Table 3 The roles of m6A modifications in complex ocular diseases.

From: N6-methyladenosine: a key regulator in ocular disease mechanisms and treatment

Diseases	Test object	m6A	Proteins	Pathway	Roles in eye diseases	Ref.
Keratitis	1. BALB/c mice 2. Mouse Corneal Stromal Cells	——	METTL3↑	METTL3-PI3K/Akt	Exacerbates inflammatory response, worsening keratitis.	[99]
	1. BALB/c mice 2. Mouse Corneal Tissue	↑	METTL3↑	METTL3-PI3K/Akt	Promotes the occurrence and progression of keratitis.	[100]
	1. BALB/c mice 2. Mouse corneal stromal cells	↑	METTL3↑	METTL3-TRAF6-p-IκB/IκB-p-p65/p65-NF-κB	Exacerbates the inflammatory response, worsening keratitis.	[101]
Corneal neovascularization	1. HUVECs 2. OIR model, mouse corneal alkali burn model 3. METTL3 knockout mice	↑	METTL3↑	METTL3-m6A-LRP6/DVL1-Wnt	Promotes hypoxia-induced pathological angiogenesis, exacerbating retinopathy and corneal neovascularization.	[80]
	1. HUVECs 2. C57BL/6J mice 3. CNV Model	↓	FTO↑	FTO-m6A demethylation-FAK (via YTHDF2)	Inhibits corneal neovascularization, alleviating pathological angiogenesis.	[83]
	1. Limbal stem cell-specific METTL3 knockout mice 2. Mouse Corneal Alkali Burn Model	——	METTL3↓	METTL3-m6A-AHNAK/DDIT4	Facilitates corneal injury repair, reducing neovascularization and inflammation.	[105]
	1. HUVECs 2. BALB/c mice 3. HSV-1 Induced Corneal Neovascularization Model	↑	METTL3↑	METTL3-m6A-LRP6-Wnt-VEGFA	Promotes corneal neovascularization.	[106]
Cataract	1. ARC Patient Lens Samples 2. HLE-B3 cells	↑	METTL3↑	METTL3/has_circ_0007905/miR-6749-3p/EIF4EBP1	Promotes apoptosis and proliferation of ARC cells.	[112]
	1. ALC Organization in DC Patients and ARC Patients 2. Human lens epithelial cells	↑	METTL3↑	METTL3-miR-4654-SOD2	Exacerbates oxidative stress and apoptosis in LEC, promoting lens opacification.	[113]
	1. Anterior lens capsule tissue in DC patients and normal patients without diabetes 2. Human lens epithelial cells	↑	METTL3↑	METTL3-ICAM-1	Promotes ICAM-1 expression, contributing to DC pathogenesis.	[114]
	1. Anterior lens capsule tissue in DC patients and normal patients without diabetes 2. Human lens epithelial cells	↑	RBM15↑	Ferroptosis	Promotes oxidative stress and ferroptosis in lens epithelial cells.	[115]
	RIR injury model mice	↓	METTL3↓	RIR- Autophagy Activation-m6A-METTL3-FoxO1 mRNA-FoxO1-Inhibition of Autophagy	Reduces RGC loss and retinal dysfunction caused by RIR injury.	[124]
	Ythdf2 cKO mice	——	YTHDF2↑	YTHDF2-Hspa12a/Islr2 mRNA-Hspa12a/Islr2-RGC	Decreases dendritic atrophy and neuronal loss.	[125]
	1. Primary HTFs 2. New Zealand White Rabbit	↑	METTL3↑	TGF-β1-smad3-METTL3-ECM	Increases HTFs proliferation and ECM accumulation, leading to scarring.	[128]
Uveitis	1. EAU Mouse Model 2. Human microglial cell line HMC3	↑	FTO↓	FTO-GPC4-TLR4-NF-xB	Enhances microglial activation and migration, exacerbating the inflammatory response.	[296]
	1. EAU Mouse Model 2. Human retinal pigment epithelial cell line ARPE-19	↑	FTO↓	FTO-ATF4- P-STAT3	Promotes secretion of inflammatory factors and degradation of tight junction proteins.	[133]
	1. EAU Mouse Model 2. BV2 microglial cell line	↓	YTHDC1↓	YTHDC1 -SIRT1 -STAT3 -M1	Upregulates pro-inflammatory phenotypic markers, worsening uveitis.	[134]
	Ocular tissue and T cell samples from the EAU model mice	↓	METTL3↓	METTL3-YTHDC2-ASH1L mRNA-ASH1L-IL-17/IL-23R-Th17	Suppresses Th17 cell responses, mitigating EAU.	[91]
	1. EAU Mouse Model 2. Mouse DCs	——	METTL3↑	METTL3-pri-miR-338-miR-338-3p-Dusp16-p38-DCs-Th17	Promotes Th17 cell generation and function, exacerbating EAU.	[136]
GO/TED	EMO specimens from 7 GO patients and 5 control subjects	↑	WTAP↑ ELF3↑ YTHDF2↑ YTHDC2↑	WTAP/YTHDF2/YTHDC2-IL-6/IL-18/TNF-α-NF-κB signaling pathway/Toll-like receptor signaling pathway/TNF signaling pathway	Triggers pro-inflammatory responses in EOMs, disrupting immune homeostasis and interfering with tissue remodeling and fibrosis of extraocular muscles.	[141]
	1. RAW 264.7 Mouse Macrophages Stimulated by LPS and Knockdown of YTHDF2	——	YTHDF2↓	YTHDF2-MAP2K4/MAP4K4 mRNA-NF-κB and MAPKsignaling pathway	Promotes expression of inflammatory factors, exacerbating macrophage inflammatory response.	[142]
	1. GD patients and healthy controls 2. PBMCs	↓	METTL3↓	METTL3-SOCS family	Affects RGC survival, optic nerve repair, and inflammatory response balance.	[145]
	GSE175399 (DNA methylation sequencing data), GSE186480 (tRFs expression data), and GSE185952 (mRNA, lncRNA, and circRNA expression data) in the GEO database	↑	——	M6A modification affects key pathways such as the IL-17 signaling pathway and cytokine receptor pathway	Promotes immune cell activation and inflammatory response.	[146]
TON	1. Establishment of the TON model in male Sprague-Dawley rats	↑	METTL3↑ WTAP↑ FTO↑ ALKBH5↑	METTL3/WTAP/FTO/ALKBH5-MAPK/NF-κB/TNF	Increases optic nerve injury, inflammation, and cellular homeostasis imbalance.	[210]
TON	Sciatic nerve compression and optic nerve compression models	↑	ALKBH5↓	ALKBH5-LPIN2	Promotes nerve regeneration, reducing optic nerve injury.	[214]
PM	1. SRAMP database 2. HSFs to construct myopic cell models	↓	METTL3↓	FOXM1-YTHDF2/METTL3-APOA1	Promotes HSF transdifferentiation into myofibroblasts, facilitating scleral remodeling.	[253]
	1. Form deprivation myopia models were established in pigmented guinea pigs and C57BL/6J mice 2. RF/6A cells	↓	METTL3↓	METTL3-Axin1/Arid1b mRNA-YTHDF2-Axin1/Arid1b	Facilitates choroidal vasculopathy.	[259]
	Anterior lens capsule in patients with simple nuclear cataract and nuclear cataract combined with high myopia	↑	METTL3↓ METTL14↑ FTO↓ ALKBH5↓ YTHDF1↓ YTHDF2↓	METTL3/METTL14/FTO/ALKBH5/YTHDF1/YTHDF2-ECM gene hypermethylation	Promotes abnormal ECM accumulation or change, affecting fundus anatomy and advancing high myopia pathology.	[10]
DR	1. STZ-induced DM mouse model 2. RMECs, rMCs	——	YTHDF2↓	KAT1-YTHDF2-ITGB1-FAK/PI3K/AKT	Abnormal vascular proliferation promotes inflammation and vascular leakage.	[157]
	1. STZ-induced DM mouse model 2. Pericytes	↑	METTL3↑	METTL3-YTHDF2-PKC-η/FAT4/PDGFRA	Inhibits pericyte survival, proliferation, and differentiation, compromising retinal vascular stability.	[163]
	1. Peripheral venous blood samples from T2D patients and healthy volunteers 2. Normal retinal cell line (ARPE-19)	——	METTL3↓	METTL3-miR-25-3p-/PTEN/Akt	Inhibits RPE cell proliferation, accelerating apoptosis and pyroptosis.	[166]
	Normal retinal cell line (ARPE-19)	↑	FTO↑	miR-192-FTO-NLRP3	Increases pyroptosis of RPE cells.	[168]
	1. STZ-induced DM mouse model 2. HRMECs	↓	METTL3↓	METTL3-SNHG7-KHSRP-MKL1-EndoMT	Increases pyroptosis of REP cells.	[171]
	1. Patients with PDR due to T1D or T2D 2. STZ-induced murine model of T1D and high-fat diet combined with STZ-induced T2D 3. EC FtoΔ/Δ mouse model 4. HRMECs	↓	FTO↑	FTO-TNIP1-NF-κB Pathway-IL-1β and IL-18 Release	Retinal vascular leakage and acellular capillary formation.	[88]
	1. STZ-induced DM mouse model 2. OIR mouse model 3. HUVECs	↓	FTO↑	FTO-CDK2	Aggravates DM-induced angiogenesis, microvascular leakage, inflammation, and neurodegeneration.	[90]
	1. THP-1, HRMECs 2. STZ-induced DM mouse model	↑	FTO↓	FTO-FGF2-PI3K/AKT	Polarizes macrophages toward M1, worsening the inflammatory response.	[86]
	1. STZ-induced DM rat model 2. Microglial cell line BV2	——	ALKBH5↓	ALKBH5-A20 (TNFAIP3)	Affects microglial polarization state, leading to aggravated inflammation.	[178]
ROP	1. OIR mouse model 2. GO and KEGG analysis 3. ceRNA Network Analysis	——	——	1. Association between m6A modification levels and circRNA expression levels in OIR retinas. 2. circRNA-miRNA-mRNA network was constructed	Provides new insights into the molecular mechanisms of m6A-modified retinal neovascularization.	[183]
ROP	OIR mouse model	——	——	M6A modification changes in mRNA and lncRNA in OIR retina	Investigates the potential role of m6A modification in retinal neovascularization.	[184]
RP	Normal retinal cell line (ARPE-19)	↓	METTL1↓	METTL14-MAP2-NEUROD1	Decreases RPE phagocytic ability, disrupts tight junctions, increases apoptosis, and induces cell cycle arrest.	[189]
PVR	HTERT RPE-1 cell line	——	METTL3↓ YTHDF1↑	TGF-β2-METTL3/YTHDF1 ↑ -EMT	Induces EMT in RPE cells, promoting PVR fibrosis.	[196]
	1. Tissue samples from PVR patients and normal donor eyes 2. Normal retinal cell lines (ARPE-19) 3. rats with intravitreal METTL3 overexpression	↓	METTL3↓	METTL3-Wnt/β-catenin signaling pathway	Promotes RPE cell EMT, enhancing proliferation and migration, accelerating proliferative membrane formation.	[198]
	HTERT RPE-1 cell line	——	——	MeCP2 treatment: 9,041 m6A peaks downregulated, 4 upregulated	Facilitates EMT process in RPE cells.	[197]
AMD	1. Primary mouse RPE cells and the human RPE cell line ARPE-19 2. C57BL/6 mice injected with Aβ1-40 and the FTO inhibitor MA1 in the vitreous	——	FTO↑	2.FTO-PKA/CREB Signaling Pathway	Exacerbates RPE cell degeneration.	[205]
CM	1. 88 ocular melanoma tissues and 28 normal melanocyte tissues 2. Multiple ocular melanoma cell lines and normal melanocyte cell lines 3. Nude mice that were subcutaneously injected with melanoma cells	↓	YTHDF1↑ METTL3↓	METTL3-YTHDF1-HINT2	Accelerates melanoma progression, leading to poor prognosis.	[220]
CM	1. 9 CM patients in the GEO database 2. 41 CM samples and 11 normal melanocytic nevus samples clinically	↓	FTO↑	FTO-EGR1/VEGFA	Promotes tumor angiogenesis mediated by CAFs.	[222]
UM	1. 88 ocular melanoma tissues and 28 normal melanocyte tissues 2. multiple ocular melanoma cell lines and normal melanocyte cell lines 3. Nude mice that were subcutaneously injected with melanoma cells	↓	YTHDF1↑ METTL3↓	METTL3-YTHDF1-HINT2	Accelerates melanoma progression, leading to poor prognosis.
	3 UM tissues and 3 normal choroid tissues	↓	FTO↑	FTO-ATG5	Inhibits autophagy in UM cells.	[231]
	1. CM tissue and normal choroid tissue samples from 36 patients 2. Two human CM cell lines, OCM1 and MUM-2B 3. Nude mice injected with CM cells into the caudal vertebrae	——	METTL4↑	METTL4-RUNX2 mRNA-Wnt/β-catenin signaling pathway	Facilitates CM cell migration and invasion.	[233]
	1. GEPIA database analysis 2. MuM-2B and C918 3. Nude mice that were subcutaneously injected with ALKBH5 stably knocked down C918 cells	——	ALKBH5↑	ALKBH5-FOXM1 mRNA	Promotes UM cell proliferation and inhibits apoptosis.	[234]
	1. UM cell line 2. 11 primary UM samples	↑	METTL3↑	METTL3-c-Met/Akt signaling pathway	Promotes UM cell proliferation, colony formation, migration, and invasion.	[235]
	1. 5 UM tissues and 5 normal uveal melanocyte tissue samples 2. 6 Ocular melanoma cell lines and 1 retinal pigment epithelial cell line	——	IGF2BP3↑	circ_0053943-IGF2BP3/EGFR	Promotes UM cell proliferation, migration, and invasion.	[236]
	Pan-Cancer Datasets for TCGA, TARGET, and GTEx	——	ZC3H13↑	ZC3H13-ACKR2	Significantly associated with longer OS and PFI in UM patients.	[237]
	The TCGA database obtains RNA-seq and clinical data from UM patients	——	RBM15B↑	1.LINC00665/hsa-let-7b-5p/RBM15B axis 2.LINC00638/hsa-miR-103a-3p/RBM15B axis	UM patients had significantly longer OS, DSS, and PFI.	[238]
	The TCGA database obtains RNA sequencing transcriptome data and clinical data from 80 UM patients	——	RBM15B↑ YTHDF3↑ IGF2BP2↑	LncRNA	Highly expressed RBM15B and IGF2BP2 are associated with better prognosis, whereas highly expressed YTHDF3 is associated with worse prognosis.	[239]
RB	1. GEO database and miRDB database 2. with RB cell lines (WERI-Rb-1 and Y 79) and normal retinal cell lines (ARPE-19)	——	METTL14↑	METTL14-LINC00340-Notch signaling pathway	Promotes RB cell growth and inhibits apoptosis.	[244]
	1. GSE24673 dataset obtained from the GEO database 2. Multiple RB cell lines	——	IGF2BP3↑	IGF2BP3-USP49-SIRT1	Aggravats RB resistance to carboplatin CBP.	[297]
	1. GSE208143 dataset 2. RB cell line 3. Nude mouse models injected intraocularly with sh-FTO and E2F3	↓	FTO↑	FTO-YTHDF2-E2F3	Promotes the malignant progression of RB cells.	[246]
	1. 30 RB patients and normal tissue samples 2. RB cell lines (WERI-Rb-1 and Y 79)	——	METTL14↑	METTL14-CDKN2A-p53 signaling pathway	Promotes RB cell proliferation and inhibit apoptosis.	[298]
	1. mRNA sequencing data 2. RB cell lines (WERI-Rb-1 and Y 79) and normal retinal cell lines (ARPE-19)	——	YTHDF1↑	MYCN-YTHDF1-CDK5R1	Promotes the proliferation and tumor growth of RB cells	[248]
	1. RB tissue samples and two RB cell lines (Y 79 and WERI-Rb-1) 2. Subcutaneous injection of RB cells with METTL3 knockdown in nude mice	——	METTL3↑	METTL3-PI3K/AKT/mTOR	Promotes migration and invasion of RB cells	[191]

ACKR2 atypical chemokine receptor 2, AHNAK AHNAK nucleoprotein, Akt protein kinase B, ALC anterior lens capsule, ALKBH5 AlkB homolog 5, ARC age-related cataract, ARPE-19 adult retinal pigment epithelial cell line, BACE2 beta-secretase 2, C918 C918 cell line, CAFs cancer-associated fibroblasts, CBP carboplatin, CDK2 cyclin-dependent kinase 2, CDKN2A cyclin-dependent kinase inhibitor 2A, CM conjuncval melanoma, CNV choroidal neovascularization, DC diabetic cataract, DCs dendritic cells, DDIT4 DNA-damage-inducible transcript 4, DM diabetes mellitus, DR diabetic retinopathy, DRG dorsal root ganglion, DVL1 disheveled segment polarity protein 1, E2F3 E2F transcription factor 3, EAU experimental autoimmune uveitis, EC FtoΔ/Δ endothelial cell-specific Fto-deficient mice, EGR1 early growth response 1, EMT epithelial-mesenchymal transition, EndoMT endothelial-mesenchymal transition, EOMs extraocular muscles, FAK focal adhesion kinase, FAT4 FAT atypical cadherin 4, FOXM forkhead box M1, FTO fat mass and obesity-associated protein, FTO FTO α-ketoglutarate-dependent dioxygenase, GEPIA gene expression profiling interactive analysis, GTEx the genotype-tissue expression, HINT2 histidine triad nucleotide-binding protein 2, HRMECs human retinal microvascular endothelial cells, HSFs human scleral fibroblasts, HTFs human tenon’s capsule fibroblasts, HUVECs human umbilical vein endothelial cells, IGF2BP3 insulin-like growth factor 2 mRNA-binding protein 3, IL-1β interleukin-1 beta, ITGB1 integrin beta 1, KAT1 lysine acetyltransferase 1, LEC lens epithelium cell, LncRNA long non-coding RNA, LRP6 low-density lipoprotein receptor-related protein 6, M6A N6-methyladenosine, MAP2 microtubule-associated protein 2, MCP-1 monocyte chemoattractant protein 1, MeCP2 methyl-CpG binding protein 2, METTL3 methyltransferase-like 3, MKL1 megakaryocytic leukemia 1, MuM-2B malignant uveal melanoma cell line 2B, MYCN N-Myc proto-oncogene protein, NEUROD1 neuronal differentiation 1, NF-κB nuclear factor kappa-B, NLRP3 nucleotide-binding domain leucine-rich repeat family protein 3, Notch Notch signaling pathway, OIR oxygen-induced retinopathy, ONC optic nerve compression, OS overall survival, PBMCs peripheral blood mononuclear cells, PDGFRA platelet-derived growth factor receptor alpha, PFI progression-free interval, PI3K phosphatidylinositol 3-kinase, p-IκB/IκB phosphorylated/inhibitor of nuclear factor kappa-B, PKC-η protein kinase C eta, p-p65/p65 phosphorylated/nuclear factor kappa-B subunit p65, PRV proliferative vitreoretinopathy, PTEN phosphatase and tensin homolog, PVR proliferative vitreoretinopathy, PXG pseudoexfoliation glaucoma, RB retinoblastoma, RIR retinal ischemia-reperfusion, rMCs retinal Müller cells, RMECs retinal microvascular endothelial cells, ROP retinopathy of prematurity, RP retinitis pigmentosa, RPE retinal pigment epithelium, SIRT1 sirtuin 1, SNC sciatic nerve compression, SNHG7 small nucleolar RNA host gene 7, STZ streptozotocin, T1D type 1 diabetes mellitus, T2DM type 2 diabetes mellitus, TARGET therapeutically applicable research to generate effective treatments, TCGA The Cancer Genome Atlas, TGF-β2 transforming growth factor beta 2, THP-1 human acute monocytic leukemia cell line, TMEM38B transmembrane protein 38B, TNFAIP3 tumor necrosis factor-α induced protein 3, TNIP1 TNFAIP3 interacting protein 1, TRAF6 TNF receptor-associated factor 6, UM uveal melanoma, USP49 ubiquitin-specific peptidase 49, VEGFA vascular endothelial growth factor A, YTHDF2 YTH domain family 2, ZC3H13 zinc finger CCCH-type containing 13.

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Table 3 The roles of m6A modifications in complex ocular diseases.

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