Jia Zhe, Lu Shan, Wang Zhenchuan, Ge Pengfei
Department of Neurosurgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
Oncol Lett. 2025 Nov 11;31(1):28. doi: 10.3892/ol.2025.15381. eCollection 2026 Jan.
As a novel lactate-derived post-translational modification, histone lactylation links metabolic reprogramming and epigenetic regulation in cancer. Histone lactylation, particularly at histone H3 lysine 18 lactylation (H3K18la), has been implicated in tumor initiation, progression, metastasis, immune evasion and therapy resistance. It modulates oncogenic pathways (such as PI3K/Akt/mTOR, NF-κB, JAK/STAT) and metabolic pathways (such as glycolysis enhancement, fatty acid synthesis via stearoyl-CoA desaturase and glutamine metabolism) and by altering chromatin structure and gene transcription. In the tumor microenvironment, lactate-induced H3K18la polarizes macrophages toward an M2 phenotype, upregulates immune checkpoints and induces CD8 T cells dysfunction, which promotes immunosuppression. However, CD8 T cell-intrinsic lactylation may enhance antitumor immunity during checkpoint blockade. Histone lactylation also induces chemoresistance via autophagy activation, DNA repair and ferroptosis suppression. Therapeutic strategies targeting lactylation include inhibiting lactate transporters, glycolysis or regulation enzymes (such as E1A-binding protein, lysine acetyltransferase 2A and brahma-related gene 1). Furthermore, the clinical potential is emerging, with H3K18la and H4K5la serving as prognostic biomarkers in multiple types of cancer. However, key questions regarding the non-enzymatic modification mechanisms, identification of histone lactation regulatory enzymes and pan-cancer functional heterogeneity are yet to be elucidated. Future research should prioritize translational validation of lactylation-targeted therapies and their integration with existing regimens to overcome resistance and improve immunotherapy efficacy.
作为一种新型的源自乳酸的翻译后修饰，组蛋白乳酸化将癌症中的代谢重编程与表观遗传调控联系起来。组蛋白乳酸化，特别是组蛋白H3赖氨酸18乳酸化（H3K18la），与肿瘤的起始、进展、转移、免疫逃逸和治疗耐药性有关。它通过改变染色质结构和基因转录来调节致癌途径（如PI3K/Akt/mTOR、NF-κB、JAK/STAT）和代谢途径（如糖酵解增强、通过硬脂酰辅酶A去饱和酶的脂肪酸合成和谷氨酰胺代谢）。在肿瘤微环境中，乳酸诱导的H3K18la使巨噬细胞向M2表型极化，上调免疫检查点并诱导CD8 T细胞功能障碍，从而促进免疫抑制。然而，CD8 T细胞内在的乳酸化可能在检查点阻断期间增强抗肿瘤免疫力。组蛋白乳酸化还通过自噬激活、DNA修复和铁死亡抑制诱导化疗耐药性。针对乳酸化的治疗策略包括抑制乳酸转运蛋白、糖酵解或调节酶（如E1A结合蛋白、赖氨酸乙酰转移酶2A和婆罗门相关基因1）。此外，随着H3K18la和H4K5la作为多种癌症的预后生物标志物，其临床潜力正在显现。然而，关于非酶促修饰机制、组蛋白乳酸化调节酶的鉴定以及泛癌功能异质性的关键问题仍有待阐明。未来的研究应优先对靶向乳酸化的疗法进行转化验证，并将其与现有方案整合，以克服耐药性并提高免疫治疗疗效。
