Chlorogenic acid promotes macrophage phagocytosis through the METTL3–SIRPA axis in an m6A-dependent manner for colon cancer therapy
Open accessAbstract
Epigenetic modifications, particularly N6-methyladenosine (m6A) modifications, alter the phenotype of macrophages. Among the m6A-related proteins, methyltransferase 3 (METTL3), as the catalytic core methyltransferase subunit, plays an essential role in regulating the function of macrophages. This study aimed to explore novel m6A inhibitors from natural products that target METTL3 to modulate the phagocytic function of macrophages in the treatment of colon cancer. In this work, first, a high-throughput screening of biological m6A by colorimetric assay was conducted to rapidly identify candidate inhibitors from a natural product library. Second, bioinformatics analysis and molecular biological methods revealed the underlying mechanisms through which METTL3 regulates macrophage-mediated phagocytosis. Subsequently, Mettl3 f/f Lyz2 -Cre mice were generated to further elucidate the mechanism through which METTL3 inhibition promotes the phagocytic function of macrophages by modulating the mRNA stability of SIRPA, a key phagocytic-related protein, in vivo . We determined that chlorogenic acid (CHA) is a potential therapeutic METTL3 inhibitor because of its influence on METTL3 enzymatic activity and expression. METTL3 inhibition promoted the phagocytic function of macrophages. METTL3 increases the mRNA stability of the intrinsic immune checkpoint SIRPA by activating IGF2BP2 in an m6A-dependent manner, which subsequently increases its protein expression and suppresses the phagocytosis of macrophages both in vivo and in vitro . In conclusion, CHA is a candidate inhibitor compound that targets the METTL3–SIRPA axis through enhancing the phagocytic function of macrophages and is thus a promising therapy for treating colon cancer.
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- Authors
- Zhou, E., Xing, Z., Wang, M., Lu, D., Hao, M., Tang, G., Li, S., Chen, Y., Zhang, W., Li, X., Zhang, B., Wang, F., Ju, W., & Jin, J.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Wang, Mingchao
- Wang, Fang
- Ju, Wenhao
- Jin, Jing
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2026-10
- Volume
- 252
- Pages
- 118198
- ISSN
- 0006-2952 (ISSN-L)
- OpenAlex
- W7165961585
- Cited by
- 0
- References
- 45
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biochemical Pharmacology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Key Research and Development Program of China (2023YFC3502804, 2024YFE0201300)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- chlorogenic acid, METTL3, SIRPα, N6-methyladenosine, m6A RNA methylation, macrophage phagocytosis, colon cancer, IGF2BP2, mRNA stability, immune checkpoint, tumor-associated macrophages
- MeSH terms
- RAW 264.7 Cells, RNA Methylation, Adenosine, Animals, Chlorogenic Acid, Colonic Neoplasms, Humans, Macrophages, Male, Methyltransferases, Mice, Inbred C57BL, Phagocytosis, Mice
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