bims-mideyd 2026-03-08 papers

Front Cell Dev Biol. 2026 ;14 1718715

The contribution of ferroptosis to the epithelial-mesenchymal transition phenotype in models of age-related macular degeneration.

Xingyu Yang, Weichen Xu, Hang Xie, Xiaoyu Guo, Feiyan Zhu, Yiqiao Xing, Changzheng Chen.

Purpose: Age-related macular degeneration (AMD) involves dysfunction of the retinal pigment epithelium (RPE), where cellular senescence and epithelial-mesenchymal transition (EMT) are key pathological features. The upstream mechanisms linking these processes are not fully understood. This study investigates the potential role of ferroptosis in contributing to senescence-associated EMT in RPE cells.
Methods: We utilized an aging mouse model and two cellular models in ARPE-19 cells, induced by D-galactose (D-gal) and low-dose sodium iodate (SI), respectively. Ferroptosis, EMT, and oxidative stress markers were evaluated via immunofluorescence, flow cytometry, and Western blotting. The specific ferroptosis inhibitor Ferrostatin-1 was used to assess the involvement of ferroptosis.
Results: Aged mouse RPE/choroid complexes and stressed ARPE-19 cells exhibited features of EMT along with increased ferroptosis hallmarks, including lipid peroxidation and iron accumulation. A downregulation of the xCT/GPX4 anti-ferroptotic axis was observed. Pretreatment with Fer-1 alleviated ferroptosis by reducing iron levels and lipid peroxidation, and restored xCT/GPX4 expression. Furthermore, Fer-1 attenuated the EMT phenotype, as evidenced by the restoration of epithelial markers and reduction of mesenchymal markers (Vimentin, α-SMA) in both D-gal and SI models.
Conclusion: Our findings suggest that ferroptosis may contribute to linking RPE senescence with EMT, potentially via oxidative stress pathways. The combined targeting of both senescence and ferroptosis could therefore represent a potential therapeutic strategy for addressing RPE dysfunction and AMD progression.

Keywords: age-related macular degeneration (AMD); cellular senescence; epithelial-mesenchymal transition (EMT); ferroptosis; oxidative stress; retinal pigment epithelium (RPE)

DOI: https://doi.org/10.3389/fcell.2026.1718715

Mol Metab. 2026 Mar 02. pii: S2212-8778(26)00027-X. [Epub ahead of print] 102343

Photoreceptor deletion of pyruvate dehydrogenase E1 subunit α1 induces retinal degeneration and reprograms retinal metabolism.

Hongwei Ma, Lilliana R York, Shujuan Li, Grayson Gagnon, Junhuang Zou, Haoran Yu, Jun Yang, Yun Le, Mark Eminhizer, Isabella Mascari, Jianhai Du, Xi-Qin Ding.

Rod and cone photoreceptors are among the most energy-demanding cells in the body, exhibiting a high rate of ATP consumption. Their primary energy source is glucose, which is metabolized through both glycolysis and mitochondrial pyruvate oxidative phosphorylation. The pyruvate dehydrogenase E1 subunit α1 is a critical component of the pyruvate dehydrogenase, which catalyzes the conversion of pyruvate to acetyl-CoA, thereby regulating mitochondrial pyruvate metabolism. To determine the significance of mitochondrial pyruvate metabolism in these cells, we investigated the impact of photoreceptor-specific Pdha1 deletion in the mouse retina. Rod- or cone-specific Pdha1 knockout mice at 2-4 months were used. These mice were evaluated across multiple modalities, including retinal structure and integrity (morphometry), retinal function (electroretinogram), photoreceptor ultrastructure (transmission electron microscopy), retinal metabolic profiles (mass spectrometry), gene expression (RT-PCR), and retinal stress response (glial activation analysis). Mice with rod- or cone-specific Pdha1 deletion exhibited retinal degeneration phenotype, manifested by impaired retinal morphology and light responses and significant retinal glial activation. Mechanistically, these retinas displayed profound metabolism reprogramming, evidenced by changes in key glycolysis and decreased tricarboxylic acid (TCA) cycle intermediates, carbohydrates, amino acids, nucleotides and their derivatives. This metabolic remodeling was further supported by enhanced glycolysis and decreased TCA cycle gene expression and was accompanied by impaired mitochondrial morphology. Our findings demonstrate that PDHA1 is essential for photoreceptor energy metabolism and for maintaining both their structural and functional integrity, thus highlighting the critical importance of proper mitochondrial glucose metabolism for photoreceptor health.

Keywords: Glucose metabolism; Mitochondrial metabolism; PDHA1; Photoreceptor; Photoreceptor metabolism; Pyruvate dehydrogenase; Pyruvate metabolism

DOI: https://doi.org/10.1016/j.molmet.2026.102343

Int J Biol Macromol. 2026 Mar 03. pii: S0141-8130(26)01066-4. [Epub ahead of print] 151140

Enhancing retinal cells anti-attenuation under oxidative stress by NMN-loaded gelatin nanoparticles via efficiently intracellular delivery.

Tien-Chun Yang, Pei-Hsin Chu, Huai-An Chen, Yu-Yi Wu, Ching-Li Tseng.

Oxidative stress plays a critical role in retinal degeneration, contributing to cellular apoptosis and senescence in retinal pigment epithelial (RPE) cells and retinal ganglion cells (RGCs). Nicotinamide mononucleotide (NMN), a key precursor of NAD+, has shown potential in protecting against oxidative damage; however, its clinical translation is hindered by poor cellular uptake and rapid degradation. In this study, carrier gelatin nanoparticles (GNPs) were used to encapsulate NMN (NMN-GNPs) to resolve that disadvantage for NMN usage. We investigated the efficacy of nano-formulated NMN to protect cells under H2O2-induced oxidative stress in human retinal cell models: adult retinal pigment epithelial (ARPE)-19 and human induced pluripotent stem cell (hiPSC)-derived RGCs. Results revealed that both free NMN and NMN-GNPs significantly attenuated H2O2-induced apoptosis and cellular senescence in ARPE-19 cells. However, free NMN showed a limited effect in hiPSC-RGCs, while NMN-GNPs provided significant cytoprotection under a damaged condition. In addition, cellular uptake assays revealed that free NMN had a limited ability to get into RGCs, which was substantially improved by the nanoparticle-mediated formulation (NMN-GNPs) which enhanced intracellular delivery. These results suggest that nanoformulated NMN exhibited facilitated intracellular delivery and enhanced bioavailability which contributed to oxidative stress resilience in retinal cell types and helped retard senescence in both ARPE-19 and hiPSC-RGC scenarios. These findings support the use of NMN-GNPs as a promising nanotherapeutic approach for clinical translation for oxidative stress-related retinal diseases especially for RGC related damages in the future.

Keywords: ARPE; Gelatin; NMN; Nanoparticles; Oxidative damage; Senescence; hiPSC-RGCs

DOI: https://doi.org/10.1016/j.ijbiomac.2026.151140

Autophagy. 2026 Mar 04. 1-3

Chaperone-mediated autophagy: the Achilles heel of the retinal pigment epithelium during age-related macular degeneration.

Juan Ignacio Jiménez-Loygorri, Ana Maria Cuervo, Deborah A Ferrington, Patricia Boya.

Chaperone-mediated autophagy (CMA) is a selective autophagy pathway that targets specific proteins containing a KFERQ-like motif for lysosomal degradation. It has been shown by us and others that CMA decreases during physiological aging in most tissues, and its impairment is associated with increased incidence of age-related pathologies, such as cardiovascular disease, neurodegenerative disorders or sarcopenia. However, its involvement in age-related macular degeneration (AMD), a prevalent progressive maculopathy that leads to bilateral central vision loss, had not been explored. In the early stages of AMD, the retinal pigment epithelium (RPE), a monolayer of cells that provides trophic support to photoreceptors, already presents major morphological and functional alterations but the cause of this cell type-specific vulnerability is unknown. In our latest work, we analyzed human donor RPE samples and found that CMA is selectively impaired in the RPE of AMD patients compared to healthy donors. These alterations lead to the accumulation of undegraded CMA substrates and untimely recycling of other proteins. Crucially, these findings are conserved in donor-derived iPSC-RPE models. We used this clinically relevant model to assess the consequences of dysfunctional CMA in AMD and found that it caused proteotoxicity, increased oxidative damage, and altered metabolism. Most importantly, using the new-generation CMA activator CA77.1, we restored proteostasis in AMD iPSC-RPE. Our findings shed light on the selective vulnerability of the RPE in AMD and provide evidence in support of CMA as a novel druggable target against AMD.

Keywords: Age-related macular degeneration; chaperone-mediated autophagy; oxidative stress; proteostasis; retinal pigment epithelium

DOI: https://doi.org/10.1080/15548627.2026.2636093

Invest Ophthalmol Vis Sci. 2026 Mar 02. 67(3): 5

Neddylation-Mediated hnRNPA2B1 Degradation Aggravates Retinal Endothelial Cell Dysfunction in Diabetic Retinopathy by Regulating miR-93-5p/VEGFA.

Tian-Ran Chen, Jia-Xing Zhou, Ya-Ru Hou, Yun-Nan Zhang, Chen-Xi Li, Jing Zhu, Zi-Rui Guo, Yan Cui.

Purpose: Retinal endothelial cells (RECs) are key targets of diabetes-induced microvascular complications. HnRNPA2B1 suppresses pathological neovascularization in diabetic retinopathy (DR). Although hnRNPA2B1 suppresses pathological neovascularization, its role in hyperglycemia-induced REC dysfunction remains unclear.
Methods: Primary mouse retinal vascular endothelial cells (mRVECs) under high-glucose (HG) conditions and streptozotocin-induced diabetic mice were analyzed using quantitative real-time PCR (qRT-PCR), Western blotting, RNA immunoprecipitation, immunofluorescence staining, and functional assays (wound healing, Transwell invasion, and tube formation). Co-immunoprecipitation and pharmacological inhibitors were used to validate protein interactions and degradation pathways. Retinal morphology and vascular integrity were assessed using hematoxylin-eosin staining, optical coherence tomography angiography, Evans blue leakage, and trypsin digestion.
Results: HG-induced neddylation mediated hnRNPA2B1 degradation, exacerbating REC dysfunction. Mechanistically, hnRNPA2B1 facilitated miR-93-5p maturation by recruiting DGCR8 within the microprocessor complex, thereby suppressing VEGFA expression via direct targeting of its 3'-untranslated regions. Intravitreal delivery of AAV2-hnRNPA2B1 or miR-93-5p into diabetic mice partially restored retinal hnRNPA2B1/miR-93-5p levels, reduced VEGFA overexpression, and improved retinal histological markers of microvascular damage.
Conclusions: HG-induced effects associated with neddylation pathways lead to hnRNPA2B1 degradation, exacerbating REC dysfunction. HnRNPA2B1, as an RNA binding protein, facilitated miR-93-5p maturation by recruiting DGCR8 within the microprocessor complex. Targeting either hnRNPA2B1 or miR-93-5p may represent a potential therapeutic strategy for preserving retinal vascular homeostasis in diabetes pending functional validation.

DOI: https://doi.org/10.1167/iovs.67.3.5