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ALKBH5 fuels angiogenesis and collagen deposition via m6A-YTHDF2-Dependent NLRP3 mRNA stabilization aggravating scarring after glaucoma surgery [scRNA-seq]

ABSTRACT: Glaucoma is a leading cause of irreversible blindness. For patients unresponsive to medical therapy, glaucoma filtration surgery (GFS) is the primary intervention to lower intraocular pressure (IOP). However, postoperative scarring often causes surgical failure, and the mechanisms remain poorly defined. Here, we identify the RNA demethylase alkB homolog 5 (ALKBH5) as a regulator of fibrotic remodeling after GFS via an epitranscriptomic mechanism involving N6-methyladenosine (m6A) modification. In both patients and rabbit models, increased vascular perfusion and decreased bleb height—quantified by anterior segment optical coherence tomography angiography (AS-OCTA) and ultrasound biomicroscopy (UBM)—were associated with elevated IOP. Immunohistochemistry and single-cell RNA sequencing revealed ALKBH5 upregulation in vascular endothelial cells (VECs) within scar tissue. Functional assays, rabbit GFS models, and Alkbh5-deficient mice revealed that ALKBH5 promotes angiogenesis and collagen deposition, accelerating postoperative fibrosis. Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-Seq) identified NLR family pyrin domain containing 3 (NLRP3) as a downstream target of ALKBH5. Mechanistically, ALKBH5 removes m6A modifications from NLRP3 mRNA, preventing YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-mediated degradation and stabilizing its expression. These findings uncover a role of ALKBH5–YTHDF2–NLRP3 axis in GFS-induced fibrosis and suggest targeting this epitranscriptomic pathway in VECs may improve outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE304420 | GEO | 2026/06/09

REPOSITORIES: GEO

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Project description:Purpose: The optic nerve head (ONH) is the likely site of initial damage in the glaucomatous eye. Despite the recognition of elevated intraocular pressure (IOP) as a leading risk factor for the development of glaucoma, ocular hypertension (OHT) eyes displaying consistently elevated IOP do not experience ONH damage. This study aims to identify global gene expression variations in glaucomatous ONHs and their relationship to those identified in OHT derived ONHs in order to improve our understanding of IOP-induced ONH damage. Methods: (N=6) ONHs were collected from clinically confirmed glaucoma, OHT and age-matched control donor eyes. Total RNA extracted from ONHs was reverse transcribed and assayed using the Affymetrix Human Exon 1.0 ST array. Differentially expressed genes in glaucoma versus control and OHT derived ONHs were identified using an ANOVA analysis with a 1.25 fold change limit and P-value < 0.05. Quantitative RT-PCR was performed to validate selected differentially expressed genes. Results: Microarray analysis revealed 149 under under-expressed genes in POAG versus control ONHs, many of which are involved in ion transport, axonogenesis and macromolecule catabolic processes. 297 genes were over expressed in OHT versus glaucoma derived ONHs. Mediators of oxidation-reduction and chemical homeostasis were among the most prominent gene groups identified. The over expression of prostaglandin-endoperoxide synthase 2, integrin, beta-like 1 and fibulin 5 in glaucomatous ONHs was confirmed by qRT-PCR. Conclusions: Our data demonstrates marked alteration in global gene expression patterns in the glaucomatous ONH, likely due to extensive tissue injury. The observed overlapping of several differentially expressed genes in glaucoma and OHT derived ONHs suggests the induction of common mechanisms in response to elevated IOP. Preferential over-expression of certain gene groups in OHT but not glaucoma derived ONHs may confer possible protection against IOP-induced ONH damage, which remains to be investigated in future studies. (N=6) Glaucoma, ocular hypertension and age-matched control ONHs were assayed to investigate and compare global gene expression patterns in each sample group.

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ALKBH5 fuels angiogenesis and collagen deposition via m6A-YTHDF2-Dependent NLRP3 mRNA stabilization aggravating scarring after glaucoma surgery [scRNA-seq]

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