bims-mideyd 2026-04-12 papers

Front Cell Dev Biol. 2026 ;14 1733888

CircAFF3 modulation of p53-ID2 signaling in the retinal pigment epithelium links inflammation with cell death in dry age-related macular degeneration.

Yeongseo Ryu, Dahee Jeong, Jeong Hun Kim, Young-Kook Kim.

Introduction: Age-related macular degeneration (AMD) represents a multifactorial disease that is influenced by age, genetic, and environmental factors. AMD is characterized by dysfunction of the retinal pigment epithelium (RPE) resulting from oxidative stress, inflammation, and complement activation. As the disease progresses, the loss of the RPE and photoreceptors leads to geographic atrophy, which is a hallmark of dry AMD. Although research is ongoing, there is currently no established effective treatment for dry AMD. Notably, circular RNAs (circRNAs) have been studied in various diseases; however, the role of circRNAs in eye diseases remains poorly understood. To fill this gap, this study aimed to investigate circRNAs as potential therapeutic targets for dry AMD.
Methods: We identified candidate circRNAs using a laser-induced choroidal neovascularization (CNV) model. The function of circAFF3 was investigated through knockdown experiments in ARPE-19 cells, followed by transcriptomic analysis, pathway enrichment, and functional assays, including qPCR, western blotting, immunofluorescence, monocyte adhesion, and measurements of ROS, iron, lipid peroxidation, and apoptosis. Interaction between circAFF3 and p53 was explored using binding prediction, RNA-binding protein immunoprecipitation, and cycloheximide chase assay.
Results: We found that circAff3 levels were downregulated in RPE samples at day 3 after laser injury. Moreover, silencing circAFF3 induced an inflammatory response in ARPE-19 cells. Based on these results, a subsequent transcriptomic analysis of circAFF3 knockdown in ARPE-19 cells was conducted to further elucidate its function. These analyses showed that genes downregulated by circAFF3 knockdown in ARPE-19 cells were significantly associated with retinal degeneration. Additionally, reduced circAFF3 expression promoted a decrease in ID2 levels, resulting in increased oxidative stress and cell death. Our study further demonstrated that circAFF3 directly interacts with p53, thereby regulating ID2 expression in ARPE-19 cells.
Conclusion: Collectively, our study reveals that circAFF3 plays a crucial role in RPE dysfunction by modulating a circAFF3/p53/ID2 pathway, suggesting that circAFF3 can serve as a key regulator with therapeutic potential in dry AMD.

Keywords: RNA-sequencing; age-related macular degeneration; circAFF3; geographic atrophy; inflammation; retinal pigment epithelium

DOI: https://doi.org/10.3389/fcell.2026.1733888

Redox Biol. 2025 Dec 20. pii: S2213-2317(25)00489-6. [Epub ahead of print]93 103976

Mitochondrial dynamics and their role in the pathogenesis of age-related macular degeneration: A comprehensive review.

Kai-Yang Chen, Hoi-Chun Chan, Wan-Wan Lin, Chi-Ming Chan.

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the elderly and has a multifactorial etiology involving advanced age, genetic susceptibility, and environmental risk factors. Accumulating evidence suggests that mitochondrial dysfunction is a central pathogenic mechanism in AMD, particularly in the retinal pigment epithelium (RPE). The RPE is critical for retinal homeostasis, and its high metabolic activity renders it vulnerable to age-related mitochondrial dysfunction. In AMD, the core processes of mitochondrial dynamics-fission, fusion, biogenesis, and mitophagy-are profoundly dysregulated, leading to a fragmented and dysfunctional mitochondrial network. This failure of quality control results in bioenergetic deficits, excessive oxidative stress, and the release of damage-associated molecular patterns that fuel chronic inflammation and complement-mediated damage. Experimental models and human tissue studies have strengthened the link between mitochondrial dysfunction and AMD pathology, revealing structural abnormalities, mitochondrial DNA (mtDNA) damage, and altered metabolic signatures. Therapeutic strategies targeting mitochondrial pathways, including mitochondria-targeted antioxidants, dynamic modulators, and enhancers of biogenesis and mitophagy, such as agents that restore defective mitophagosome formation, represent promising avenues for intervention. As the field advances, the integration of biomarker development and personalized approaches holds the potential to transform the clinical landscape of AMD by addressing the root causes of cellular dysfunction.

Keywords: Age-related macular degeneration; Biogenesis; Fission; Fusion; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; Retinal pigment epithelium

DOI: https://doi.org/10.1016/j.redox.2025.103976

Front Pharmacol. 2026 ;17 1777313

Gypenoside XLIX ameliorates diabetic retinopathy by downregulating prostaglandin-endoperoxide synthase 2 in retinal pigment epithelium cells to inhibit ferroptosis and preserve tight junction integrity.

Jiayi Gu, Manhui Zhu, Lele Li, Xin Cao, Xiaoli Yu, Xiaobo Huang, Lili Huang, Qi Cai, Yan Zhu, Wendie Li, Yong Wang.

Introduction: Diabetic retinopathy (DR) represents a prevalent and severe eye complication in diabetic patients. With DR progresses, destruction of tight junctions (TJs) in RPE cells leads to irreversible visual impairment. Gypenoside XLIX (Gyp XLIX) is a dammarane-type glycoside, which can suppress inflammation and oxidative stress. This study sought to investigate and verify the mechanism underlying the regulatory effects of Gyp XLIX in the early protection of junctional integrity of DR.
Methods: We combined bioinformatics and network pharmacology to pinpoint the core therapeutic targets of Gyp XLIX for DR. Mice with diabetes mellitus (DM) and high glucose (HG)-stimulated ARPE-19 cells were treated with Gyp XLIX. Its impact on TJ integrity in RPE cells and ferroptosis was evaluated via Western blotting, immunofluorescence staining, and assays for iron content, lipid peroxidation, and glutathione (GSH) levels. Prostaglandin-endoperoxide synthase 2 (PTGS2) was overexpressed to elucidate the mechanism of action of Gyp XLIX in the early protection of junctional integrity of DR.
Results: Among the shared targets between Gyp XLIX and DR, ALB, VEGFA, JUN, ESR1, PTGS2, STAT3, MMP9, HSP90AA1, BCL2L1 and AR were identified. Western blotting and immunofluorescence staining revealed that Gyp XLIX preserved TJ integrity in RPE cells. In addition, iron, lipid peroxidation and GSH assays revealed that Gyp XLIX inhibited ferroptosis in both mice with DM and HG-stimulated ARPE-19 cells. Overexpression of PTGS2 partially reversed the protective impacts induced by Gyp XLIX.
Discussion: This study demonstrated that Gyp XLIX suppressed ferroptosis and preserved TJ integrity in RPE cells, with these effects being closely associated with the downregulation of PTGS2, thereby exerting early protective effects on junctional integrity of DR.

Keywords: diabetic retinopathy; ferroptosis; gypenoside XLIX; networkpharmacology; prostaglandin-endoperoxide synthase 2; retinal pigment epithelium

DOI: https://doi.org/10.3389/fphar.2026.1777313

Biomaterials. 2026 Mar 30. pii: S0142-9612(26)00216-4. [Epub ahead of print]333 124192

Molybdenum-based antioxidative nanomedicine fighting against retinal pigment epithelium degeneration.

Yahan Ju, Hengli Lu, Siwei Liu, Xirui Chen, Ni Ni, Yun Su, Yan Liu, Dandan Zhang, Moxin Chen, Rui Huang, Jing Zhang, Huijing Xiang, Yu Chen, Zhimin Tang, Ping Gu.

Oxidative stress-induced retinal pigment epithelium (RPE) degeneration is the pathologic basis of most retinal degenerative diseases, especially dry age-related macular degeneration (AMD), for which corresponding therapeutic strategies currently were still in their infancy and lack optimal efficacy. In the present study, cerium-doped molybdenum-based polyoxometalate (MoCe) nanoclusters (NCs) are designed as antioxidative nanocatalysts to inhibit oxidative stress-induced RPE degeneration and subsequent retinal damage. The synthesized MoCe NCs display prominent reactive oxygen species (ROS) scavenging efficacy with excellent in vivo biocompatibility. In RPE degeneration mice model, a single intravitreal administration of MoCe NCs effectively inhibit RPE oxidative degeneration and substantially protect retinal structure and visual function. Upon high-throughput sequencing combined with bioinformatics analysis, MoCe administration predominantly restores the expression of DNA repair-related genes and inhibits oxidative stress-induced apoptosis by suppressing the JNK/c-Jun signaling pathway. The ideal biocompatibility and remarkable protective effect render MoCe NCs as the promising nanomedicines combating RPE degeneration-associated retinal diseases especially AMD.

Keywords: Antioxidant; Apoptosis; Molybdenum-based polyoxometalate; RPE degeneration; Retinal pigment epithelium

DOI: https://doi.org/10.1016/j.biomaterials.2026.124192

Exp Eye Res. 2026 Apr 06. pii: S0014-4835(26)00158-2. [Epub ahead of print] 111002

Retinal Pigment Epithelium in Diabetic Retinopathy: Interplay of Inflammation, Oxidative Stress, Apoptosis, and ncRNA Alterations.

Zahra Souri, Mohammad Malekahmadi, Fatemeh Sanie-Jahromi.

Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults and results from chronic hyperglycemia-induced damage to retinal cells. The retinal pigment epithelium (RPE), located between the neuroretina and choroid, is a critical regulator of retinal homeostasis and an important target of hyperglycemic injury. The aim of this review is to systematically summarize and critically evaluate the molecular mechanisms by which prolonged hyperglycemia disrupts RPE function, with emphasis on four interconnected pathological processes: inflammation, oxidative stress, apoptosis, and non-coding RNA (ncRNA) dysregulation. Hyperglycemia promotes the production of pro-inflammatory cytokines and reactive oxygen species, activates signaling pathways that compromise barrier integrity, and induces apoptotic cell loss. Concurrent alterations in microRNA and long ncRNA expression further impair cellular resilience, metabolic homeostasis, and angiogenic balance. We also review experimental evidence supporting the use of natural and synthetic compounds that target these pathways and may preserve RPE function under hyperglycemic conditions. In addition, we integrate a bioinformatic analysis of DR associated protein-protein interaction networks to identify central regulatory nodes and highlight potential molecular targets for future mechanistic and translational studies.

Keywords: Apoptosis; Hyperglycemia; Inflammation; Oxidative Stress; Retinal Pigmented Epithelium

DOI: https://doi.org/10.1016/j.exer.2026.111002

Cureus. 2026 Mar;18(3): e104820

Effects of Metformin on Mitochondrial Health and Oxidative Stress in Age-Related Macular Degeneration: A Systematic Review.

Raghavee Neupane, Jami Rance, Tara McKenna, Marc M Kesselman.

Age-related macular degeneration (AMD) is a chronic, progressive condition and a leading cause of irreversible central vision loss in older patients. It is driven by oxidative stress, mitochondrial dysfunction, chronic inflammation, and degeneration of retinal pigment epithelium (RPE) cells. Current AMD treatments include lifestyle modifications, nutritional supplements, and/or anti-vascular endothelial growth factor therapies and primarily aim to slow disease progression. As a result, interest has grown in repurposing established medications with potential cytoprotective properties. Metformin, a widely-used anti-diabetic agent, has been proposed as a candidate due to its anti-inflammatory and mitochondrial-modulating effects. We conducted a systematic review to identify studies published between January 2015 and November 2025 that evaluate metformin therapy in (1) adults with AMD and (2) experimental retinal models designed to replicate AMD-related degeneration or pathogenesis. Comparators included individuals with AMD who were not taking metformin therapy, were untreated, and/or were given standard treatment therapy. Outcomes of interest included in the review focused on clinical endpoints of AMD incidence and severity and mechanistic endpoints of mitochondrial function, oxidative stress markers, and cellular senescence. This systematic review includes evidence from epidemiologic, clinical, and experimental studies to link molecular mechanisms with observed disease progression. A total of 10 studies published met the inclusion criteria and demonstrated that metformin is associated with cytoprotective effects in RPE cells by reducing oxidative stress (ROS) and upregulating antioxidant enzymes through activation of the Nrf2 pathway. The drug was also shown to preserve mitochondrial function via activation of AMP-activated protein kinase by enhancing mitophagy, supporting DNA repair, and promoting mitochondrial biogenesis. Observational studies suggested that metformin use was associated with a lower risk of AMD development, particularly dry AMD, with stronger associations observed with a longer duration and higher cumulative exposure. However, findings were context-dependent. Under certain stress conditions, such as sodium iodate exposure, metformin-mediated inhibition of mitochondrial complex I appeared to increase oxidative stress, highlighting a potential "double-edged" effect. Overall, current preclinical and observational studies suggest a possible association between metformin use and mitochondrial modulation in AMD. Prospective studies are needed to clarify dosing, safety, and therapeutic relevance before clinical recommendations can be made.

Keywords: age-related macular degeneration; cellular senescence; longevity; metformin; mitochondrial function; telomere maintenance

DOI: https://doi.org/10.7759/cureus.104820