Epigenetics of glaucoma in the trabecular meshwork

Glaucoma represents a predominant cause of irreversible blindness globally, characterized by the association of elevated intraocular pressure (IOP) and retinal ganglion cell loss with dysfunction of the trabecular meshwork (TM), the principal tissue regulating conventional aqueous humor outflow. Emerging evidence suggests that this dysfunction is not exclusively driven by genetic variation or mechanical stress; rather, it is significantly influenced by epigenetic mechanisms that integrate factors such as aging, hypoxia/oxidative stress, glucocorticoid exposure, and other environmental challenges into enduring alterations in TM phenotype. This review synthesizes current understanding of the primary epigenetic mechanisms involved in glaucomatous TM remodeling, encompassing DNA methylation, histone modifications, non-coding RNAs (including microRNAs and long non-coding RNAs), and RNA N⁶-methyladenosine (m⁶A) methylation. In this study, we elucidate the role of aberrant DNA methylation in the regulation of profibrotic genes, such as TGF-β1 and GDF7, elasticity-modifying genes like LOXL1, and repetitive elements, which collectively contribute to extracellular matrix (ECM) accumulation, tissue stiffening, and increased outflow resistance. Furthermore, we explore how dysregulated miRNA-lncRNA networks and histone acetylation/methylation influence central signaling pathways, including TGF-β/BMP-Smad, Wnt/β-catenin, RhoA/ROCK, PI3K-Akt, and NF-κB. These pathways are crucial in orchestrating trabecular meshwork (TM) fibrosis, cytoskeletal remodeling, cellular senescence, and impaired stress responses. Additionally, we investigate the emerging roles of m⁶A regulators, such as METTL3, YTHDF2, and YTHDC2, at the intersection of outflow pathway fibrosis and retinal ganglion cell vulnerability. We propose that epigenetic modifiers, ncRNA-based therapies, and partial epigenetic reprogramming could offer innovative, TM-targeted, and neuroprotective strategies beyond conventional IOP-lowering treatments. Collectively, our findings support an integrated model wherein diverse epigenetic modifications converge to produce a stereotypical glaucomatous TM phenotype, thereby presenting novel opportunities for mechanism-based diagnosis and therapeutic intervention in glaucoma.