bims-mideyd 2026-08-02 papers

Int J Mol Sci. 2026 Jul 15. pii: 6291. [Epub ahead of print]27(14):

Induction of Oxidative Stress on Retinal Pigment Epithelial Cells Triggered a Proangiogenic Environment.

Mohamed Abdouh, Alicia Goyeneche, Morgan Yurchuk, Miguel N Burnier.

Dry age-related macular degeneration (AMD) can progress to wet AMD when leaking capillaries grow under the macula. Although rare, this transition holds significant risk as it causes more rapid and severe vision loss. Oxidative stress is damaging to cellular components and plays a pivotal role in chronic diseases. We aim to determine whether oxidative stress in retinal pigment epithelial (RPE) cells elicits a proangiogenic microenvironment. We exposed human primary RPE cells to hydrogen peroxide (H2O2), and we analyzed their metabolic activity, and the production of reactive oxygen species (ROS) and angiogenic factors. In addition, we evaluated the potential of RPE cell-conditioned medium (CM) to induce HUVEC cell tube formation. RPE cells exposed to H2O2 displayed a dose-dependent decrease in their metabolic activity, and increased ROS levels. The analysis of the CM of exposed RPE cells revealed differential expression of a panel of proangiogenic factors. Notably, the expression of the major angiogenic factors (VEGF, FGF) was increased. Exposure of HUVEC cells to the CM of H2O2-exposed RPE cells promoted tube formation suggestive of microvessel formation. Our findings bring new insights into the role of oxidative stress in altering RPE cell behavior that might have consequences in the progression of AMD towards the exudative form.

Keywords: age-related macular degeneration; angiogenesis; cell culture; disease progression; human primary retinal pigment epithelial cells; oxidative stress

DOI: https://doi.org/10.3390/ijms27146291

J Ophthalmol. 2026 ;2026 8106992

SPI1 Promotes TNF-α-Induced Epithelial-Mesenchymal Transition-Like Changes in Retinal Pigment Epithelial Cells: Implications for the Pathogenesis of Age-Related Macular Degeneration.

Xingyi Zhang, Hua Liu.

Background/Aims: Age-related macular degeneration (AMD) is a progressive degenerative disease of the retinal macula associated with aging, which is one of the main causes of vision loss in the elderly. This research aims to investigate the mechanism of SPI1 in EMT of RPE cells in AMD, providing new targets for AMD treatment.
Methods: SPI1, ALKBH5, and NURR1 expression was assayed by RT-qPCR and Western blot in AMD patients and cell models. The relationship between SPI1 expression and clinical features of AMD patients was analyzed, and the correlations among SPI1, ALKBH5, and NURR1 were analyzed. The diagnostic value of SPI1 in AMD was verified via ROC curve. ROS levels were detected. N-cadherin and E-cadherin were detected by Western blot. Cell migration was detected by transwell assay. The binding of SPI1 to ALKBH5 in cells was verified. m6A levels on NURR1 were detected.
Results: SPI1 and ALKBH5 were highly expressed, while NURR1 was lowly expressed in TNF-α-induced human RPE cells. SPI1 expression was correlated with age and staging of AMD patients. SPI1 expression exhibited a positive association with ALKBH5 expression, while showing a negative association with NURR1 expression. After downregulation of SPI1, N-cadherin was downregulated, E-cadherin was upregulated, ROS levels were decreased, and cell migration was reduced. SPI1 promoted ALKBH5 expression, and ALKBH5 downregulated NURR1 expression via m6A modification. ALKBH5 overexpression or NURR1 downregulation partially reversed the attenuating effect of SPI1 downregulation on EMT-like changes in RPE cells.
Conclusion: SPI1 stimulates EMT-like changes of RPE cells via the ALKBH5/NURR1 axis. This pathway may participate in AMD-related pathological processes.

Keywords: ALKBH5; SPI1; age-related macular degeneration; epithelial–mesenchymal transition; retinal pigment epithelial cells

DOI: https://doi.org/10.1155/joph/8106992

Am J Ophthalmol. 2026 Jul 30. pii: S0002-9394(26)00420-4. [Epub ahead of print]

Stem Cell Therapy for Inherited Retinal Disorders: Rebuilding the Retina.

Anupam K Garg, Ishrat Ahmed.

Inherited retinal disorders (IRDs) are a group of ophthalmic conditions that are characterized by progressive degeneration of photoreceptors and/or retinal pigment epithelium (RPE), leading to irreversible vision loss. IRDs are a promising target for stem cell therapies, which have largely aimed to restore vision by either replacement of degenerated photoreceptors or retinal pigment epithelial cells via transplantation of stem cells or preservation of cells through expression of neuroprotective factors. Several therapies have recently moved into early clinical trials, demonstrating that stem cell therapies can be safely administered through different routes of administration including intravitreal, sub-retinal, and suprachoroidal injection. However, further larger-scale studies are needed to demonstrate efficacy of these treatments for the prevention or reversal of vision loss from photoreceptor or RPE degeneration.

Keywords: inherited retinal disorders; photoreceptors; retinal pigment epithelium; stem cells

DOI: https://doi.org/10.1016/j.ajo.2026.07.033

iScience. 2026 Aug 21. 29(8): 116727

DGAT1-associated lipid-retinoid dysregulation correlates with metabolic impairment in the RPE of Stargardt disease.

Arpita Dave, Eunice Sze Yin Ng, Zhichun Jiang, Jane Hu, Jordan Tatang, Antonio Paniagua, Jeffrey Doeve, Sachin Parikh, Kevin J Williams, Linsey Stiles, Roxana A Radu.

Mutations in ABCA4 cause Stargardt disease (STGD1) by disrupting retinoid handling and retinal pigment epithelium (RPE) homeostasis, yet the metabolic drivers of RPE degeneration remain unclear. Given that photoreceptor health relies heavily on the support of the RPE, loss of the RPE cells is central to STGD1 pathology. In this study, we show that dysregulation of diacylglycerol O-acyltransferase-1 (DGAT1) is associated with disrupted retinoid-lipid metabolism in STGD1 RPE cells, accompanied by excess retinyl esters and neutral lipid accumulation, impaired lipid processing, and reduced mitochondrial activity. These findings implicate DGAT1-mediated lipid remodeling as a contributing factor to RPE dysfunction in ABCA4-associated retinopathies.

Keywords: ABCA4; ATP-binding cassette transporter protein; Stargardt disease; lipidomics; macular degeneration; mitochondrial dysfunction; retinal pigment epithelium; retinoids

DOI: https://doi.org/10.1016/j.isci.2026.116727

SLAS Technol. 2026 Jul 31. pii: S2472-6303(26)00070-1. [Epub ahead of print] 100456

Cell-state-resolved transcriptomic analysis reveals macrophage-centered pyroptosis-related inflammatory programs in age-related macular degeneration.

Xinxin Li, Fu Gui, Zheng Zheng, Ke Shi.

BACKGROUND: Age-related macular degeneration (AMD) is accompanied by inflammatory changes in the retinal pigment epithelium/choroid complex, but the cellular sources of pyroptosis-related transcriptional programs in human AMD tissue remain unclear. This study profiled these programs at single-cell resolution and explored candidate regulatory molecules.
METHODS: We analyzed the human retinal pigment epithelium (RPE)/choroid single-cell RNA-sequencing dataset GSE135922 to define cell clusters, pyroptosis-related genes, and regulons. AUCell was applied to estimate pyroptosis-related signature activity in individual cell types. The macrophage cluster with the highest score was examined by pathway enrichment, subclustering, and Monocle 2 pseudo-time analysis, and SCENIC-based regulon analysis was used to infer candidate transcriptional regulators. Pyroptosis-related genes and transcription factors were also evaluated in T-cell, endothelial-cell, and fibroblast subclusters. Bulk RNA sequencing and immunofluorescence in a laser-induced choroidal neovascularization (CNV) mouse model were used for supportive evidence.
RESULTS: Across human RPE/choroid cell clusters, 60 cluster-specific pyroptosis-related marker genes were detected. At the cell-type ranking level, macrophages, T cells, endothelial cells, and fibroblasts showed relatively higher pyroptosis-related signature activity across clusters, with the highest signal in Macrophages-2 and lower activity in RPE cells. Marker genes of Macrophages-2 were enriched in immune and inflammatory pathways, including complement and coagulation cascades, NOD-like receptor signaling, and NF-κB signaling. Pseudo-time analysis resolved Macrophages-2 into divergent trajectories, and NLRP3 was enriched in one post-branch state, consistent with macrophage state heterogeneity rather than uniform activation. IRF1, STAT3, and NEAT1 recurred in cell-type-specific analyses, and Irf1/Stat3 protein signals were higher in CNV lesions.
CONCLUSION: These findings indicate a macrophage-centered, cell-state-specific pattern of pyroptosis-related inflammatory remodeling in AMD. Branch-associated NLRP3 inflammasome signatures, together with IRF1, STAT3, and NEAT1, define candidate molecular features that warrant further mechanistic evaluation.

Keywords: Age-related macular degeneration; bulk RNA sequencing; macrophage; pyroptosis; single-cell RNA sequencing

DOI: https://doi.org/10.1016/j.slast.2026.100456