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World Journal of Gastroenterology
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1007-9327
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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Basic Study
Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.
World J Gastroenterol. Jan 21, 2027; 33(3): 123673
Published online Jan 21, 2027. doi: 10.3748/wjg.123673
METTL1-mediated N7-methylguanosine modification promotes glycolysis and H4K5 lactylation-dependent Snail-1 activation in pancreatic adenocarcinoma peritoneal metastasis
Chen Yang, Chen-Zhiang Qiu, Zhi-Gang Yin, Yong Mao, Xiao-Song Ge, Fang Wang
Chen Yang, Chen-Zhiang Qiu, Yong Mao, Xiao-Song Ge, Fang Wang, Department of Cancer Diagnosis and Treatment Center, Affiliated Hospital of Jiangnan University, Wuxi 214122, Jiangsu Province, China
Zhi-Gang Yin, Department of Pathology, Affiliated Hospital of Jiangnan University, Wuxi 214122, Jiangsu Province, China
Co-first authors: Chen Yang and Chen-Zhiang Qiu.
Co-corresponding authors: Xiao-Song Ge and Fang Wang.
Author contributions: Yang C and Qiu CZA contributed equally to this work, with major intellectual contributions to study design, experimental data acquisition-analysis, and manuscript drafting and revision, they are co-first authors of this manuscript. Yang C, Ge XS, and Wang F designed the research study; Mao Y, Ge XS, and Wang F supervised the study; Yang C, Qiu CZA, and Yin ZG performed most experiments, analyzed data, drafted and revised the manuscript; Ge XS and Wang F contributed equally to this manuscript and are co-corresponding authors. All authors read and approved the final manuscript.
AI contribution statement: Portions of this manuscript were edited using AI tools solely for language refinement. The authors carefully reviewed and verified all AI-assisted outputs and take full responsibility for the scientific content of the manuscript.
Institutional review board statement: This study was approved by the Medical Ethics Committee of Affiliated Hospital of Jiangnan University (No. LS2025036).
Institutional animal care and use committee statement: All animal experimental protocols were reviewed and approved by the Animal Ethics Committee of Jiangnan University School of Medicine (Ethics approval JN. No. 20231130m0871322).
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: All the data generated or analyzed in this study are included in this published article. The data are available upon request from the corresponding author.
Corresponding author: Fang Wang, PhD, Department of Cancer Diagnosis and Treatment Center, Affiliated Hospital of Jiangnan University, No. 1000 Hefeng Road, Binghu District, Wuxi 214122, Jiangsu Province, China. wangfang_lukas@jiangnan.edu.cn
Received: June 1, 2026
Revised: July 6, 2026
Accepted: October 8, 2026
Published online: January 21, 2027
Processing time: 172 Days and 12.2 Hours
Abstract
BACKGROUND

Pancreatic adenocarcinoma (PAAD) is highly malignant with extremely poor prognosis, and peritoneal metastasis serves as a major lethal cause. Both N7-methylguanosine (m7G) RNA methylation and histone lactylation participate in tumor malignant progression. The molecular mechanism underlying their interactive regulation on PAAD metastasis remains to be further explored.

AIM

To investigate the biological function of METTL1 in PAAD peritoneal metastasis. We clarified that METTL1 upregulates PKM2 expression by modifying PKM mRNA, regulates glycolysis and lactate production, and subsequently activates Snail-1 and triggers epithelial-mesenchymal transition (EMT) through histone H4K5 lactylation (H4K5 La).

METHODS

Clinical PAAD specimens and peritoneal metastatic tissues were collected to analyze the correlation of METTL1 expression with clinicopathological parameters and patient prognosis. METTL1 knockdown and overexpression PAAD cell lines were constructed. In vitro assays including cell proliferation, colony formation, migration and invasion were performed. A nude mouse intraperitoneal colonization metastasis model was established to verify in vivo biological functions. m7G methylated RNA immunoprecipitation-sequencing and RNA immunoprecipitation quantitative polymerase chain reaction were applied to confirm the targeted m7G modification of PKM mRNA mediated by METTL1. Cellular glycolytic level and lactate content were detected. Western blot and Cleavage Under Targets & Tagmentation assays were used to verify the regulatory effect of H4K5 La on Snail-1 transcription. Rescue experiments were conducted to define the upstream and downstream molecular relationships.

RESULTS

METTL1 was markedly overexpressed in PAAD and peritoneal metastatic tissues, acting as an independent risk factor for unfavorable prognosis. METTL1 significantly facilitated malignant phenotypes and intraperitoneal metastatic colonization of PAAD cells. Molecular mechanism assays revealed that METTL1 directly elevated m7G modification level of PKM mRNA and increased PKM2 protein expression. Abnormally high PKM2 expression enhanced glycolytic capacity and induced massive lactate accumulation. Intracellular lactate specifically increased histone H4K5 La. H4K5 La was enriched in the Snail-1 promoter region and prominently promoted Snail-1 transcription, thereby inducing EMT in PAAD cells. Clinical samples verified synergistically elevated expression of METTL1, PKM2, H4K5 La and Snail-1 in peritoneal metastatic lesions.

CONCLUSION

METTL1 catalyzes m7G modification on PKM mRNA to upregulate PKM2 expression, accelerates glycolysis activation and lactate accumulation in PAAD, and further induces abnormal H4K5 La to activate Snail-1 signaling pathway, ultimately facilitating EMT progression and peritoneal metastasis of tumor cells. This study established a synergistic regulatory axis of RNA m7G modification-glycolysis-histone lactylation, providing novel insights for mechanism elucidation and targeted intervention of PAAD peritoneal metastasis.

Keywords: Pancreatic adenocarcinoma; METTL1; N7-methylguanosine modification; Histone lactylation; Peritoneal metastasis

Core Tip: High METTL1 expression is associated with poor prognosis and peritoneal metastasis in pancreatic adenocarcinoma (PAAD). METTL1 promotes malignant phenotypes and intraperitoneal colonization by directly increasing N7-methylguanosine (m7G) modification of PKM mRNA, leading to PKM2 upregulation, enhanced glycolysis, and lactate accumulation. Elevated lactate specifically drives histone H4K5 lactylation, which activates Snail-1 transcription and subsequent epithelial-mesenchymal transition. This study establishes an RNA m7G modification-glycolysis-histone lactylation regulatory axis, offering novel insights for targeted intervention in PAAD peritoneal metastasis.
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