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Objective <p>While the RNA modification N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) is known to influence immune cell function, its specific role in regulating macrophage migration and invasion remains poorly defined. This study aimed to elucidate the function and mechanism of the core m<sup>6</sup>A methyltransferase METTL3 in the migratory and invasive capacities of macrophages.</p> Methods <p>A macrophage-specific METTL3-knockdown model was established. The functional effects of METTL3 deficiency were systematically evaluated using migration, invasion, phagocytosis, and polarization assays. Subsequent transcriptome sequencing (RNA-seq) and methylated RNA immunoprecipitation-quantitative PCR (MeRIP-qPCR) were employed to identify the key differentially expressed gene, lysyl oxidase-like 2 (<i>LOXL2</i>). This mechanistic link was ultimately confirmed through functional rescue experiments and reconstitution assays.</p> Results <p>METTL3 deficiency significantly increased the migratory and invasive capacities of macrophages but attenuated their phagocytic activity, promoting a shift toward an M2-like polarization state. Mechanistically, METTL3 knockdown reduced m<sup>6</sup>A modification at a specific site of LOXL2 mRNA, thereby decreasing its RNA stability and leading to decreased expression. Importantly, this phenotype was validated through functional inhibition assays. Reconstitution of LOXL2 in METTL3-deficient macrophages substantially reversed the enhanced migratory and invasive phenotypes.</p> Conclusion <p>This study reveals a novel METTL3–m<sup>6</sup>A–LOXL2 signaling axis that posttranscriptionally fine-tunes macrophage migration and invasion by regulating gene expression. These findings provide a mechanistic explanation for the functional dynamics of macrophage migration and invasion and underscore that m<sup>6</sup>A modification is a key regulator of innate immune cell behavior.</p>

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METTL3–m6A–LOXL2 Axis Post-Transcriptionally Fine-Tunes Macrophage Migration and Invasion

  • 期刊论文

  • 发表日期：

    2026年5月27日

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  • Zheng Li,
  • Xiao-han Sa,
  • Yu-wen Han,
  • Pu Wang,
  • Xue-yan Song,
  • Min-xuan Sun

摘要

Objective

While the RNA modification N6-methyladenosine (m6A) is known to influence immune cell function, its specific role in regulating macrophage migration and invasion remains poorly defined. This study aimed to elucidate the function and mechanism of the core m6A methyltransferase METTL3 in the migratory and invasive capacities of macrophages.

Methods

A macrophage-specific METTL3-knockdown model was established. The functional effects of METTL3 deficiency were systematically evaluated using migration, invasion, phagocytosis, and polarization assays. Subsequent transcriptome sequencing (RNA-seq) and methylated RNA immunoprecipitation-quantitative PCR (MeRIP-qPCR) were employed to identify the key differentially expressed gene, lysyl oxidase-like 2 (LOXL2). This mechanistic link was ultimately confirmed through functional rescue experiments and reconstitution assays.

Results

METTL3 deficiency significantly increased the migratory and invasive capacities of macrophages but attenuated their phagocytic activity, promoting a shift toward an M2-like polarization state. Mechanistically, METTL3 knockdown reduced m6A modification at a specific site of LOXL2 mRNA, thereby decreasing its RNA stability and leading to decreased expression. Importantly, this phenotype was validated through functional inhibition assays. Reconstitution of LOXL2 in METTL3-deficient macrophages substantially reversed the enhanced migratory and invasive phenotypes.

Conclusion

This study reveals a novel METTL3–m6A–LOXL2 signaling axis that posttranscriptionally fine-tunes macrophage migration and invasion by regulating gene expression. These findings provide a mechanistic explanation for the functional dynamics of macrophage migration and invasion and underscore that m6A modification is a key regulator of innate immune cell behavior.