bims-mideyd 2025-12-21 papers

Invest Ophthalmol Vis Sci. 2025 Dec 01. 66(15): 55

iPLA2β Protects Retinal Pigment Epithelium From Ferroptosis in a Sodium Iodate-Induced Model of Dry AMD.

Takafumi Suzuki, Ryo Terao, Masako Nagahara, Kentaro Hayashi, Kunihiro Azuma, Koei Shinzawa, Kenta Moriwaki, Tomoyasu Shiraya, Megumi Honjo, Takashi Ueta.

Purpose: Ferroptosis, characterized by lipid peroxidation, has been implicated in retinal pigment epithelium (RPE) degeneration in dry age-related macular degeneration (AMD). This study aimed to investigate the role of calcium-independent phospholipase A2 group VI (iPLA2β) in protecting RPE cells from oxidative stress using a sodium iodate (NaIO3)-induced dry AMD model.
Methods: The iPLA2β knockout (KO) and wild-type (WT) mice were subjected to NaIO3 administration. Retinal structure and function were evaluated by histology and electroretinography. The involvement of ferroptosis was assessed by quantitative real-time polymerase chain reaction (qPCR) and Western blotting. Pharmacological intervention experiments used ferrostatin-1, α-tocopherol, and necrostatin-1s to evaluate protective effects. Western blotting was performed for RIP3 phosphorylation, and RIP3 KO mice were used to further assess necroptosis involvement.
Results: The iPLA2β KO mice exhibited normal retinal morphology and function under baseline conditions. NaIO3 exposure caused pronounced RPE and photoreceptor degeneration, a characteristic downregulation of genes responsive to ferroptotic stress, elevated lipid peroxidation, and impaired visual function, which were markedly rescued by ferrostatin-1 and α-tocopherol, and partially by necrostatin-1s. NaIO3 did not induce RIP3 phosphorylation, and necrostatin-1s appeared to exert antioxidative effects. RIP3 KO mice developed severe RPE degeneration after NaIO3 exposure, significantly attenuated by necrostatin-1s. These findings indicate that lipid peroxidation-mediated ferroptosis, rather than necroptosis, is the primary mechanism of NaIO3-induced retinal degeneration, particularly at low doses of NaIO3.
Conclusions: The iPLA2β functions as a key suppressor of lipid peroxidation-mediated RPE degeneration in the NaIO3 model. Targeting ferroptosis-particularly via iPLA2β-may represent a potential therapeutic approach for protecting the RPE from oxidative stress-induced injury in dry AMD, although further validation in human tissues will be necessary.

DOI: https://doi.org/10.1167/iovs.66.15.55

Life Sci. 2025 Dec 11. pii: S0024-3205(25)00781-7. [Epub ahead of print]385 124145

Gene editing of JNK alleviates sodium iodate-induced retinal degeneration in mice.

Lei Tao, Danxue He, Yuling Chen, Peixin Cai, Kunhuan Yang, Jianfeng Wu, Chunyan Liao, Jingmeng Chen, Yalin Wu.

PURPOSE: Dry age-related macular degeneration (dry AMD) still lacks effective treatment strategies due to its complex mechanisms. Although c-Jun N-terminal kinase (JNK) signaling has been reported to be associated with retinal degeneration in dry AMD, the efficacy of JNK gene editing in treating dry AMD remains unclear. This study aims to investigate the protective potential of JNK genetic inhibition in a sodium iodate (SI)-induced retinal degeneration model that recapitulates the key features of human dry AMD.
METHODS: A retinal degeneration model was constructed from a single intraperitoneal injection of 50 mg/kg body weight SI into C57BL/6 J mice. The retina was examined by electroretinography (ERG), fundus imaging, optical coherence tomography (OCT), hematoxylin and eosin (H&E) staining, and whole-mount ZO-1 immunofluorescence staining. Protein levels were determined using Western blotting. Jnk1+/-Jnk2-/- mice were obtained by crossbreeding Jnk2-/- mice with Jnk1+/- mice.
RESULTS: In C57BL/6 J mice, SI robustly activated JNK signaling in the retinal pigment epithelium (RPE)/choroid, triggering a parallel loss of retinal function and structural integrity. By contrast, Jnk1+/-Jnk2-/- mice were largely protected: both the SI-evoked JNK response in the RPE/choroid and the ensuing retinal degeneration were markedly attenuated.
CONCLUSIONS: Gene editing of JNK is effective in ameliorating SI-driven retinal injury and may serve as a promising therapeutic avenue for dry AMD.

Keywords: Age-related macular degeneration; JNK gene editing; Photoreceptor; Retinal pigment epithelium; Sodium iodate

DOI: https://doi.org/10.1016/j.lfs.2025.124145

Cureus. 2025 Nov;17(11): e96926

Retinal Ganglion Cell Senescence Links Diabetes to Retinal Neurodegeneration.

Ayana Suzumura, Hideyuki Shimizu, Kazuhisa Yamada, Junya Ota, Seina Ito, Koji M Nishiguchi, Hiroki Kaneko.

Background Diabetic retinopathy (DR) is a leading cause of blindness worldwide and traditionally considered a microvascular complication. However, accumulating evidence indicates that retinal neurodegeneration is also crucial in DR pathogenesis. Retinal ganglion cells (RGCs), the output neurons of the retina, are particularly vulnerable to diabetic stress. Cellular senescence has been implicated in diabetes-related tissue damage, but its contribution to RGC degeneration remains unclear. We hypothesized that diabetes contributes to retinal neurodegeneration by inducing senescence in RGCs. Methods In streptozotocin (STZ)-induced diabetic mice, retinal function was assessed via full-field electroretinography (ERG), and molecular changes were evaluated in senescence markers. The expression of p16INK4a and monocyte chemotactic protein-1 (MCP-1) in retinal tissue was evaluated by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time polymerase chain reaction (qRT-PCR), and the localization of p16INK4a was confirmed by immunostaining. To explore the direct effects of senescence, primary RGCs isolated from rat retina were exposed to oxidative stress or treated with the CDK4/6 inhibitor palbociclib. The isolated RGCs were analyzed via senescence-associated β-galactosidase (SA-β-gal) staining and live-cell neurite imaging. Results The STZ-induced diabetic mice exhibited significant hyperglycemia without weight loss. ERG revealed markedly reduced amplitudes of the a-wave, b-wave, and oscillatory potentials, indicating impaired retinal neural function. Molecular analyses revealed significant upregulation of MCP-1 and p16INK4a at mRNA and protein levels. Immunostaining demonstrated p16INK4a co-expression in a subset of NeuN-positive cells within the ganglion cell layer, suggesting RGC senescence. Palbociclib-induced senescence (confirmed by SA-β-gal positivity) in vitroresulted in progressive neurite shortening in RGCs. Similarly, oxidative stress induced by antioxidant-free culture conditions caused neurite degeneration, highlighting the dual contributions of oxidative stress and senescence to RGC injury. Conclusions Cellular senescence was identified as a critical mechanism underlying RGC dysfunction in diabetes. Diabetes was found to induce retinal senescence and senescence-associated secretory phenotype activation, with RGCs exhibiting senescence-associated changes. Moreover, oxidative stress and pharmacologically induced senescence directly impaired RGC morphology and function in vitro. These results expanded our understanding of DR from a solely vascular disorder to a neurodegenerative disease, providing mechanistic insights into the role of senescence in retinal aging and neuronal susceptibility in diabetes.

Keywords: diabetic retinal neurodegeneration; diabetic retinopathy; p16 gene; retinal ganglion cell; senescence-associated secretory phenotype (sasp)

DOI: https://doi.org/10.7759/cureus.96926

J Diabetes Complications. 2025 Dec 13. pii: S1056-8727(25)00303-4. [Epub ahead of print]40(2): 109250

Ezetimibe attenuates diabetic retinopathy via NRF2-mediated suppression of inflammation and oxidative stress.

Lei Cheng, Shan Cheng, Ran Zhu, Guoxu Xu.

BACKGROUND: Diabetic retinopathy (DR) is a leading cause of blindness in working-age adults, driven by chronic inflammation and oxidative stress. Ezetimibe (EZE), a lipid-lowering agent, has been shown to activate the NRF2 pathway, but its role in DR remains unexplored. Our study utilized in vitro and in vivo models to investigate the protective effects of EZE on diabetic retinopathy (DR).
METHODS: ARPE-19 cells were exposed to high glucose (HG, 25 mM) with or without EZE (5-20 μM) and/or ML385 (NRF2 inhibitor). NRF2 nuclear translocation, mitochondrial ROS (mtROS), and inflammatory mediators were assessed by Western blot, Immunofluorescence analysis, qPCR, and flow cytometry. In vivo, streptozotocin-induced diabetic wild-type (WT) and NRF2 knockout (Nrf2 KO) mice were treated with EZE (2 or 10 mg/kg/day) for 4 weeks. Retinal inflammation and structural integrity were evaluated by Western blot, H&E staining, and immunohistochemistry.
RESULTS: EZE dose-dependently promoted NRF2 nuclear translocation and reduced HG-induced mtROS, NF-κB activation, and expression of TNF-α, IL-6, MCP-1, COX-2, iNOS, and VEGFA in ARPE-19 cells. These effects were abolished by ML385. In WT diabetic mice, EZE improved fasting glucose, preserved retinal layer thickness, and reduced retinal inflammation. In contrast, EZE failed to exert protective effects in Nrf2 KO mice.
CONCLUSIONS: EZE exerts retinal protection in DR via NRF2-mediated suppression of oxidative stress and inflammation. These findings support the potential repurposing of EZE as a safe intervention for DR.

Keywords: Diabetic retinopathy; Ezetimibe; Mitochondrial ROS; NRF2 knockout; NRF2 signaling; Oxidative stress

DOI: https://doi.org/10.1016/j.jdiacomp.2025.109250

Cell Death Discov. 2025 Dec 15. 11(1): 557

MKK4 and MKK7 control degeneration of retinal ganglion cell somas and axons after glaucoma-relevant injury.

Olivia J Marola, Stephanie B Syc-Mazurek, Sarah E R Yablonski, Peter G Shrager, Simon W M John, Richard T Libby.

Retinal ganglion cell (RGC) death is a critical component of glaucoma pathology. The degenerative signaling pathways that lead to RGC death in glaucoma are incompletely defined. Recently, the transcription factors JUN and DDIT3 were identified as critical hubs regulating RGC somal loss after mechanical axonal injury. However, their position within the degenerative cascade remains unclear. One possibility is that JUN and DDIT3 activity in the soma initiates signaling events that trigger axonal degeneration. Alternatively, JUN and DDIT3 may function downstream of the primary insult, acting specifically to mediate somal degeneration without influencing axonal pathology. Disentangling these possibilities is critical for understanding the compartment-specific mechanisms of RGC degeneration in glaucoma. The MAP2Ks MKK4 and MKK7 control JNK and JUN activity and can indirectly activate DDIT3. Furthermore, MKK4 and MKK7 have been shown to drive RGC axonal degeneration after mechanical axonal injury. The present work investigated whether JUN and DDIT3, or their upstream activators MKK4 and MKK7, control degeneration of RGC axons and somas after glaucoma-relevant injuries; including ocular hypertension in aged DBA/2J mice and after mechanical axonal injury (controlled optic nerve crush, CONC) in C57BL/6J mice. Ddit3 and Jun deletion did not prevent RGC axonal degeneration in DBA/2J mice but prevented nearly all somal loss. Despite robust somal survival, Ddit3 and Jun deletion did not prevent RGC somal shrinkage or pattern electroretinography (PERG) amplitude decline in DBA/2J mice or after CONC in C57BL/6J mice. In contrast, Mkk4 and Mkk7 deletion from C57BL/6J mice significantly lessened RGC soma and axon degeneration while preserving PERG amplitude and soma size after CONC. In summary, activation of MKK4 and MKK7 may be an inciting mechanism governing RGC somal and axonal degeneration after glaucoma-relevant axonal injury.

DOI: https://doi.org/10.1038/s41420-025-02842-w