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World J Gastroenterol. Aug 21, 2026; 32(31): 118472
Published online Aug 21, 2026. doi: 10.3748/wjg.118472
H3K18 La-METTL5-CCT2 signaling axis promotes colorectal cancer progression by inhibiting pyroptosis
Xiao-Peng Wang, Chang Liu, Hao-Wen Zhang, Jing-Ming Zhai, Jia-Xin Zhu, Guan-Duo Sun, Ya-Hang An, Hai-Jun Yang, Dong-Shuai Jing, De-Chun Liu
Xiao-Peng Wang, Jing-Ming Zhai, Jia-Xin Zhu, Guan-Duo Sun, Ya-Hang An, Dong-Shuai Jing, De-Chun Liu, Department of Gastrointestinal Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, Henan Province, China
Chang Liu, Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710000, Shaanxi Province, China
Hao-Wen Zhang, Department of Hepatobiliary Surgery, Anyang Tumor Hospital, Anyang 455000, Henan Province, China
Hai-Jun Yang, Department of Pathology, Anyang Tumor Hospital, Anyang 455000, Henan Province, China
Author contributions: Wang XP and Liu DC conceptualized, supervised, and supported this study; Wang XP and Liu C designed the research studies; Wang XP performed most of the experiments, and wrote the manuscript; Liu C, Zhu JX, Sun GD, and Yang HJ provided technical support; Zhang HW, Zhai JM, An YH, and Jing DS carried out data analysis. All authors have read and approved the final version to publish.
Supported by Henan Province Science and Technology Research Project, No. 232102310043; Henan Provincial Science and Technology Research and Development Plan Joint Fund Project, No. 222103810047; and Key Scientific Research Project Plan of Colleges and Universities in Henan Province, No. 22A320033.
Institutional review board statement: The study protocol was approved by the Medical Research Ethics Committee of Anyang Tumor Hospital, No. 2017WZ11K02.
Institutional animal care and use committee statement: The animal protocol was reviewed and approved by the Medical Research Ethics Committee of Anyang Tumor Hospital, No. 2025WZ04K03.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The data described in this article can be requested from the corresponding authors upon reasonable request.
Corresponding author: De-Chun Liu, MD, PhD, Professor, Department of Gastrointestinal Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, No. 24 Jinghua Road, Jianxi District, Luoyang 471003, Henan Province, China.
lydocliu666@163.com
Received: January 4, 2026
Revised: March 31, 2026
Accepted: May 25, 2026
Published online: August 21, 2026
Processing time: 213 Days and 22.5 Hours
BACKGROUND
Histone lactylation, a novel epigenetic mark, has been revealed to be involved in tumorigenesis. However, its role in colorectal cancer (CRC) remains unclear. In this study, the functional roles and mechanisms of histone lactylation in CRC progression were explored.
AIM
To investigate the functional roles and molecular mechanisms of histone H3K18 lactylation (H3K18 La) in CRC progression, focusing on its regulation of pyroptosis and the downstream METTL5/CCT2 axis.
METHODS
Using 80 paired CRC/normal tissues, we assessed histone H3K18 La levels via immunohistochemistry and western blotting. Lactate levels were modulated pharmacologically. Cleavage under targets and tagmentation, transcriptome sequencing, and RNA immunoprecipitation assays were used to investigate transcriptional regulation and mRNA stability. The functional roles of METTL5 and CCT2 were tested in vitro via proliferation, migration, and invasion assays and in vivo. Pyroptosis-related protein levels were analyzed by flow cytometry and western blotting.
RESULTS
Significantly elevated H3K18 La levels were observed in CRC tissues and correlated with advanced stage and poor prognosis. Lactate depletion reduced global lactylation and H3K18 La levels, thus suppressing CRC malignancy. Mechanistically, H3K18 La enrichment at the METTL5 promoter drove its transcription. METTL5, in turn, stabilized CCT2 mRNA via m6A modification, upregulating CCT2 expression. METTL5 and CCT2 promoted CRC proliferation and metastasis in vitro and in vivo, whereas CCT2 overexpression reversed the effects of METTL5 knockdown. This H3K18 La-METTL5-CCT2 axis suppressed pyroptosis by downregulating GSDMD-N, NLRP3, and cleaved caspase-1. CCT2 can regulate inflammasome activation by directly binding to NLRP3, thereby inhibiting the progression of pyroptosis in CRC cells. Furthermore, the AKT inhibitor AZD6482 synergized with oxaliplatin to increase cytotoxicity in CRC cells.
CONCLUSION
This study systematically reveals for the first time that the H3K18 La-METTL5-CCT2 axis promotes the malignant progression of CRC through the inhibition of pyroptosis. This mechanism integrates the crosstalk among metabolic reprogramming, histone lactylation, and m6A RNA methylation, providing a novel perspective for understanding the multilevel regulatory network underlying CRC progression. On the basis of these findings, the therapeutic strategy of combining AZD6482 with oxaliplatin has promising translational potential in chemosensitization. This study provides a new theoretical basis and potential intervention targets for the prognostic evaluation and targeted therapy of CRC.
Core Tip: Lactate-induced histone H3K18 lactylation drives colorectal cancer progression by activating METTL5 transcription. METTL5 stabilizes CCT2 mRNA via m6A modification, upregulating CCT2 expression and inhibiting pyroptosis. This H3K18 lactylation-METTL5-CCT2 signaling axis links metabolic reprogramming, epigenetics, and RNA methylation to suppress cell death and promote malignancy. Targeting this pathway with the PI3Kβ inhibitor AZD6482 increases oxaliplatin cytotoxicity in high-lactate microenvironments, offering a novel therapeutic strategy for colorectal cancer.
