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<p>Endometriosis (EMs) is a chronic inflammatory disorder featured by infertility and pain. The role of N6-methyladenosine (m6A) in EMs has been evidenced. This study investigated the molecular mechanism of <i>METTL14</i>-m6A-<i>KLF4</i> modulating macrophage polarization in EMs.&#xa0;RT-qPCR assay was conducted to test <i>METTL14</i> levels in tissues and cells and the relative mRNA levels of M2 (<i>Arg-1</i>, <i>Fizz1</i>) and M1 (<i>iNOS</i>, <i>IL-1β</i>) factors in the supernatant after co-culture of macrophages with normal endometrial stromal cells (nESCs) or ectopic endometrial stromal cells (eESCs). <i>CD206</i> and <i>CD86</i> expression, as well as <i>Arg-1</i>, IL-10, and IL-4 levels, were assessed. Meanwhile, the relationship between <i>METTL14</i> and the m6A modification of <i>KLF4</i> was analyzed. Additionally, the effect of <i>KLF4</i>-activated M2 macrophages on in vitro ESC progression was observed.&#xa0;Cellular and tissue <i>METTL14</i> was under-expressed in EMs. <i>METTL14</i> expression might be related to macrophage M2 polarization. Co-culture of eESCs overexpressing <i>METTL14</i> and macrophages downregulated <i>Arg-1</i>, <i>Fizz1</i>, <i>CD206</i>, IL-10, and IL-4 levels. Mechanistically, <i>METTL14</i> could mediate <i>KLF4</i> m6A modification through the m6A reading protein <i>YTHDF2</i>. <i>KLF4</i> overexpression could nullify <i>METTL14</i> re-expression-repressed M2 macrophage polarization. In addition, <i>KLF4</i>-activated M2 macrophages accelerated the proliferation and migration of ESCs in vitro.&#xa0;<i>METTL14</i>-m6A-<i>KLF4</i> regulated macrophage polarization in EMs.</p>

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METTL14/YTHDF2 m6A Axis Protects Against M2 Macrophage Polarization in Endometriosis by Regulating KLF4 Stability

  • 期刊论文

  • 发表日期：

    2025年6月23日

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  • Li Li,
  • Xiaoyan Wang,
  • You Wu,
  • Yi Liu,
  • Mingzhe Zhang

摘要

Endometriosis (EMs) is a chronic inflammatory disorder featured by infertility and pain. The role of N6-methyladenosine (m6A) in EMs has been evidenced. This study investigated the molecular mechanism of METTL14-m6A-KLF4 modulating macrophage polarization in EMs. RT-qPCR assay was conducted to test METTL14 levels in tissues and cells and the relative mRNA levels of M2 (Arg-1, Fizz1) and M1 (iNOS, IL-1β) factors in the supernatant after co-culture of macrophages with normal endometrial stromal cells (nESCs) or ectopic endometrial stromal cells (eESCs). CD206 and CD86 expression, as well as Arg-1, IL-10, and IL-4 levels, were assessed. Meanwhile, the relationship between METTL14 and the m6A modification of KLF4 was analyzed. Additionally, the effect of KLF4-activated M2 macrophages on in vitro ESC progression was observed. Cellular and tissue METTL14 was under-expressed in EMs. METTL14 expression might be related to macrophage M2 polarization. Co-culture of eESCs overexpressing METTL14 and macrophages downregulated Arg-1, Fizz1, CD206, IL-10, and IL-4 levels. Mechanistically, METTL14 could mediate KLF4 m6A modification through the m6A reading protein YTHDF2. KLF4 overexpression could nullify METTL14 re-expression-repressed M2 macrophage polarization. In addition, KLF4-activated M2 macrophages accelerated the proliferation and migration of ESCs in vitro. METTL14-m6A-KLF4 regulated macrophage polarization in EMs.