A systematic literature search was performed using the PubMed(https://pubmed.ncbi.nlm.nih.gov/) and Web of Science databases(https://www.webofscience.com), covering the period from database inception to October 2025. The search strategy combined terms related to m6A modification and retinal diseases. For m6A modification, the following keywords were used: ‘N6-methyladenosine’, ‘m6A’, ‘METTL3’, ‘METTL14’, ‘WTAP’, ‘FTO’, ‘ALKBH5’, ‘YTHDF1’, ‘YTHDF2’ and ‘YTHDC1’. For search of retinal diseases, full list search terms used included ‘diabetic retinopathy’, ‘age-related macular degeneration’, ‘retinoblastoma’, ‘uveitis’ and ‘retinitis pigmentosa’. Boolean operators (AND/OR) were applied to combine these term groups. Additional relevant studies were identified by manually screening the reference lists of retrieved articles and previous reviews. Inclusion and exclusion criteria: Only peer-reviewed, original research articles and review papers published in English were included. The final reference list was selected based on relevance to the regulatory roles, pathological implications and therapeutic targeting of m6A modification in the retina.

The vertebrate retina is a highly organized layered structure comprising multiple cell types that work in concert to process visual information. Neuronal components include photoreceptors (rods and cones), bipolar cells, ganglion cells, horizontal cells and amacrine cells, with over 60 distinct neuronal subtypes identified in mammals (18). In addition to these neurons, Müller glial cells provide structural and metabolic support, and the retinal pigment epithelium (RPE) forms the outer blood-retinal barrier and maintains photoreceptor homeostasis (19). Rod photoreceptors dominate in number and mediate dim-light vision, whereas cones enable color and high-acuity vision. The cone output is decomposed into ~12 parallel channels via distinct bipolar cell types, which then relay specific visual features to different subsets of retinal ganglion cells (18). Amacrine cells, of which nearly 30 types exist, refine these signals through lateral and crossover inhibition, generating diverse encodings such as direction selectivity and motion detection (18).

From a clinical perspective, standard therapeutic approaches for common retinal diseases have been well established. For DR and neovascular AMD, intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents represent first-line therapy; laser photocoagulation and corticosteroids are also used as adjunctive or alternative treatments (19). In early and intermediate AMD, lifestyle modifications (smoking cessation) and nutritional supplementation with the AREDS2 formulation (lutein, zeaxanthin, vitamins C and E, and zinc) are recommended to reduce the risk of progression (19). For RP, no curative therapy exists for most genetic subtypes, but gene replacement therapy has been approved for RPE65-associated RP, and optogenetic strategies are under investigation (20). Autoimmune retinopathy, a rare inflammatory condition, is diagnosed based on clinical, imaging and electrophysiological criteria, and treatment primarily aims to prevent progression (21). Understanding normal retinal physiology and the existing treatment landscape provides a foundation for exploring emerging epitranscriptomic regulators, such as m6A modification, in retinal diseases.

RB is the most common intraocular malignancy in children, primarily caused by biallelic mutations in the RB1 gene. Clinical manifestations include leukocoria, strabismus or visual impairment, with potential metastasis and poor treatment outcomes in advanced cases (42,43). Recent research has highlighted the role of m6A modification in tumor progression, as it regulates gene expression at the post-transcriptional level and may contribute to the malignant progression of RB (44).

Although studies on m6A in RB remain limited, mechanisms observed in other cancers may provide insights. METTL3-mediated m6A modification enhances the stability and translation efficiency of oncogenic transcripts, promoting tumor progression (45). YTHDF2 recognizes m6A marks to facilitate the degradation of target mRNAs, affecting genes related to cell cycle and apoptosis (46). FTO regulates signaling pathways such as MYC through demethylation (47). These mechanisms suggest potential analogous functions of m6A modification in RB.

Indirect experimental evidence supports its potential role. In lung cancer, METTL3 knockdown suppresses the expression of genes such as cyclin-dependent kinase 6 (CDK6) and matrix metalloproteinase-2, delaying tumor progression (48). In hepatocellular carcinoma, ALKBH5 influences malignant phenotypes by regulating signal transducer and activator of transcription 1 mRNA stability (49). In bladder cancer, YTHDF2 promotes tumor growth by degrading period circadian regulator 1 mRNA (50). These findings offer a reference for understanding the role of m6A in RB.

Therapeutic strategies targeting the m6A regulatory network show promising potential. The METTL3 inhibitor STM2457 suppresses acute myeloid leukemia cell proliferation (51). The FTO inhibitor FB23-2 induces cell differentiation and apoptosis (52). The YTHDF1 inhibitor ebselen exhibits antitumor effects in breast cancer (53). These discoveries provide new directions for RB treatment.

Uveitis is an inflammatory disease involving the iris, ciliary body and choroid that is frequently associated with autoimmune dysregulation. Characterized by immune cell infiltration and breakdown of the blood-retinal barrier, it represents a significant cause of vision impairment in young and middle-aged adults (54). m6A modification, which is critically involved in immunoregulation, may contribute to the development of uveitis. METTL3-mediated m6A modification promotes the stability of T cell immunoreceptor with Ig and ITIM domains (TIGIT) mRNA, thereby regulating T cell function. During T-cell exhaustion, METTL3 upregulates TIGIT expression by enhancing its mRNA stability, leading to T-cell dysfunction. T cell-mediated autoimmune responses play a central role in its pathogenesis (55). This suggests that m6A modification may influence immune homeostasis in uveitis by modulating immune checkpoint molecules.

Furthermore, m6A modification participates in innate immune regulation. In conditions such as juvenile idiopathic arthritis, decreased expression of FTO and ALKBH5 in monocytes at inflammatory sites leads to elevated m6A levels, promoting aberrant monocyte activation (56). Given that monocyte/macrophage infiltration is a key feature of uveitis, m6A may influence the inflammatory process by regulating their activation state.

An experimental study indicated that METTL3 knockdown ameliorates T cell exhaustion (57), and peripheral blood m6A levels correlate with disease activity in autoimmune disorders. Although direct evidence in uveitis is limited, these findings imply that m6A may participate in disease pathogenesis through its regulation of T cells and monocytes/macrophages.

Therapeutic targeting of m6A regulators, such as the METTL3 inhibitor STM2457, have demonstrated anti-inflammatory effects in various models, offering new avenues for immunotherapy in uveitis

Due to the scarcity of direct studies on m6A modification in RB and uveitis, the above discussion partly relies on findings from other cancers or inflammatory diseases. These extrapolations should be interpreted with caution, and future work using RB-specific and uveitis-specific models (for example patient-derived xenografts for RB, experimental autoimmune uveitis models) is urgently needed to validate the proposed mechanisms and to explore the therapeutic potential of targeting m6A regulators in these conditions.

The m6A regulatory network exhibits marked context-dependent functions across different retinal diseases. An example is ALKBH5, a m6A demethylase. In DR, ALKBH5 exerts protective effects by reducing ferroptosis through YTHDF1-mediated degradation of ACSL4 mRNA (28). Conversely, in AMD, ALKBH5 promotes choroidal neovascularization and subretinal fibrosis by stabilizing ID2 mRNA (36). Such opposing roles highlight that the therapeutic outcome of targeting a single m6A regulator may vary dramatically depending on disease context, cell type and microenvironment. Similarly, METTL3 has been consistently reported as pathogenic in both DR and AMD, driving inflammation in the former and fibrosis in the latter (33,63). However, functional redundancy among methyltransferases (for example METTL3 and METTL14) may complicate the interpretation of single-enzyme inhibition studies. These discrepancies underscore the need for cell-type-specific and disease-stage-specific investigations before clinical translation (41).

Despite disease-specific differences, several common m6A-regulated pathological modules recur across DR, AMD, RP and other retinal disorders. First, inflammation is a contributing factor. METTL3-mediated m6A modification enhances PIEZO1 mRNA stability in DR (25) and activates the NLRP3 inflammasome in AMD (38), both leading to inflammatory damage. Second, angiogenesis represents another convergent module. ALKBH5-driven ID2 upregulation promotes choroidal neovascularization in AMD (36), while METTL3 influences VEGF expression in DR (29). Third, cell death pathways including ferroptosis, pyroptosis and autophagy are commonly regulated by m6A. For instance, ALKBH5 protects against ferroptosis in DR via ACSL4 (28), whereas FTO promotes pyroptosis in AMD via Neat1 (38), and METTL3 modulates autophagy in retinal ganglion cells (64). These shared modules suggest that targeting a single m6A regulator may have pleiotropic effects across multiple diseases, but also raises concerns about off-target outcomes.

Current standard therapies for major retinal diseases include anti-VEGF agents (for DR and neovascular AMD), laser photocoagulation, corticosteroids and, for selected RP cases, gene replacement therapy (65,66). While these treatments have proven efficacy, limitations such as frequent intravitreal injections, non-response in a subset of patients (for example anti-VEGF resistance in DR), and lack of curative options for degenerative conditions persist. In this context, m6A-targeted agents could be positioned in several ways: i) As adjunctive therapy combined with anti-VEGF to enhance efficacy or reduce injection frequency; ii) as an alternative or add-on for anti-VEGF-resistant patients, particularly those with persistent inflammation or ferroptosis-driven pathology; and iii) for early-stage intervention, targeting m6A modules before irreversible vascular or neuronal damage occurs. For RP and uveitis, where anti-VEGF is not the mainstay, m6A modulators may complement gene therapy (by stabilizing photoreceptor transcripts) or immunosuppressants (by fine-tuning T cell responses) (67).

Systemic administration of m6A-targeting small molecules (for example STM2457 and FB23-2) poses a risk of off-target effects due to the ubiquitous expression of m6A machinery across tissues. However, the eye offers unique advantages for local delivery. Intravitreal injection can achieve high retinal drug concentrations while minimizing systemic exposure (68). Nevertheless, several challenges remain. First, current inhibitors lack long-term safety data in large animal models; non-human primate studies are urgently needed. Second, retinal cell-type specificity is difficult to achieve with small molecules alone. Emerging delivery strategies include adeno-associated virus (AAV) vectors for targeted expression of m6A enzyme modulators (41), nanoparticle-based carriers to enhance retinal penetration (69), and biodegradable hydrogels for sustained release. Third, potential immune responses against viral vectors or repeated injections must be addressed. These safety and delivery considerations are critical for clinical translation.

Future research should prioritize the development of tissue-specific regulatory tools, such as AAV vectors for precise editing of m6A enzymes (41). Mapping m6A epitranscriptomes across disease stages via single-cell sequencing will help elucidate their dynamic changes (70). Concurrently, deeper investigation into the interplay between m6A and other epigenetic mechanisms such as histone modifications and DNA methylation is warranted (71). Optimizing nanoparticle-based delivery systems may enhance retinal drug accumulation and reduce systemic toxicity (72). Establishing non-human primate models will be crucial for evaluating long-term safety and efficacy. Furthermore, advancing the clinical translation of m6A-related biomarkers (for example blood METTL14 levels) could support personalized treatment strategies (73).

Notably, m6A-targeted agents may synergize with conventional therapies. In diabetic retinopathy, combining m6A regulators with anti-VEGF drugs could enhance efficacy, while in RP, integrating gene therapy with m6A modulation may yield synergistic protective effects. Artificial intelligence-driven multi-omics analyses hold promise for uncovering novel m6A regulatory networks, providing a theoretical foundation for combination therapies. Progress in these areas will require interdisciplinary collaboration across epigenetics, bioinformatics, materials science and clinical medicine.

In summary, m6A modification serves as a critical epitranscriptomic regulatory mechanism in retinal diseases (Fig. 2). Although m6A-targeted therapies face multiple challenges, advancing mechanistic studies, developing precise regulatory tools and promoting clinical validation may offer new hope for patients. Future efforts should focus on multi-omics integration, delivery system optimization, and rigorous clinical trial design to accelerate the translation of m6A-based treatments into clinical practice.