。研究表明，乳酸化通过直接修饰组蛋白赖氨酸残基，调节肿瘤细胞的基因表达和染色质构象，进而促进肿瘤的增殖、侵袭和转移。乳酸化通过影响组蛋白与DNA的结合方式，改变染色质的开放性，增强癌基因的转录活性。此外，调控乳酸化水平或抑制乳酸化相关酶，如乳酸脱氢酶抑制剂、乳酸生成抑制剂及特定组蛋白乳酸化酶的靶向治疗，能够有效地抑制肿瘤的发生与发展，并在临床前模型中展示出潜在的治疗效果。本文从不同类型的消化道癌症出发，系统总结组蛋白乳酸化的作用机制，旨在为基于乳酸化修饰的靶向治疗策略提供新的研究方向和理论支持。

关键词: 组蛋白乳酸化, 乳酸, 翻译后修饰, 肿瘤

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

曾丹丹, 罗文凤, 叶甲舟, 林燕, 梁嵘. 组蛋白乳酸化在消化系统肿瘤中的研究进展及展望[J]. 中国癌症杂志, 2025, 35(4): 424-430.

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.

图/表 1

表1

组蛋白乳酸化与消化系统肿瘤关系的概述"

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]

表1

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