bims-mideyd 2025-10-26 papers

FASEB J. 2025 Oct 31. 39(20): e71166

FTO Fuels Aβ1-40-Induced Retinal Pigment Epithelium Cell Injury Associated With Pyroptosis by Erasing m6A Methylation of the lncRNA Neat1.

Qiang Xue, Junyi Huang, Bing Wang, Jingyan Ji, Li Wang, Sneha Kumari, Chunlin Lan, Meichun Xiao.

Retinal pigment epithelium (RPE) degeneration in association with inflammation is a key feature of age-related macular degeneration (AMD) pathology. Amyloid β (Aβ) in drusenoid deposits, the hallmark of AMD, is a critical initiating component that causes RPE cell damage through the activation of the NLR family pyrin domain containing 3 (NLRP3)-mediated inflammatory response. Epigenetic mechanisms have been reported to contribute to the pathogenesis of AMD. However, the extent to which epigenetic modifications regulate Aβ-mediated RPE inflammatory damage and cell death remains unclear. N6-methyladenosine (m6A) is the most abundant RNA epigenetic regulation in eukaryotes. Herein, based on bioinformatics analysis, we identified that fat mass and obesity-associated protein (FTO) acts as an essential epigenetic regulator in Aβ1-40-mediated RPE inflammatory cell death. Activation of NLRP3 inflammasome-related RPE pyroptosis was evident through enhanced NLRP3, gasdermin D immunoreactivity, increased caspase-1 cleavage, elevated IL-1β secretion, and higher LDH activity. Deletion of FTO resulted in the inhibition of RPE pyroptosis in vitro and in vivo. Mechanistically, methylated RNA immunoprecipitation (MeRIP) combined with RNA-seq demonstrated that long noncoding RNA (lncRNA) Neat1 served as a downstream target of FTO, with FTO knockdown suppressing Neat1 expression in an m6A-dependent manner. Neat1 depletion deactivated inflammatory factors, thereby hindering Aβ1-40-induced RPE pyroptosis. Furthermore, FTO silencing attenuated Neat1-mediated pyroptosis, resulting in compromised retinal structure and function. These findings suggest that the FTO-Neat1-NLRP3 network provides potential targets to treat AMD while expanding our understanding of the role of epigenetically modified lncRNAs in Aβ-driven RPE injury.

Keywords: FTO; N6‐methyladenosine; age‐related macular degeneration; pyroptosis; retinal pigment epithelium

DOI: https://doi.org/10.1096/fj.202500272RRRR

Med Hypothesis Discov Innov Ophthalmol. 2025 ;14(3): 136-145

Reactive oxygen species and oxidative stress in ocular disease: from molecular mechanisms to targeted therapies.

Yara Abukhaled.

Background: Reactive oxygen species and oxidative stress are increasingly recognized as central drivers in the development of major ocular diseases, including cataracts, age-related macular degeneration, glaucoma, and diabetic retinopathy. The eye's unique environment-continuous light exposure, high oxygen tension, and abundant photosensitizers-renders it particularly vulnerable to ROS-mediated damage. This narrative review aims to synthesize current evidence on the molecular mechanisms of oxidative stress in ocular disease and highlight emerging therapeutic approaches.
Methods: Targeted searches of PubMed, Scopus, and Google Scholar for literature published between 2000 and June 2025 were conducted. Keywords included "oxidative stress", "reactive oxygen species", "ocular disease", "cataract", "age-related macular degeneration", "glaucoma", and "diabetic retinopathy". Only English-language, peer-reviewed articles were considered. Relevant primary studies, clinical trials, reviews, and experimental reports were selectively incorporated, with an emphasis on recent publications and high-impact contributions to the field.
Results: Evidence consistently demonstrates that ROS induce lipid peroxidation, protein oxidation, DNA damage, mitochondrial dysfunction, and disruption of redox-sensitive cellular signaling pathways across ocular tissues. In cataracts, oxidation of crystalline proteins and glutathione depletion are primary drivers of lens opacification. In age-related macular degeneration, mitochondrial dysfunction and lipofuscin accumulation promote retinal pigment epithelium degeneration and neovascularization. Glaucoma involves both trabecular meshwork oxidative injury, contributing to elevated intraocular pressure, and mitochondrial-driven retinal ganglion cell apoptosis. In diabetic retinopathy, hyperglycemia-induced ROS overload activates pathogenic pathways, leading to microvascular damage and neuronal dysfunction. Clinical and experimental studies support antioxidant therapies as adjunctive strategies, with the strongest evidence for Age-Related Eye Disease Study-based formulations in age-related macular degeneration and promising results for agents such as Coenzyme Q10 in glaucoma and sulforaphane in diabetic retinopathy. For cataracts, supplementation trials have yielded mixed outcomes and surgery remains the definitive treatment.
Conclusions: Oxidative stress represents a unifying mechanism in the pathogenesis of vision-threatening ocular diseases. Antioxidant-based interventions show potential, particularly when integrated with existing treatment regimens, but their translation into routine practice remains limited by heterogeneous trial results and the absence of robust biomarkers for patient selection. Future research should focus on precision antioxidant therapy, leveraging stage-specific interventions, novel delivery systems, and pathway-targeted compounds, to transform ocular care from reactive management toward prevention.

Keywords: active oxygen species; age-related macular degeneration; antioxidant; cataracts; diabetic retinopathies; glaucomas; mitochondrial dysfunctions; oxidative dna damage; oxidative injury; oxidative stresses; reactive oxygen species

DOI: https://doi.org/10.51329/mehdiophthal1527

J Biol Chem. 2025 Oct 22. pii: S0021-9258(25)02698-5. [Epub ahead of print] 110846

The retinol-binding protein receptor STRA6 and melanin cooperatively sustain retinoid signaling and outer blood-retinal barrier integrity.

Aicha Saadane, Johannes von Lintig.

Disruption of the outer blood-retinal barrier (oBRB) is a central feature of retinal degenerative diseases, including age-related macular degeneration, yet the molecular mechanisms maintaining this barrier in the adult eye remain poorly defined. STRA6, a high-affinity receptor for retinol-binding protein (RBP4), mediates vitamin A uptake at the basolateral membrane of the retinal pigment epithelium (RPE), while melanin protects ocular retinoid stores from photooxidative stress. We previously showed that STRA6 deficiency leads to downregulation of junctional proteins in the RPE. Here, we demonstrate that STRA6 and melanin act synergistically to preserve the integrity of the oBRB. In albino Stra6 knockout mice, ocular retinoid levels were severely reduced despite normal circulating retinol levels, and dietary vitamin A delivered via chylomicrons failed to compensate for the loss of RBP4-mediated transport. This led to a functional impairment of both rod- and cone-mediated responses, even under vitamin A-sufficient conditions. Mice also showed downregulated tight junction proteins (ZO-1, Claudin-1, Claudin-3), RPE disorganization, barrier leakage, and immune cell infiltration into the subretinal space. These defects were further exacerbated under dietary vitamin A restriction. Importantly, systemic treatment with the pan-retinoic acid receptor (RAR) agonist TTNPB restored junctional gene expression and oBRB function in Stra6-/- mice, providing evidence that barrier failure arises from impaired retinoid signaling rather than structural loss of STRA6 and melanin. These findings define a novel role for retinoic acid in sustaining RPE barrier function and highlight the combined importance of STRA6-mediated transport and melanin-dependent photoprotection in retinal homeostasis.

Keywords: Barrier Function; Epithelia; Lipid Transport; Metabolism; Retinoids

DOI: https://doi.org/10.1016/j.jbc.2025.110846