Research progress on regulatory mechanisms and clinical application prospects of lactylation modification in progression of gastric cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

HU Pengtao ¹ , LU Jian ² ,  Lü Chengyu ¹

1. Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, P. R. China;
2. International Oncology Institute, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310053, P. R. China;

Corresponding?author：

Lü Chengyu, Email: lcy_1234@aliyun.com

Keywords：

lactate metabolism; lactylation modification; gastric cancer; drug resistance; targeted therapy

DOI：

10.7507/1007-9424.202511118

Video：

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Objective To systematically summarize the role and molecular basis of lactylation modification in gastric cancer progression (including tumor initiation, development, and drug resistance), and to explore its potential clinical translational value. Method The literature published in recent years, both domestically and internationally, focusing on the regulatory mechanisms and clinical applications of lactylation modification in gastric cancer progression was reviewed. Results A substantial number of lysine lactylation sites have been systematically identified in gastric cancer. Lactylation modification dynamically regulates the functions of histones (e.g., H3K18la) and non-histone proteins (e.g., PKM2, CPT2) through the “writer–reader–eraser” enzymatic mechanism. It drives cancer cell proliferation, invasion, and metastasis via the NLRP12/HK2 axis and the H3K18la/METTL14/ATF5 pathway. Furthermore, lactylation mediates immune escape by upregulating programmed death-ligand 1 and inducing M2 polarization of macrophages. It also confers resistance to treatments such as oxaliplatin and anlotinib through the BASP1-AS1/LDHA/PCBP2 positive feedback loop and lactate dehydrogenase (LDH) B delactylation. Preclinical studies have demonstrated that targeting glycolysis (inhibiting LDHA), restoring delactylase (SIRT1/2) activity, precisely intervening in the lactylation levels of specific proteins (such as LDHBK58 and TRIM29), or combining with cuproptosis inducers can effectively inhibit tumor growth and sensitize therapeutic responses. Additionally, prognostic models based on lactylation-related genes (e.g., NLRP12) have shown significant potential for clinical outcome assessment. Conclusions Lactylation modification synergistically promotes the malignant progression and multidrug resistance of gastric cancer by integrating metabolic reprogramming with epigenetic regulation. Interventions targeting key components of this modification demonstrate promising therapeutic prospects. However, there is currently a lack of highly specific targeting tools. Future research should focus on deeply deciphering the regulatory networks of lactylation, developing selective inhibitors, and establishing reliable prognostic evaluation models to facilitate clinical translation.

Citation： HU Pengtao, LU Jian, Lü Chengyu. Research progress on regulatory mechanisms and clinical application prospects of lactylation modification in progression of gastric cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2026, 33(5): 726-732. doi: 10.7507/1007-9424.202511118 Copy

1.	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2.	Hu Z, Liu Z, Li W, et al. Health economic evaluation on population-based Helicobacter pylori eradication and endoscopic screening for gastric cancer prevention. Chin J Cancer Res, 2023, 35(6): 595-605.
3.	Chen W, Shi K, Liu J, et al. Sustained co-delivery of 5-fluorouracil and cis-platinum via biodegradable thermo-sensitive hydrogel for intraoperative synergistic combination chemotherapy of gastric cancer. Bioact Mater, 2022, 23: 1-15.
4.	Luo QY, Yang J, Di T, et al. The novel BCL-2/BCL-XL inhibitor APG-1252-mediated cleavage of GSDME enhances the antitumor efficacy of HER2-targeted therapy in HER2-positive gastric cancer. Acta Pharmacol Sin, 2025, 46(4): 1082-1096.
5.	Hong H, Han H, Wang L, et al. ABCF1-K430-lactylation promotes HCC malignant progression via transcriptional activation of HIF1 signaling pathway. Cell Death Differ, 2025, 32(4): 613-631.
6.	Zhang C, Yu R, Li S, et al. KRAS mutation increases histone H3 lysine 9 lactylation (H3K9la) to promote colorectal cancer progression by facilitating cholesterol transporter GRAMD1A expression. Cell Death Differ, 2025, 32(12): 2225-2238.
7.	Zhang C, Zhou L, Zhang M, et al. H3K18 lactylation potentiates immune escape of non-small cell lung cancer. Cancer Res, 2024, 84(21): 3589-3601.
8.	Tsukihara S, Akiyama Y, Shimada S, et al. Delactylase effects of SIRT1 on a positive feedback loop involving the H19-glycolysis-histone lactylation in gastric cancer. Oncogene, 2025, 44(11): 724-738.
9.	de la Cruz-López KG, Castro-Mu?oz LJ, Reyes-Hernández DO, et al. Lactate in the regulation of tumor microenvironment and therapeutic approaches. Front Oncol, 2019, 9: 1143. doi: 10.3389/fonc.2019.01143.
10.	Felmlee MA, Jones RS, Rodriguez-Cruz V, et al. Monocarboxylate transporters (SLC16): function, regulation, and role in health and disease. Pharmacol Rev, 2020, 72(2): 466-485.
11.	Faghihkhorasani F, Moosavi M, Rasool Riyadh Abdulwahid AH, et al. Role of monocarboxylate transporters in cancer immunology and their therapeutic potential. Br J Pharmacol, 2025, 182(19): 4421-4457.
12.	Huang YF, Wang G, Ding L, et al. Lactate-upregulated NADPH-dependent NOX4 expression via HCAR1/PI3K pathway contributes to ROS-induced osteoarthritis chondrocyte damage. Redox Biol, 2023, 67: 102867. doi: 10.1016/j.redox.2023.102867.
13.	Ruan D, Hu T, Yang X, et al. Lactate in skin homeostasis: metabolism, skin barrier, and immunomodulation. Front Immunol, 2025, 16: 1510559. doi: 10.3389/fimmu.2025.1510559.
14.	Zhang D, Tang Z, Huang H, et al. Metabolic regulation of gene expression by histone lactylation. Nature, 2019, 574(7779): 575-580.
15.	Ren H, Tang Y, Zhang D. The emerging role of protein L-lactylation in metabolic regulation and cell signalling. Nat Metab, 2025, 7(4): 647-664.
16.	Duan Y, Zhan H, Wang Q, et al. Integrated lactylome characterization reveals the molecular dynamics of protein regulation in gastrointestinal cancers. Adv Sci (Weinh), 2024, 11(35): e2400227. doi: 10.1002/advs.202400227.
17.	Shi P, Ma Y, Zhang S. Non-histone lactylation: unveiling its functional significance. Front Cell Dev Biol, 2025, 13: 1535611. doi: 10.3389/fcell.2025.1535611.
18.	Li S, Dong L, Wang K. Current and future perspectives of lysine lactylation in cancer. Trends Cell Biol, 2025, 35(3): 190-193.
19.	Jenke R, Oliinyk D, Zenz T, et al. HDAC inhibitors activate lipid peroxidation and ferroptosis in gastric cancer. Biochem Pharmacol, 2024, 225: 116257. doi: 10.1016/j.bcp.2024.116257.
20.	Dong L, Zhu J, Deng A, et al. Relationship between histone demethylase LSD family and development and prognosis of gastric cancer. Front Immunol, 2023, 14: 1170773. doi: 10.3389/fimmu.2023.1170773.
21.	Gaffney DO, Jennings EQ, Anderson CC, et al. Non-enzymatic lysine lactoylation of glycolytic enzymes. Cell Chem Biol, 2020, 27(2): 206-213.
22.	Trujillo MN, Jennings EQ, Hoffman EA, et al. Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation. Mol Metab, 2024, 81: 101888. doi: 10.1016/j.molmet.2024.101888.
23.	Lv M, Huang Y, Chen Y, et al. Lactylation modification in cancer: mechanisms, functions, and therapeutic strategies. Exp Hematol Oncol, 2025, 14(1): 32. doi: 10.1186/s40164-025-00622-x.
24.	Yang D, Yin J, Shan L, et al. Identification of lysine-lactylated substrates in gastric cancer cells. iScience, 2022, 25(7): 104630. doi: 10.1016/j.isci.2022.104630.
25.	Zhou L, Wang Z, Huang Y, et al. NLRP12 decreases TRIM25-mediated HK2 degradation to promote glycolysis and H3K18la in gastric cancer. Cell Death Dis, 2025, 16(1): 615. doi: 10.1038/s41419-025-07923-3.
26.	Shao M, Zhang J, Zhang J, et al. SALL4 promotes gastric cancer progression via hexokinase Ⅱ mediated glycolysis. Cancer Cell Int, 2020, 20: 188. doi: 10.1186/s12935-020-01275-y.
27.	Shi B, Liu WW, Yang K, et al. The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer. Mol Cancer, 2022, 21(1): 163. doi: 10.1186/s12943-022-01634-5.
28.	Zhang P, Xiang H, Peng Q, et al. METTL14 attenuates cancer stemness by suppressing ATF5/WDR74/β-catenin axis in gastric cancer. Cancer Sci, 2025, 116(1): 112-127.
29.	Yang H, Yang S, He J, et al. Glucose transporter 3 (GLUT3) promotes lactylation modifications by regulating lactate dehydrogenase A (LDHA) in gastric cancer. Cancer Cell Int, 2023, 23(1): 303. doi: 10.1186/s12935-023-03162-8.
30.	Shen X, Shi H, Liu L, et al. PFKM promotes the progression of gastric cancer by up-regulating CNTN1 expression through H3K18la modification. Appl Biochem Biotechnol, 2025, 197(9): 5885-5901.
31.	Zhao Y, Jiang J, Zhou P, et al. H3K18 lactylation-mediated VCAM1 expression promotes gastric cancer progression and metastasis via AKT-mTOR-CXCL1 axis. Biochem Pharmacol, 2024, 222: 116120. doi: 10.1016/j.bcp.2024.116120.
32.	Li Z, Liang P, Chen Z, et al. CAF-secreted LOX promotes PD-L1 expression via histone lactylation and regulates tumor EMT through TGFβ/IGF1 signaling in gastric cancer. Cell Signal, 2024, 124: 111462. doi: 10.1016/j.cellsig.2024.111462.
33.	Zhang L, Li S. Lactic acid promotes macrophage polarization through MCT-HIF1α signaling in gastric cancer. Exp Cell Res, 2020, 388(2): 111846. doi: 10.1016/j.yexcr.2020.111846.
34.	Jin Z, Lu Y, Wu X, et al. The cross-talk between tumor cells and activated fibroblasts mediated by lactate/BDNF/TrkB signaling promotes acquired resistance to anlotinib in human gastric cancer. Redox Biol, 2021, 46: 102076. doi: 10.1016/j.redox.2021.102076.
35.	Zhao Y, Liu W, Deng K, et al. LncRNA BASP1-AS1 drives PCBP2 K115 lactylation to suppress ferroptosis and confer oxaliplatin resistance in gastric cancer. Free Radic Biol Med, 2025, 240: 717-734.
36.	Xiao X, Yang Y, Yang Y, et al. Lactate dehydrogenase B delactylation promotes gastric cancer metastasis via enhancing glutathione-mediated resistance to ferroptosis. Cell Biol Toxicol, 2026, 42(1): 46. doi: 10.1007/s10565-026-10165-4.
37.	Hua R, Yu J, Niu Y, et al. Lactylation-drived TRIM29 induces invasive behavior and lymph node metastasis in gastric cancer via hnRNPA1-mediated Wnt/β-catenin pathway. Cell Death Dis, 2026, 17(1): 222. doi: 10.1038/s41419-026-08468-9.
38.	Sun L, Zhang Y, Yang B, et al. Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer. Nat Commun, 2023, 14(1): 6523. doi: 10.1038/s41467-023-42025-8.
39.	Huang C, Liu T, Zhao Y, et al. Histone H4K8 lactylation modulated immunosuppressive properties by promoting FAP transcription and ECM remodeling. Gastric Cancer, 2026, 29(1): 70-82.
40.	Yin X, Xing W, Yi N, et al. Comprehensive analysis of lactylation-related gene sets and mitochondrial functions in gastric adenocarcinoma: implications for prognosis and therapeutic strategies. Front Immunol, 2024, 15: 1451725. doi: 10.3389/fimmu.2024.1451725.
41.	Yang H, Zou X, Yang S, et al. Identification of lactylation related model to predict prognostic, tumor infiltrating immunocytes and response of immunotherapy in gastric cancer. Front Immunol, 2023, 14: 1149989. doi: 10.3389/fimmu.2023.1149989.
42.	Sun XZ, Dong HF, Su RS, et al. Lactylation-related gene signature accurately predicts prognosis and immunotherapy response in gastric cancer. Front Oncol, 2024, 14: 1485580. doi: 10.3389/fonc.2024.1485580.

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2. Hu Z, Liu Z, Li W, et al. Health economic evaluation on population-based Helicobacter pylori eradication and endoscopic screening for gastric cancer prevention. Chin J Cancer Res, 2023, 35(6): 595-605.
3. Chen W, Shi K, Liu J, et al. Sustained co-delivery of 5-fluorouracil and cis-platinum via biodegradable thermo-sensitive hydrogel for intraoperative synergistic combination chemotherapy of gastric cancer. Bioact Mater, 2022, 23: 1-15.
4. Luo QY, Yang J, Di T, et al. The novel BCL-2/BCL-XL inhibitor APG-1252-mediated cleavage of GSDME enhances the antitumor efficacy of HER2-targeted therapy in HER2-positive gastric cancer. Acta Pharmacol Sin, 2025, 46(4): 1082-1096.
5. Hong H, Han H, Wang L, et al. ABCF1-K430-lactylation promotes HCC malignant progression via transcriptional activation of HIF1 signaling pathway. Cell Death Differ, 2025, 32(4): 613-631.
6. Zhang C, Yu R, Li S, et al. KRAS mutation increases histone H3 lysine 9 lactylation (H3K9la) to promote colorectal cancer progression by facilitating cholesterol transporter GRAMD1A expression. Cell Death Differ, 2025, 32(12): 2225-2238.
7. Zhang C, Zhou L, Zhang M, et al. H3K18 lactylation potentiates immune escape of non-small cell lung cancer. Cancer Res, 2024, 84(21): 3589-3601.
8. Tsukihara S, Akiyama Y, Shimada S, et al. Delactylase effects of SIRT1 on a positive feedback loop involving the H19-glycolysis-histone lactylation in gastric cancer. Oncogene, 2025, 44(11): 724-738.
9. de la Cruz-López KG, Castro-Mu?oz LJ, Reyes-Hernández DO, et al. Lactate in the regulation of tumor microenvironment and therapeutic approaches. Front Oncol, 2019, 9: 1143. doi: 10.3389/fonc.2019.01143.
10. Felmlee MA, Jones RS, Rodriguez-Cruz V, et al. Monocarboxylate transporters (SLC16): function, regulation, and role in health and disease. Pharmacol Rev, 2020, 72(2): 466-485.
11. Faghihkhorasani F, Moosavi M, Rasool Riyadh Abdulwahid AH, et al. Role of monocarboxylate transporters in cancer immunology and their therapeutic potential. Br J Pharmacol, 2025, 182(19): 4421-4457.
12. Huang YF, Wang G, Ding L, et al. Lactate-upregulated NADPH-dependent NOX4 expression via HCAR1/PI3K pathway contributes to ROS-induced osteoarthritis chondrocyte damage. Redox Biol, 2023, 67: 102867. doi: 10.1016/j.redox.2023.102867.
13. Ruan D, Hu T, Yang X, et al. Lactate in skin homeostasis: metabolism, skin barrier, and immunomodulation. Front Immunol, 2025, 16: 1510559. doi: 10.3389/fimmu.2025.1510559.
14. Zhang D, Tang Z, Huang H, et al. Metabolic regulation of gene expression by histone lactylation. Nature, 2019, 574(7779): 575-580.
15. Ren H, Tang Y, Zhang D. The emerging role of protein L-lactylation in metabolic regulation and cell signalling. Nat Metab, 2025, 7(4): 647-664.
16. Duan Y, Zhan H, Wang Q, et al. Integrated lactylome characterization reveals the molecular dynamics of protein regulation in gastrointestinal cancers. Adv Sci (Weinh), 2024, 11(35): e2400227. doi: 10.1002/advs.202400227.
17. Shi P, Ma Y, Zhang S. Non-histone lactylation: unveiling its functional significance. Front Cell Dev Biol, 2025, 13: 1535611. doi: 10.3389/fcell.2025.1535611.
18. Li S, Dong L, Wang K. Current and future perspectives of lysine lactylation in cancer. Trends Cell Biol, 2025, 35(3): 190-193.
19. Jenke R, Oliinyk D, Zenz T, et al. HDAC inhibitors activate lipid peroxidation and ferroptosis in gastric cancer. Biochem Pharmacol, 2024, 225: 116257. doi: 10.1016/j.bcp.2024.116257.
20. Dong L, Zhu J, Deng A, et al. Relationship between histone demethylase LSD family and development and prognosis of gastric cancer. Front Immunol, 2023, 14: 1170773. doi: 10.3389/fimmu.2023.1170773.
21. Gaffney DO, Jennings EQ, Anderson CC, et al. Non-enzymatic lysine lactoylation of glycolytic enzymes. Cell Chem Biol, 2020, 27(2): 206-213.
22. Trujillo MN, Jennings EQ, Hoffman EA, et al. Lactoylglutathione promotes inflammatory signaling in macrophages through histone lactoylation. Mol Metab, 2024, 81: 101888. doi: 10.1016/j.molmet.2024.101888.
23. Lv M, Huang Y, Chen Y, et al. Lactylation modification in cancer: mechanisms, functions, and therapeutic strategies. Exp Hematol Oncol, 2025, 14(1): 32. doi: 10.1186/s40164-025-00622-x.
24. Yang D, Yin J, Shan L, et al. Identification of lysine-lactylated substrates in gastric cancer cells. iScience, 2022, 25(7): 104630. doi: 10.1016/j.isci.2022.104630.
25. Zhou L, Wang Z, Huang Y, et al. NLRP12 decreases TRIM25-mediated HK2 degradation to promote glycolysis and H3K18la in gastric cancer. Cell Death Dis, 2025, 16(1): 615. doi: 10.1038/s41419-025-07923-3.
26. Shao M, Zhang J, Zhang J, et al. SALL4 promotes gastric cancer progression via hexokinase Ⅱ mediated glycolysis. Cancer Cell Int, 2020, 20: 188. doi: 10.1186/s12935-020-01275-y.
27. Shi B, Liu WW, Yang K, et al. The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer. Mol Cancer, 2022, 21(1): 163. doi: 10.1186/s12943-022-01634-5.
28. Zhang P, Xiang H, Peng Q, et al. METTL14 attenuates cancer stemness by suppressing ATF5/WDR74/β-catenin axis in gastric cancer. Cancer Sci, 2025, 116(1): 112-127.
29. Yang H, Yang S, He J, et al. Glucose transporter 3 (GLUT3) promotes lactylation modifications by regulating lactate dehydrogenase A (LDHA) in gastric cancer. Cancer Cell Int, 2023, 23(1): 303. doi: 10.1186/s12935-023-03162-8.
30. Shen X, Shi H, Liu L, et al. PFKM promotes the progression of gastric cancer by up-regulating CNTN1 expression through H3K18la modification. Appl Biochem Biotechnol, 2025, 197(9): 5885-5901.
31. Zhao Y, Jiang J, Zhou P, et al. H3K18 lactylation-mediated VCAM1 expression promotes gastric cancer progression and metastasis via AKT-mTOR-CXCL1 axis. Biochem Pharmacol, 2024, 222: 116120. doi: 10.1016/j.bcp.2024.116120.
32. Li Z, Liang P, Chen Z, et al. CAF-secreted LOX promotes PD-L1 expression via histone lactylation and regulates tumor EMT through TGFβ/IGF1 signaling in gastric cancer. Cell Signal, 2024, 124: 111462. doi: 10.1016/j.cellsig.2024.111462.
33. Zhang L, Li S. Lactic acid promotes macrophage polarization through MCT-HIF1α signaling in gastric cancer. Exp Cell Res, 2020, 388(2): 111846. doi: 10.1016/j.yexcr.2020.111846.
34. Jin Z, Lu Y, Wu X, et al. The cross-talk between tumor cells and activated fibroblasts mediated by lactate/BDNF/TrkB signaling promotes acquired resistance to anlotinib in human gastric cancer. Redox Biol, 2021, 46: 102076. doi: 10.1016/j.redox.2021.102076.
35. Zhao Y, Liu W, Deng K, et al. LncRNA BASP1-AS1 drives PCBP2 K115 lactylation to suppress ferroptosis and confer oxaliplatin resistance in gastric cancer. Free Radic Biol Med, 2025, 240: 717-734.
36. Xiao X, Yang Y, Yang Y, et al. Lactate dehydrogenase B delactylation promotes gastric cancer metastasis via enhancing glutathione-mediated resistance to ferroptosis. Cell Biol Toxicol, 2026, 42(1): 46. doi: 10.1007/s10565-026-10165-4.
37. Hua R, Yu J, Niu Y, et al. Lactylation-drived TRIM29 induces invasive behavior and lymph node metastasis in gastric cancer via hnRNPA1-mediated Wnt/β-catenin pathway. Cell Death Dis, 2026, 17(1): 222. doi: 10.1038/s41419-026-08468-9.
38. Sun L, Zhang Y, Yang B, et al. Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer. Nat Commun, 2023, 14(1): 6523. doi: 10.1038/s41467-023-42025-8.
39. Huang C, Liu T, Zhao Y, et al. Histone H4K8 lactylation modulated immunosuppressive properties by promoting FAP transcription and ECM remodeling. Gastric Cancer, 2026, 29(1): 70-82.
40. Yin X, Xing W, Yi N, et al. Comprehensive analysis of lactylation-related gene sets and mitochondrial functions in gastric adenocarcinoma: implications for prognosis and therapeutic strategies. Front Immunol, 2024, 15: 1451725. doi: 10.3389/fimmu.2024.1451725.
41. Yang H, Zou X, Yang S, et al. Identification of lactylation related model to predict prognostic, tumor infiltrating immunocytes and response of immunotherapy in gastric cancer. Front Immunol, 2023, 14: 1149989. doi: 10.3389/fimmu.2023.1149989.
42. Sun XZ, Dong HF, Su RS, et al. Lactylation-related gene signature accurately predicts prognosis and immunotherapy response in gastric cancer. Front Oncol, 2024, 14: 1485580. doi: 10.3389/fonc.2024.1485580.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Research progress on regulatory mechanisms and clinical application prospects of lactylation modification in progression of gastric cancer

Abstract Full text Figures/Tables Video References Cited by

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