Chlorogenic acid promotes macrophage phagocytosis through the METTL3-SIRPA axis in an m6A-dependent manner for colon cancer therapy

  • Biochem Pharmacol. 2026 Jun 25:252:118198. doi: 10.1016/j.bcp.2026.118198.
Enjia Zhou  1 ,  Zeyu Xing  2 ,  Mingchao Wang  1 ,  Dongxu Lu  3 ,  Mengyao Hao  1 ,  Guodong Tang  1 ,  Shuying Li  1 ,  Yiran Chen  1 ,  Wenjing Zhang  1 ,  Xinyu Li  1 ,  Bolin Zhang  1 ,  Fang Wang  4 ,  Wenhao Ju  5 ,  Jing Jin  6
Affiliations
  • 1. Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 2. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China.
  • 3. State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing China.
  • 4. State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Haihe Laboratory of Cell Ecosystem, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing China; The Key Laboratory of RNA and Hematopoietic Regulation, Chinese Academy of Medical Sciences, Beijing, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Key Laboratory of Innovative Cardiovascular Devices, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China. Electronic address: [email protected].
  • 6. Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
PMID: 42349614 DOI: 10.1016/j.bcp.2026.118198
Abstract

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, METTL3f/fLyz2-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.

Keywords
Chlorogenic acid; Colon cancer; IGF2BP2; METTL3; Phagocytic function of macrophages; SIRPA.
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