Li Li, Xiaoyan Wang, You Wu, Yi Liu, Mingzhe Zhang
{"title":"METTL14/YTHDF2 m6A轴通过调节KLF4稳定性保护子宫内膜异位症中的M2巨噬细胞极化。","authors":"Li Li, Xiaoyan Wang, You Wu, Yi Liu, Mingzhe Zhang","doi":"10.1007/s12010-025-05290-5","DOIUrl":null,"url":null,"abstract":"<div><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. 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. 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. <i>METTL14</i>-m6A-<i>KLF4</i> regulated macrophage polarization in EMs.</p></div>","PeriodicalId":465,"journal":{"name":"Applied Biochemistry and Biotechnology","volume":"197 8","pages":"5535 - 5551"},"PeriodicalIF":3.3000,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"METTL14/YTHDF2 m6A Axis Protects Against M2 Macrophage Polarization in Endometriosis by Regulating KLF4 Stability\",\"authors\":\"Li Li, Xiaoyan Wang, You Wu, Yi Liu, Mingzhe Zhang\",\"doi\":\"10.1007/s12010-025-05290-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><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. 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. 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. <i>METTL14</i>-m6A-<i>KLF4</i> regulated macrophage polarization in EMs.</p></div>\",\"PeriodicalId\":465,\"journal\":{\"name\":\"Applied Biochemistry and Biotechnology\",\"volume\":\"197 8\",\"pages\":\"5535 - 5551\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-06-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Applied Biochemistry and Biotechnology\",\"FirstCategoryId\":\"5\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s12010-025-05290-5\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Applied Biochemistry and Biotechnology","FirstCategoryId":"5","ListUrlMain":"https://link.springer.com/article/10.1007/s12010-025-05290-5","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
METTL14/YTHDF2 m6A Axis Protects Against M2 Macrophage Polarization in Endometriosis by Regulating KLF4 Stability
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.
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This journal is devoted to publishing the highest quality innovative papers in the fields of biochemistry and biotechnology. The typical focus of the journal is to report applications of novel scientific and technological breakthroughs, as well as technological subjects that are still in the proof-of-concept stage. Applied Biochemistry and Biotechnology provides a forum for case studies and practical concepts of biotechnology, utilization, including controls, statistical data analysis, problem descriptions unique to a particular application, and bioprocess economic analyses. The journal publishes reviews deemed of interest to readers, as well as book reviews, meeting and symposia notices, and news items relating to biotechnology in both the industrial and academic communities.
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