The pathophysiology, genetics, and epigenetics of juxtacanalicular tissue and extracellular matrix dysregulation: a contemporary narrative review of normal tension glaucoma

Introduction

Normal tension glaucoma (NTG) is a subset of primary open-angle glaucoma (POAG) and is characterized by progressive retinal ganglion cell (RGC) loss despite physiological intraocular pressure (IOP) (≤21 mmHg). NTG represents a substantial proportion of glaucomatous cases, encompassing 30–40% of POAG cases in Western populations, and a larger proportion in East Asian populations, 70–92% (1-3).

Other identified risk factors include female gender, history of vascular deregulatory conditions (Raynaud’s syndrome or phenomenon, migraine headaches, coronary microvascular dysfunction, livedo reticularis, etc.), family history, and advanced age (4).

Despite its prevalence, its pathophysiology remains incompletely understood. Historically, research surrounding glaucoma has focused extensively on the contribution of aqueous humor (AH) dynamics and IOP to disease pathophysiology and progression. While these mechanisms are central to POAG, they do not fully explain disease progression in NTG, where optic nerve damage occurs at physiologic IOP values. However, in recent years, considerable advances have helped to better shape the understanding of NTG pathogenesis. Genetic studies have identified certain Mendelian causes of NTG, which account for ~2–3% of NTG (5,6).

In addition, research has focused on the potential that the ocular glymphatic system may be directly involved with the vascular aberration, impaired cerebrospinal fluid dynamics, and defective perivascular waste clearance known to contribute to NTG progression (7,8). The association of NTG with neurodegenerative conditions (Alzheimer's dementia, vascular dementia, etc.) and other small-vessel disorders has also emerged, indicating that NTG may be a manifestation of broader systemic neurovascular pathology (9,10).

Thus, given the rapid evolution of research understanding the genetic, vascular, glymphatic, and systemic connections to NTG, this review hopes to provide a comprehensive reassessment of NTG pathophysiology. This review synthesizes recent discoveries to provide an updated framework of the mechanisms that underlie NTG and highlights the interdependence of molecular, genetic, and biomechanical contributions. In addition, for clarity, this review is organized into review of: (I) extracellular matrix (ECM) dysregulation within the juxtacanalicular tissue; (II) genetic determinants of NTG; (III) epigenetic regulation; and (IV) an integrated mechanistic model linking these domains. We present this article in accordance with the Narrative Review reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-2026-0019/rc).

Methods

A structured literature search was conducted between May 2025 and July 2025 to identify and review relevant sources on the pathophysiology, genetics, and epigenetics of NTG, and mechanisms of IOP-independent glaucomatous progression in NTG eyes (Table 1). Care was taken to review the normal physiology of the trabecular meshwork (TM) and AH dynamics, with a focus on the ECM within the juxtacanalicular connective tissue. The search was conducted using electronic databases including PubMed and Google Scholar, and academic books. Keywords included “normal tension glaucoma” and “extracellular matrix” and “juxtacanalicular” and “genetics”, along with synonyms and related phrases. Sources were included if they were published in English between 1986 and 2025, if they focused on potential mechanisms of IOP-independent glaucomatous progression in NTG eyes, and if they contained empirical data or systematic reviews of NTG. Editorials, opinion pieces, and non-English articles were excluded. After removing any duplicate articles, titles and abstracts were screened for relevance, followed by full-text reviews to determine eligibility. In articles that were determined to be eligible for inclusion, the references were also screened for additional sources. All search results were organized using RefWorks.

Review

Glaucoma refers to a group of optic neuropathies that are all characterized by progressive RGC loss and characteristic correlating visual field (VF) defects (11). Although elevated IOP is a well-established risk factor and therapeutic target, NTG represents a clinical and biological exception, underscoring the existence of pressure-independent mechanisms of optic nerve injury (12). As shown in Figure 1, increased resistance to AH outflow is central to POAG, whereas NTG pathophysiology is increasingly understood to involve altered tissue biomechanics, vascular insufficiency, and neurodegeneration rather than overt obstruction of aqueous drainage.

Figure 1 Overview of aqueous humor production and drainage and pathophysiological mechanisms underlying normal tension glaucoma. AH, aqueous humor; IOP, intraocular pressure.

Physiology of aqueous flow and normal TM function

AH physiology is summarized here to provide necessary context for subsequent discussion of trabecular ECM pathology, rather than as a primary focus on NTG pathogenesis. Figure 1 outlines how AH is first produced by the ciliary body and flows from the posterior chamber to the anterior chamber before exiting the eye via the trabecular (conventional) and uveoscleral (unconventional) pathways (11,13-15). The trabecular pathway accounts for the majority of AH drainage and includes passage through the uveal, corneoscleral, and juxtacanalicular layers of the TM prior to entry into Schlemm’s canal (Figure 2A,2B) (12-19).

Figure 2 Depiction of (A) open angle and (B) closed angle.

The juxtacanalicular connective tissue (JCT) constitutes the principal site of outflow resistance and plays a key role in maintaining normal IOP through dynamic ECM remodeling. The pressure within the episcleral veins, termed episcleral venous pressure (EVP), also mediates downstream AH flow. Elevations in EVP can increase resistance to AH outflow, making it an important modulator of IOP and resulting in translaminar pressure gradients (13,15).

However, NTG IOP typically remains within physiological limits, suggesting subtle structural and biomechanical alterations—rather than gross impairment of aqueous drainage—are of greater pathogenic relevance. Though the discussion of aqueous flow dynamics is limited, subsequent sections aim to build upon this framework to focus on ECM remodeling, fibrotic signaling, and molecular dysregulation as central contributors to NTG progression.

NTG is a specific subset of POAG that is characterized by progressive glaucomatous optic nerve head (ONH) damage and VF loss despite normal or low IOP (maximum recorded IOP must be 21 mmHg or less) (20). While IOP remains a known risk factor for eyes with NTG, current consensus supports an IOP-independent disease model. Importantly, normal tonometric IOP measurements do not preclude the presence of pathological biomechanical stress within the eye, particularly at the level of the ONH (5,22).

Several IOP-independent risk factors have been proposed, including vascular dysregulation, abnormal translaminar pressure gradients, and primary neurodegenerative processes (Figure 3). An increasingly supported concept is that NTG reflects altered pressure transmission and tissue susceptibility rather than sustained elevation of IOP. Specifically, subtle changes in the TM and JCT biomechanics may alter how physiological pressure is distributed and transmitted posteriorly, even when absolute IOP remains within normal limits (23,24). Dysregulation of the JCT ECM—manifesting as increased endothelial cell thickness, reduced pore density, and increased tissue stiffness—does not necessarily result in chronically elevated IOP but may instead impair the eye’s ability to buffer transient pressure fluctuations and mechanical strain. This impaired damping capacity may result in greater transmission of pulsatile or transient pressure loads to the lamina cribrosa, thereby increasing mechanical stress on RGC axons.

Figure 3 Anatomy of the trabecular meshwork and flow of aqueous humor with key mediators in creation of a fibrotic phenotype. CMT, contractile myofibroblast transition; EDA, extra domain A; MMP2, matrix metalloproteinase 2; NTG, normal tension glaucoma; TGF-β, transforming growth factor-β; TM, trabecular meshwork; α-SMA, α-smooth muscle actin.

Other neurodegenerative processes have been studied in their potential association with NTG progression, as they may cause RGC injury. This has included mitochondrial dysregulation, persistently high oxidative stress, neuronal excitotoxicity, and neuroinflammation (25). In addition, genetic predispositions, particularly in OPTN and TBK1 genes, may play a role in disease presentation and progression (12,26). In addition, dysregulation of the JCT ECM—including increased cellular thickness of the endothelial cells, reduction in the number of pores formed, and increased stiffness—is implicated in impaired aqueous outflow. This supports the role of JCT dysregulation in NTG pathophysiology (19). The JCT ECM is normally composed of several structural proteins including collagen, fibronectin, laminin, proteoglycans (heparan sulfate and chondroitin sulfate), and elastic fibers (27). Alterations in any of these components can compromise the ECM structure and therefore compromise its role as the primary site of resistance to AH drainage, potentially contributing to stress on the optic nerve even in the absence of elevated IOP. Other components found in lesser quantities within the ECM include vitronectin, tenascin, fibrillin-1, microfibril-associated glycoprotein-1 (MAGP-1), decorin, hyaluronic acid, myocilin, secreted protein acidic and rich in cysteine (SPARC), connective tissue growth factor (CTGF), and thrombospondins (TSP-1 and TSP-2). These other components exist in smaller quantities, and their direct relationship to NTG pathogenesis remains unknown at this juncture. Like the association between NTG and systemic vascular disorders, systemic ECM dysregulation in the eye can result in several pathological conditions. To name one, ECM dysregulation and degeneration are associated with other vascular pathologies, including the cystic medial necrosis that underlies aortic aneurysmal diseases (28).

ECM dysregulation

Focusing on the dysregulation within the ECM of the TM may provide an explanation for continuous IOP-independent glaucomatous progression seen in many NTG eyes. Key mediators of the pathological changes seen in NTG eyes include increased ECM remodeling and a shift to a fibrotic phenotype (Figure 2B and Figure 3). The shift to a more fibrotic phenotype results from upregulation of several pro-inflammatory and fibrotic pathways and downregulation of other anti-fibrotic mediators (29). Histologically, this can be seen as a reduction in the JCT space and decreased cellularity when compared to normal controls. This represents a loss of TM cellularity and a compaction of the normal ECM architecture, resulting in impaired outflow facility at normal IOP (29). Biomechanically, this results in a stiffer JCT ECM with increased actin stress fiber formation and deposition. Subsequent alterations in the cell-to-ECM interaction then contribute to impaired AH outflow (17). Importantly, in the context of NTG, these structural and biomechanical changes within the JCT do not necessarily result in sustained elevations of IOP. Instead, emerging evidence supports a model in which fibrotic remodeling of the JCT alters the dynamic regulation of outflow resistance rather than producing a fixed obstruction. In this framework, mean IOP remains within normal limits, but the TM loses normal viscoelastic compliance and capacity to buffer the transient pressure changes.

The JCT normally functions as a biomechanically adaptive, viscoelastic tissue, capable of remodeling in response to physiologic fluctuations in IOP, circadian variation, and ocular pulse-related stress. Fibrotic remodeling reduces this adaptive capacity, leading to increased JCT stiffness, reduced porosity, and endothelial cell thickening, all of which impair the ability of the JCT to dissipate transient or localized pressure loads. As a result, physiological IOP fluctuations—rather than sustained IOP elevation—may be transmitted more effectively and with a greater magnitude to posterior ocular structures, including the lamina cribrosa.

This altered pressure transmission provides a mechanistic explanation for how JCT-mediated outflow impairment can contribute to the NTG pathophysiology without elevating IOP. Increased stiffness of the JCT ECM may amplify pulsatile mechanical stress, pressure gradients, and focal strain, thereby increasing susceptibility of RGC axons at the ONH. Thus, NTG may reflect a disease of altered biomechanical homeostasis and tissue susceptibility rather than absolute pressure elevation.

The proteins that have been identified to be upregulated include α-smooth muscle actin (α-SMA), N-cadherin, contractile myofibroblast transition (CMT), and transforming growth factor-β (TGF-β). In combination, these proteins are implicated in shifting the ECM towards a more fibrotic state (23,30-33). α-SMA is encoded by ACTA2 on 10q23.21 and is associated with shifting the ECM to a more fibrotic, endothelial-to-mesenchymal transition (EndMT)-like phenotype; EndMT is the process by which endothelial cells lose endothelial markers and adopt mesenchymal features, including enhanced contractility and altered morphology. Upregulation of α-SMA contributes not only to increased ECM deposition, but also to heightened cellular contractility, further reducing the biomechanical compliance of the JCT (20). Interplay between CMT, N-cadherin (on chromosome 18q11.2), TGF-β (isoform coded on chromosome 1q41), and α-SMA further contributes to stiffening of the TM architecture (31,34).

TGF-β signaling is a significant driver of EndMT, as it induces canonical (SMAD2/3) and non-canonical pathways that promote the more fibrotic phenotype through increased expression of α-SMA, N-cadherin, and other mesenchymal mediators. This phenotypic transition is accompanied by progressive loss of endothelial identity, characterized by enhanced cytoskeletal organization, increased deposition of collagen and fibronectin, and reduced matrix metalloproteinase (MMP) activity, resulting in a more myofibroblast-like contractile state. The cumulative effect is a JCT ECM that is stiffer, less deformable, and less capable of adapting to physiological pressure variability, even in the absence of elevated IOP.

Concurrent downregulation of MMP2, SERPINF1 (pigment epithelium-derived factor), and CHI3L1 (chitinase-3-like protein 1) contributes to shifting the ECM to a more fibrotic EndMT-like phenotype (35-37). Loss of these regulatory checkpoints disrupts ECM turnover and impairs the TM’s ability to dynamically remodel in response to mechanical cues. MMP2 normally facilitates collagen turnover within the ECM; its dysregulation results in abnormal accumulation and organization of collagen, further increasing tissue stiffness (34). This suggests that dysregulated ECM remodeling—rather than simple excess ECM deposition—is a key driver of altered tissue biomechanics in NTG.

SERPINF1 is a protein encoded by the SERPINF1 gene on chromosome 17p13.3 and normally functions as a potent anti-fibrotic and anti-angiogenic factor that typically inhibits TGF-β fibrotic changes. In glaucomatous eyes, SERPINF1 expression in the TM is reduced at both the mRNA and protein levels, allowing unopposed TGF-β signaling and facilitating fibrotic remodeling (13,19,34). Loss of SERPINF1 also diminishes cytoprotective and anti-apoptotic signaling within the TM, further reducing cellularity and biomechanical resilience of the JCT. CHI3L1, a protein encoded by CHI3L1 on chromosome 1q32.1, contributes to glaucomatous transformation by reducing the tissues’ ability to counteract pro-fibrotic signaling, ultimately allowing for the transformation to an EndMT fibrotic change (37). CHI3L1 normally modulates ECM turnover by acting as a checkpoint inhibitor of TGF-β; thus, loss of the checkpoint contributes to the unregulated activity of TGF-β (40,41). Two other proteins that are expressed at varying levels in the ECM of NTG eyes, but whose functions are dysregulated, include fibronectin [specifically the extra domain A (EDA) isoform] and collagen VI (COL6A3) (35). Fibronectin extra domain A (FN-EDA) can be seen in normal or increased quantities in the TM and is induced by TGF-β2 to act as a damage-associated molecular pattern (DAMP) that activates toll-like receptor 4 (TLR4) signaling. This contributes to the increased ECM deposition and shift to a pro-inflammatory, fibrotic TM. This phenotypic switch has been demonstrated in both human tissue and transgenic mouse models (42-44). COL6A3 is a major component of collagen type VI and is involved in normal ECM remodeling. Pathological TGF-β2 stimulation of COL6A3 results in increased ECM remodeling, specifically within invadasomes, in TM cells. However, despite its involvement with ECM remodeling and fibrotic change, COL6A3 is typically downregulated within glaucomatous TM.

Thus, cumulatively these biomechanical changes within the ECM result in loss of ONH integrity in the absence of elevated IOP via altered pressure transmission. Normal physiological conditions allow for the TM and JCT to function as a viscoelastic buffer to transient IOP fluctuations generated by pulse pressure, blinking, and circadian variations. However, as the fibrotic remodeling occurs as described above, the JCT reduces its buffering ability. Transient pressure fluctuations cannot be adequately damped and are transmitted with greater amplitude posteriorly to the ONH, and all structures in between. Over time, the mechanical loading creates degeneration in numerous structures, including the lamina cribrosa, leading to disrupted axoplasmic flow and RGC injury. Thus, despite normal IOP values, the alterations in the ECM and subsequent flow dynamics result in ONH damage via amplified transmission of physiological pressure variations.

However, even though ECM remodeling within the JCT has been well described as a biomechanical driver of NTG, these structural changes do not occur in isolation. Increasing evidence suggests that upstream genetics and epigenetics play a large role in expression of ECM-related proteins and signaling pathways (Figure 3) (6,10). In particular, genes involved in autophagy, cytoskeletal regulation, and TGF-β signaling may directly influence ECM degradation vs. stability. This predisposes the TM to a fibrotic state. Overall, though directly integral to the pathogenesis of NTG, ECM dysregulation may represent the downstream phenotypic manifestations of molecular and genetic abnormalities (6,10,20,44).

Genetic determinants of NTG

In recent years, a number of genes involved with neuroprotection of RGCs have been implicated in NTG pathogenesis. Importantly, genetic studies of NTG support a heterogeneous disease architecture that includes both rare, highly penetrant causative genes and more common risk loci identified through genome-wide association studies (GWAS).

While GWAS have demonstrated that NTG exhibits a complex polygenic risk architecture, they primarily identify susceptibility loci rather than directly causative genes. In contrast, Table 2 highlights that several genes have been identified as causative or high-penetrance NTG genes through linkage analysis, copy-number variation studies, and whole-exome sequencing, particularly in familial or early-onset NTG cases.

Specifically, Mendelian gene variants in OPTN (optineurin), TBK1 (TANK-binding kinase 1), MYOC (myocilin), and METTL23 have all been implicated in familial forms of NTG. These genes were not identified through GWAS, but rather through targeted genetic studies designed to detect rare pathogenic variants with large effect sizes. Pathogenic variants in OPTN (at position p.Glu50Lys and p.Met98Lys), TBK1 (gene duplications and triplications), MYOC (at position p.Gln368Ter), and METTL23 (position p.Glu28Gly, p.Ala7Val, p.Pro22Arg, p.Arg63Trp) account for 1% of NTG in specific populations (7,26).

Physiologically, proteins OPTN and TBK1 both play key roles in the regulation of autophagy of RGCs and the nuclear factor-κB (NF-κB) signaling pathway. OPTN functions as a selective autophagy receptor, activated only when phosphorylated by TBK1. Aberrancies of this interaction and pathway thus result in excessive autophagy activation and increased RGC apoptosis independent of IOP, highlighting a direct neurodegenerative mechanism distinct from pressure-related injury (26).

In contrast to these causative genes, GWAS have identified multiple common genetic risk loci that contribute to NTG susceptibility through modest individual effects. These loci include: CDKN2B-AS1 at chromosome 9p21, SIX1/SIX6, SRBD1, ELOVL5, OPA1, HK2, EDNRA, TP53, NCK2, BMP4, TBKBP1, and loci at chromosome 9q21 (7,32,36,42). Unlike Mendelian NTG genes, these loci identified in GWAS do not directly cause disease but instead modify the risk by increasing RGC vulnerability to vascular, biomechanical, and neuroinflammatory factors.

Lastly, variations in these loci largely increase susceptibility to ONH damage, rather than determining disease onset independently. Notably, several GWAS loci—including CDKN2B-AS1 and SIX1/SIX6—are more strongly associated with NTG than with high-pressure POAG. This further supports their role in IOP-independent glaucomatous pathogenesis (7,20,46-48).

Together, these findings emphasize the NTG genetics encompassing both the causative mutations identified through non-GWAS approaches and a broader polygenic risk landscape, identified through GWAS. This distinction is crucial for accurate interpretation of genetic data and reinforces the multifactorial and heterogeneous nature of NTG pathophysiology.

Epigenetic factors influencing NTG: a functional modular framework

Epigenetic modifications within NTG pathophysiology function to regulate gene expression in response to cellular stress, mechanical strain, and environmental factors. These modulations influence the fibrotic signaling that occurs as a result, in addition to ECM turnover and loss of neuroprotection. Organizing epigenetic contributions into functional categories provides clarity of how these modulations converge to drive NTG pathophysiology.

Histone modification and chromatin remodeling

Histone modifications play a central role in regulation of chromatin and transcription of genes that are integral for RGC survival and TM function (49,50). Mutations in METTL23, a histone arginine methyltransferase, cause impaired demethylation of histone H3 (H3R17me2). This results in abnormal transcription to occur that normally is involved with neuroprotection and cellular stress response (48). This includes altered NF-κB signaling and decreased expression of pS2—a protective gene. Functionally, this contributes to increased RGC susceptibility to degeneration and impairs the ability of TM cells to adapt to mechanical stress (48,51).

DNA methylation, post-transcriptional control, and regulation of mechanotransduction

In addition to genetic contributions, epigenetic factors also play a key role in the pathophysiology of NTG, as demonstrated in Table 3. Specifically, alterations in histone methylation, DNA methylation, and regulatory function of non-coding RNA all contribute to abnormal modulation of genes relevant to RGC function and survival (26,33,36). Specifically, genetic mutations in METTL23—encoding histone arginine methyltransferase—can result in defective demethylation of histone H3 at arginine 17 (H3R17me2) (33,36). This disrupts transcription of pS2, a neuroprotective gene, and alters the NF-κB pathway, resulting in increased susceptibility to IOP-independent RGC damage (7,47-49). For a summary of the proposed epigenetic and genetic interactions in NTG, refer to Table 4.

A study by Liu and Sun specifically described the association between METTL23 mutations and early-onset NTG by detailing a family in Japan in which this mutation was present (51). The family had a mutation in the METTL23 (methyltransferase-like 23) gene, which resulted in abnormal coding for histone arginine methyltransferase and subsequent aberrant mRNA splicing. Haploinsufficiency of this gene resulted in decreased subcellular protein levels and reduced catalysis of demethylation reactions within the retina. The absence of METTL23 within the RGC somas led to a decreased RGC lifespan and loss of ONH protection (51). Thus, defective histone arginine methylation due to METTL23 mutations, DNA methylation, and non-coding RNA transcription modulation may all play an epigenetic role in the development of NTG.

Collectively, these epigenetic modulations do not act independently but instead act together to regulate the TM via cellular and molecular mechanisms. Histone modifications act to influence transcriptional ability. DNA methylation stabilizes gene expression patterns. Finally, non-coding RNAs fine-tune the post-transcriptional responses. Together, these mechanisms modulate the integral pathways involved in ECM fibrotic remodeling and mechanical stress response. Importantly, integrated epigenetic modulation provides a bridge between the genetic susceptibility and observed phenotypes of ECM in NTG eyes. By controlling gene expression in response to various stimuli, epigenetic processes may drive the transition to a stiffened fibrotic ECM, and subsequent pressure transmission to the ONH. Overall, epigenetic regulation provides a dynamic layer of control that links genetic susceptibility to observed phenotypes.

Integrated pathophysiology: linking ECM, genetics, and epigenetics

Overall, despite each isolated factor, NTG represents a complex disease with numerous intertwined pathophysiologic factors. Though easy to examine in isolation, ECM dysregulation, genetic predisposition, and epigenetic processes all synergistically act to drive disease progression.

For example, the genetic variants (OPTN, TBK1, METTL23) establish a baseline susceptibility by altering intrinsic cellular processes (47,52). These inherited alterations can predispose the TM cells to lack normal responses to physiological stressors. Epigenetic modifications subsequently act as dynamic regulators, modulating gene expression in response to various stimuli. Specifically, changes in histone methylation, DNA methylation, and non-coding RNA activity can amplify or suppress the pathways integral to ECM remodeling. The combined genetic and epigenetic factors ultimately converge to create a fibrotic JCT phenotype within the ECM (47,53). This causes loss of viscoelastic compliance, leading to altered pressure regulation and ONH strain despite physiologic IOP values.

Thus, ECM dysregulation should not be viewed as an isolated process, but rather as the result of genetic susceptibility and epigenetic modulation.

Evolving concepts within NTG

While the sections above synthesize the current understanding of NTG pathophysiology, genetics, and epigenetics, emerging evidence continues to challenge the earlier assumptions. Historically, glaucoma was conceptualized primarily as a pressure-driven disease. IOP served as both one of the primary risk factors and clinical therapeutic targets. Earlier literature had suggested that NTG either represented a measurement limitation (diurnal or subclinical IOP fluctuations) or an extension of POAG with RGC susceptible to death at lower IOP thresholds (6,15,20,22,24,26,43,51,52). However, emerging evidence contradicts this simplified view. Recent work has shown that NTG may exhibit a different progressive optic neuropathy despite stable and consistently normal IOP, shifting the focus more heavily towards IOP-independent disease contributors. Thus, this has shifted the current way of thinking towards trying to understand the tissue's susceptibility to damage, how biomechanical stressors play a role, and how neurodegeneration all plays a role at physiological IOP values.

Similarly, perspectives that supported that TM dysfunction was linked to ECM remodeling and increased outflow resistance created a contradiction. The contradiction arose as NTG ECM was present despite normal IOP values, even with increased outflow resistance and pressures. However, recent findings have helped to better characterize the relationship between the two. ECM dysregulation does not necessarily produce sustained IOP elevations, but instead directly impacts the viscoelastic properties within the TM and how pressure buffering occurs (40,47). This change in perspective helps to reframe that ECM remodeling may be more of a modulating factor in pressure transmission, rather than a direct determinant of IOP (50).

Previously, genetic research supported that some single causative genes may act analogous to Mendelian disorders and contribute to disease physiology directly. Specifically, OPTN and MYOC were previously thought to have a single relationship. More recent evidence somewhat contradicts this linear monogenic relationship (20,46). GWAS has recently supported that NTG likely has a more complex genetic architecture, with high-penetrance mutations in OPTN, TBK1, and METTL23 co-existing with environmental factors (46).

Previously, epigenetics has assumed that genetic risk alone may dictate disease onset; however, this may have overlooked post-transcriptional regulation (57). Newer research indicates that epigenetic modifications may play a larger role in gene expression than previously thought, as well as neuroprotection. Though recent findings have added complexity to the previously recognized pathogenesis, it does support that NTG is dynamically regulated and thus may be potentially reversible or able to be intervened upon.

Understanding the role that vascular dysregulation plays within NTG still remains a question. Current literature supports that vascular dysregulation and ECM changes may be a driver of the disease itself, or it may also represent the secondary response to the underlying disease. Thus, there remains a need for future research to better understand this.

Thus, recent findings have updated the understanding of NTG pathogenesis and are imperative to be aware of when interpreting current literature and in guiding future research.

Strengths and limitations

Overall, this provides a focused review of the IOP-independent mechanisms underlying NTG and NTG glaucomatous progression. It focuses heavily on reframing the disease pathophysiology towards the ECM remodeling that occurs within the JCT, and how its biomechanical consequences translate clinically. By integrating and understanding the molecular, genetic, epigenetic, and structural contributions to NTG, this review adds a multidimensional perspective of NTG pathophysiology. The structured literature search also allowed the authors to include multiple studies and systematic reviews, all of which supported the central hypothesis of biomechanical alterations playing a large role in NTG.

However, given that it is a review article, it lacks formal quantitative or qualitative results and is unable to establish causality. In addition, this review focuses on the IOP-independent mechanisms of NTG but may underrepresent the IOP-dependent factors known to play a large role in disease physiology. Thus, direct clinical translation is limited. In addition, as a review, it may contain synthesis bias based on a lack of formal quality assessment of each included source.

Conclusions

Accumulating evidence supports the central role of ECM remodeling within the JCT of the TM in the pathophysiology of IOP-independent normal tension glaucomatous progression. Key features of the ECM dysregulation in NTG include increased deposition of fibronectin (particularly EDA isoform), upregulation of mesenchymal markers, and stiffening of the TM, all of which impair AH outflow and increase the pressure transmitted to the ONH and RGCs. The cumulative effect of these factors results in the characteristic ONH damage and VF loss seen clinically. Additionally, ECM changes are influenced by genetic and epigenetic factors such as variants in OPTN, TBK1, MYOC, and METTL23, which can further influence patient susceptibility to NTG through shifting the TM to a fibrotic phenotypic variant. These findings emphasize that NTG is not merely a variant of open-angle glaucoma with normal or low IOP but is rather due to a distinctly different pathophysiological process. As such, the JCT ECM emerges as a significant area of interest in potentially understanding the NTG pathology, emphasizing the need for continual investigation into ECM-targeted strategies as potential therapeutic avenues.

By shifting focus away from detailed AH physiology and toward ECM biology, genetic susceptibility, and neurodegeneration, this review highlights new mechanistic frameworks and therapeutic opportunities for NTG that extend beyond conventional IOP-lowering strategies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-2026-0019/rc

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-2026-0019/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-2026-0019/coif). The authors have no conflicts of interest to declare.

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