# The Intersection of m6A Methylation and Immune Response in PCOS: A Bioinformatics Perspective

**Authors:** Wenting Xu, Lingli Shi, Aifang Lu, Lijuan Cui, Haiqing Qian, Jiahui Wang, Mengyu Tang, Lili Zhu, Lihong Wang

PMC · DOI: 10.1002/iid3.70376 · Immunity, Inflammation and Disease · 2026-02-22

## TL;DR

This study explores how RNA methylation and immune responses are connected in PCOS, identifying key genes that could help diagnose and treat the condition.

## Contribution

The study identifies specific m6A-related genes and their immune correlations in PCOS, offering new diagnostic and therapeutic insights.

## Key findings

- Five m6A genes (WTAP, METTL14, ZC3H13, PCIF1, RBM15) showed significant effect coefficients in PCOS.
- Six hub genes (METTL14, HNRNPA2B1, YTHDF3, YTHDF2, YTHDC1, YTHDC2) were identified as potential PCOS discriminators.
- m6A regulators like METTL3 were found to significantly influence immune cell infiltration in PCOS.

## Abstract

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder, the molecular underpinnings of which remain largely undefined. The most common methylation modification of RNA, N
6‐methyladenosine (m6A), plays an important role in various reproductive and endocrine disorders. This study investigates key m6A genes in PCOS and their association with immune cell infiltration using advanced bioinformatics methods.

We utilized gene expression data and clinical information from the Gene Expression Omnibus database data sets GSE137684, GSE80432, and GSE114419. The expression of m6A‐related genes was analyzed across all samples. Using the GSVA and CIBERSORT packages in R, we developed a diagnostic model based on the m6A gene–protein interaction network, conducted enrichment analysis of hub genes, and assessed the correlation between these genes and immune cell infiltration.

Analysis of data sets GSE137684 and GSE804322 identified variable expression patterns among three categories of m6A genes. A diagnostic model centered on m6A gene expression was established, highlighting five genes—WTAP, METTL14, ZC3H13, PCIF1, and RBM15—with significant effect coefficients. Unsupervised clustering of hub genes indicated that METTL14, HNRNPA2B1, YTHDF3, YTHDF2, YTHDC1, and YTHDC2 are potential discriminators in PCOS. The analysis of immune infiltration revealed a correlation between m6A regulators and immune cell levels, with METTL3 showing the most significant regulatory impact.

N
6‐methyladenosine RNA methylation regulators are intricately linked with the development of PCOS and may influence immune cell infiltration in affected individuals. This study enhances our understanding of the molecular interactions in PCOS and suggests potential biomarkers for diagnosis and targets for therapeutic intervention.

N
6‐methyladenosine RNA methylation regulators are intricately linked with the development of polycystic ovary syndrome (PCOS) and may influence immune cell infiltration in affected individuals. This study enhances our understanding of the molecular interactions in PCOS and suggests potential biomarkers for diagnosis and targets for therapeutic intervention

## Linked entities

- **Genes:** WTAP (WT1 associated protein) [NCBI Gene 9589], METTL14 (methyltransferase 14, N6-adenosine-methyltransferase non-catalytic subunit) [NCBI Gene 57721], ZC3H13 (zinc finger CCCH-type containing 13) [NCBI Gene 23091], PCIF1 (phosphorylated CTD interacting factor 1) [NCBI Gene 63935], RBM15 (RNA binding motif protein 15) [NCBI Gene 64783], HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1) [NCBI Gene 3181], YTHDF3 (YTH N6-methyladenosine RNA binding protein F3) [NCBI Gene 253943], YTHDF2 (YTH N6-methyladenosine RNA binding protein F2) [NCBI Gene 51441], YTHDC1 (YTH N6-methyladenosine RNA binding protein C1) [NCBI Gene 91746], YTHDC2 (YTH N6-methyladenosine RNA binding protein C2) [NCBI Gene 64848], METTL3 (methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit) [NCBI Gene 56339]
- **Diseases:** Polycystic ovary syndrome (MONDO:0008487), PCOS (MONDO:0008487)

## Full-text entities

- **Genes:** UBXN2A (UBX domain protein 2A) [NCBI Gene 165324] {aka UBXD4}, UBE4B (ubiquitination factor E4B) [NCBI Gene 10277] {aka E4, HDNB1, UBOX3, UFD2, UFD2A}, GLRB (glycine receptor beta) [NCBI Gene 2743] {aka HKPX2}, EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3) [NCBI Gene 9451] {aka PEK, PERK, WRS}, SMAD9 (SMAD family member 9) [NCBI Gene 4093] {aka MADH6, MADH9, PPH2, SMAD8, SMAD8/9, SMAD8A}, CYP3A5 (cytochrome P450 family 3 subfamily A member 5) [NCBI Gene 1577] {aka CP35, CYPIIIA5, P450PCN3, PCN3}, TNFRSF18 (TNF receptor superfamily member 18) [NCBI Gene 8784] {aka AITR, CD357, ENERGEN, GITR, GITR-D}, TNFSF10 (TNF superfamily member 10) [NCBI Gene 8743] {aka APO2L, Apo-2L, CD253, TANCR, TL2, TNLG6A}, FMR1 (fragile X messenger ribonucleoprotein 1) [NCBI Gene 2332] {aka FMRP, FRAXA, POF, POF1}, IL1RAP (interleukin 1 receptor accessory protein) [NCBI Gene 3556] {aka C3orf13, IL-1RAcP, IL1R3}, HIBADH (3-hydroxyisobutyrate dehydrogenase) [NCBI Gene 11112] {aka NS5ATP1}, PDIA4 (protein disulfide isomerase family A member 4) [NCBI Gene 9601] {aka ERP70, ERP72, ERp-72}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, HSP90AB1 (heat shock protein 90 alpha family class B member 1) [NCBI Gene 3326] {aka D6S182, HSP84, HSP90B, HSPC2, HSPCB}, CCL21 (C-C motif chemokine ligand 21) [NCBI Gene 6366] {aka 6Ckine, CKb9, ECL, SCYA21, SLC, TCA4}, CTTN (cortactin) [NCBI Gene 2017] {aka EMS1}, CCR5 (C-C motif chemokine receptor 5) [NCBI Gene 1234] {aka CC-CKR-5, CCCKR5, CCR-5, CD195, CKR-5, CKR5}, FASLG (Fas ligand) [NCBI Gene 356] {aka ALPS1B, APT1LG1, APTL, CD178, CD95-L, CD95L}, CBLL1 (Cbl proto-oncogene like 1) [NCBI Gene 79872] {aka HAKAI, RNF188}, FBN1 (fibrillin 1) [NCBI Gene 2200] {aka ACMICD, ECTOL1, FBN, GPHYSD2, MASS, MFLS}, PSPH (phosphoserine phosphatase) [NCBI Gene 5723] {aka PSP, PSPHD}, PYY (peptide YY) [NCBI Gene 5697] {aka PYY-I, PYY1}, ADCY3 (adenylate cyclase 3) [NCBI Gene 109] {aka AC-III, AC3, BMIQ19}, TSHB (thyroid stimulating hormone subunit beta) [NCBI Gene 7252] {aka TSH-B, TSH-BETA}, HSPA2 (heat shock protein family A (Hsp70) member 2) [NCBI Gene 3306] {aka HSP70-2, HSP70-3}, DOCK1 (dedicator of cytokinesis 1) [NCBI Gene 1793] {aka DOCK180, ced5}, AACS (acetoacetyl-CoA synthetase) [NCBI Gene 65985] {aka ACSF1, SUR-5}, ACO1 (aconitase 1) [NCBI Gene 48] {aka ACONS, HEL60, IREB1, IREBP, IREBP1, IRP1}, FPR1 (formyl peptide receptor 1) [NCBI Gene 2357] {aka FMLP, FPR}, RBMX (RNA binding motif protein X-linked) [NCBI Gene 27316] {aka HNRNPG, HNRPG, MRXS11, MRXSG, MRXSH, RBMXRT}, ATF4 (activating transcription factor 4) [NCBI Gene 468] {aka CREB-2, CREB2, TAXREB67, TXREB}, HTR1B (5-hydroxytryptamine receptor 1B) [NCBI Gene 3351] {aka 5-HT-1B, 5-HT-1D-beta, 5-HT1B, 5-HT1DB, HTR1D2, HTR1DB}, PLOD2 (procollagen-lysine,2-oxoglutarate 5-dioxygenase 2) [NCBI Gene 5352] {aka BRKS2, LH2, TLH}, ACVR2B (activin A receptor type 2B) [NCBI Gene 93] {aka ACTRIIB, ActR-IIB, HTX4}, IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, PPP2CB (protein phosphatase 2 catalytic subunit beta) [NCBI Gene 5516] {aka PP2Abeta, PP2CB}, HIBCH (3-hydroxyisobutyryl-CoA hydrolase) [NCBI Gene 26275] {aka HIBYLCOAH}, CCR2 (C-C motif chemokine receptor 2) [NCBI Gene 729230] {aka CC-CKR-2, CCR-2, CCR2A, CCR2B, CD192, CKR2}, XBP1 (X-box binding protein 1) [NCBI Gene 7494] {aka TREB-5, TREB5, XBP-1, XBP2}, PRKCB (protein kinase C beta) [NCBI Gene 5579] {aka PKC-beta, PKCB, PKCI(2), PKCbeta, PRKCB1, PRKCB2}, GRK6 (G protein-coupled receptor kinase 6) [NCBI Gene 2870] {aka GPRK6}, BMPR2 (bone morphogenetic protein receptor type 2) [NCBI Gene 659] {aka BMPR-II, BMPR3, BMR2, BRK-3, POVD1, PPH1}, SUV39H2 (SUV39H2 histone lysine methyltransferase) [NCBI Gene 79723] {aka KMT1B}, PIK3R1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 5295] {aka AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha}, AUH (AU RNA binding methylglutaconyl-CoA hydratase) [NCBI Gene 549], TNFRSF13C (TNF receptor superfamily member 13C) [NCBI Gene 115650] {aka BAFF-R, BAFFR, BROMIX, CD268, CVID4, prolixin}, IL17RB (interleukin 17 receptor B) [NCBI Gene 55540] {aka CRL4, EVI27, IL17BR, IL17RH1}, IL5RA (interleukin 5 receptor subunit alpha) [NCBI Gene 3568] {aka CD125, CDw125, HSIL5R3, IL5R}, YTHDC2 (YTH N6-methyladenosine RNA binding protein C2) [NCBI Gene 64848] {aka CAHL, hYTHDC2}, CD70 (CD70 molecule) [NCBI Gene 970] {aka CD27-L, CD27L, CD27LG, LPFS3, TNFSF7, TNLG8A}, SHC4 (SHC adaptor protein 4) [NCBI Gene 399694] {aka RaLP, SHCD}, OR1K1 (olfactory receptor family 1 subfamily K member 1) [NCBI Gene 392392] {aka hg99}, MAPK8 (mitogen-activated protein kinase 8) [NCBI Gene 5599] {aka JNK, JNK-46, JNK1, JNK1A2, JNK21B1/2, PRKM8}, DLAT (dihydrolipoamide S-acetyltransferase) [NCBI Gene 1737] {aka DLTA, E2, PBC, PDC-E2, PDCE2}, IL17B (interleukin 17B) [NCBI Gene 27190] {aka IL-17B, IL-20, NIRF, ZCYTO7}, TNFRSF17 (TNF receptor superfamily member 17) [NCBI Gene 608] {aka BCM, BCMA, CD269, TNFRSF13A}, BMP10 (bone morphogenetic protein 10) [NCBI Gene 27302], YTHDC1 (YTH N6-methyladenosine RNA binding protein C1) [NCBI Gene 91746] {aka YT521, YT521-B}, SUV39H1 (SUV39H1 histone lysine methyltransferase) [NCBI Gene 6839] {aka H3-K9-HMTase 1, KMT1A, MG44, SUV39H}, OR51A7 (olfactory receptor family 51 subfamily A member 7) [NCBI Gene 119687] {aka OR11-27}
- **Diseases:** hyperandrogenism (MESH:D017588), chronic inflammation (MESH:D007249), anovulation (MESH:D000858), GCs (MESH:D006106), developmental abnormalities (MESH:D006130), endometrial cancer (MESH:D016889), PCOS (MESH:D011085), endocrine disorder (MESH:D004700), cancer (MESH:D009369), immune dysfunction (MESH:D007154), diabetes (MESH:D003920), cardiovascular disease (MESH:D002318), IR (MESH:D007333), obesity (MESH:D009765), GC dysfunction (MESH:D006331), Overweight (MESH:D050177), African trypanosomiasis (MESH:D014353), ovarian (MESH:D010049), polycystic (MESH:D007690), reproductive dysfunction (MESH:D060737), metabolic abnormalities (MESH:D008659), chronic (MESH:D002908), ovulation disorder (MESH:D009358)
- **Chemicals:** N 6-methyladenosine (MESH:C010223), DCA (-), m6A (MESH:C005955), progesterone (MESH:D011374)
- **Species:** Danio rerio (leopard danio, species) [taxon 7955], Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], Saccharomyces cerevisiae (baker's yeast, species) [taxon 4932]
- **Mutations:** rs372790354, rs4889, rs9939609
- **Cell lines:** 17 — Homo sapiens (Human), Induced pluripotent stem cell (CVCL_8991), T — Homo sapiens (Human), Esophageal squamous cell carcinoma, Cancer cell line (CVCL_3174)

## Full text

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## Figures

9 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12928112/full.md

## References

49 references — full list in the complete paper: https://tomesphere.com/paper/PMC12928112/full.md

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Source: https://tomesphere.com/paper/PMC12928112