bims-mideyd 2026-07-26 papers

Biochim Biophys Acta Mol Cell Res. 2026 Jul 21. pii: S0167-4889(26)00096-0. [Epub ahead of print] 120197

RSL1D1 deficiency reduces FTH1 stability and induces ferroptosis and senescence in retinal pigment epithelial cells in diabetic retinopathy.

Leilei Qin, Yanli Guo, Yi Zhang, Nianting Tong, Chunning Zhao.

Ribosomal L1 domain-containing protein 1 (RSL1D1) is an RNA-binding protein that relates to senescence. Nevertheless, the mechanism of RSL1D1 in modulating senescence and ferroptosis in diabetic retinopathy (DR) remains undefined. The DR mice were developed by intraperitoneal injection of STZ, and AAV targeting RPE was used for gene intervention. ARPE-19 cells were infected using oe-RSL1D1 and sh-FTH1 lentivirus before 30 mM high glucose (HG) exposure. Cell damage was assessed by measuring the expression of senescence and ferroptosis markers in ARPE-19 cells, along with oxidative stress indicators and Fe2+ levels. RSL1D1 and FTH1 expression were significantly reduced in the retinal pigment epithelium (RPE) layer of diabetic mice and HG-induced ARPE-19 cells. Downregulation of RSL1D1 led to RPE cell senescence and dysregulated iron homeostasis-induced ferroptosis. HG treatment reduced the interaction between RSL1D1 protein and FTH1 mRNA in ARPE-19 cells, while RSL1D1 overexpression enhanced this interaction, thereby stabilizing FTH1 mRNA expression. The alleviating effects of RSL1D1 overexpression on retinal pigment epithelium cell senescence and ferroptosis in vitro and in vivo were compromised by FTH1 knockdown. Overall, this study unveils a posttranscriptional regulation of FTH1 by RSL1D1 and uncovers the implication of RSL1D1/FTH1 in cellular senescence and ferroptosis in DR.

Keywords: Diabetic retinopathy; FTH1; Ferroptosis; RSL1D1; Senescence

DOI: https://doi.org/10.1016/j.bbamcr.2026.120197

Endocrinol Diabetes Metab. 2026 Jul;9(4): e70290

FZD7 Inhibitor SRI Attenuates High Glucose-Induced Retinal Pigment Epithelial Cell Injury Accompanied by Ferroptosis-Associated Changes via Suppression of the Wnt/β-Catenin Pathway.

Jiaojiao Jiang, Liu Zheng, Liwu Tan, Zhixiang Ding.

PURPOSE: This study investigated the protective effects of the Frizzled-7 (FZD7) inhibitor SRI against high glucose-induced injury in human retinal pigment epithelial (ARPE-19) cells. It also explored the underlying mechanism, focusing on whether SRI attenuates ferroptosis and apoptosis by inhibiting the Wnt/β-catenin signalling pathway.
METHODS: ARPE-19 cells were exposed to high glucose (25 mM) and treated with a non-cytotoxic concentration of SRI (2 μmol/L), as determined by a CCK-8 assay. Wnt/β-catenin signalling was evaluated by measuring β-catenin expression and phosphorylation. The expression of GPX4, DHODH, and FSP1, together with intracellular Fe²⁺, ROS, and MDA levels, was assessed to evaluate ferroptosis and oxidative stress. Apoptosis was analysed by examining Bax and Bcl-2 expression, whereas mitochondrial ultrastructure was evaluated using quantitative transmission electron microscopy.
RESULTS: Under hyperglycaemic conditions, SRI suppressed Wnt/β-catenin signalling by reducing β-catenin expression and promoting its phosphorylation. SRI activated a GPX4-independent ferroptosis defence pathway, evidenced by increased DHODH and FSP1 expression without affecting GPX4 levels. Furthermore, SRI reduced intracellular Fe²⁺, ROS and MDA accumulation, downregulated Bax, upregulated Bcl-2 and improved mitochondrial morphology with partial restoration of cristae integrity. Collectively, these findings demonstrate that SRI alleviates high glucose-induced oxidative stress, ferroptosis, apoptosis and mitochondrial damage.
CONCLUSIONS: SRI protects ARPE-19 cells from high glucose-induced injury by reducing ferroptosis-associated oxidative stress, apoptosis and mitochondrial dysfunction. These protective effects are mediated, at least in part, through inhibition of Wnt/β-catenin signalling and activation of a DHODH/FSP1-dependent but GPX4-independent ferroptosis defence pathway. These findings suggest that FZD7 represents a promising therapeutic target for diabetic retinopathy.

Keywords: FZD7; Wnt/β‐catenin pathway; diabetic retinopathy; ferroptosis; retinal pigment epithelial cells

DOI: https://doi.org/10.1002/edm2.70290

STAR Protoc. 2026 Jul 24. pii: S2666-1667(26)00384-9. [Epub ahead of print]7(3): 104731

Protocol for purifying iPSC-derived retinal pigment epithelial cells by sequential digestion and intrinsic autofluorescence sorting.

Fengming Yang, Rui Li, Xinrun Lv, Boling Chu, Jiuhua Luo, Rongjing Ge, Yongjun Luo, Laibin Ren, Bei Liu, Jing Hu, Haijiang Zhang, Hao Qian.

Induced pluripotent stem cells (iPSC)-derived retinal pigment epithelium cells serve as a promising cell source for transplantation therapy in age-related macular degeneration. Here, we present a protocol for purifying the mature retinal pigment epithelium (RPE) cells post-differentiation. We describe steps for sequentially digesting cells with different enzymes and sorting them based on the autofluorescence of mature RPE cells, avoiding fixation and immunostaining. By maintaining high cell viability and purity, this cost-efficient protocol has broad implications for both in vitro research and transplantation applications.

Keywords: Cell Differentiation; Cell separation/fractionation; Flow Cytometry; Stem Cells

DOI: https://doi.org/10.1016/j.xpro.2026.104731

JCI Insight. 2026 Jul 22. pii: e194102. [Epub ahead of print]11(14):

Restoration of impaired lysosomal function mitigates drusen-like deposit formation and cell death in Malattia Leventinese.

Yumi Inoue, Hanako O Ikeda, Masayuki Hata, Yuto Iida, Keiko Okamoto-Furuta, Isao Asaka, Makoto Arita, Akitaka Tsujikawa.

Malattia Leventinese (MAL) is an inherited macular degeneration disorder characterized by retinal drusen formation in adolescence, leading to vision loss. A mutation in the fibulin-3 gene (EFEMP1) causes MAL; however, the mechanisms underlying disease onset and drusen formation remain unclear. In this study, we generated induced pluripotent stem cell-derived retinal pigment epithelial (iPSC-RPE) cells from a patient with MAL to investigate disease mechanisms and potential therapies. MAL iPSC-RPE exhibited fibulin-3 and apolipoprotein E (ApoE) aggregation, increased endoplasmic reticulum stress, and enhanced apoptosis. Long-term culture with photoreceptor outer segments led to drusen-like deposits containing ApoE, complement components, and collagen IV accumulation, and it showed activation of matrix metalloproteinase-2 (MMP2). Untargeted lipid analysis revealed increased hexosylceramide and bis-monoacylglycerophosphate levels in MAL iPSC-RPE cells. A key pathological feature was lysosomal dysfunction associated with altered regulation of lysosomal gene programs, including reduced transcription factor EB transcript levels. Treatment with trehalose, a lysosome-modulating compound, increased lysosomal content and function, reducing drusen-like deposit formation, inhibiting MMP2 activation, and suppressing apoptosis. This study highlighted lysosomal dysfunction as a contributor to RPE damage, drusen-like deposit accumulation, and extracellular matrix degradation. Pharmacological restoration of lysosomal function alleviated these defects, suggesting therapeutic potential for MAL and other drusen-related diseases, including age-related macular degeneration.

Keywords: Cell biology; Ophthalmology; iPS cells

DOI: https://doi.org/10.1172/jci.insight.194102

J Transl Med. 2026 Jul 18.

circKIAA1462 impaires autophagy and promotes pyroptosis in retinal pigment epithelium via the miR-183-5p/HMGB1 axis in diabetic retinopathy.

Lufei Wang, Jia'nan Xie, Longfei Yang, Jinsong Zhao, Xin Liu.

BACKGROUND: Diabetic retinopathy (DR) is one of the most prevalent complications of diabetes which could lead to vision impairment. Dysfunction of the retinal pigment epithelium (RPE) is an early pathogenic event, where various mechanisms may contribute to the disease progression. circular RNAs (circRNAs) have been reported to be important regulators in diabetic complications, acting as miRNA sponge, participating in the regulation of gene transcription or coding short peptides.
METHODS: Circular RNA microarray and RNA-seq were used to identify differentially expressed circRNAs in ARPE-19 cells in normal and high glucose treatments. The expression of cKIAA1462, miR-183-5p, and high mobility group box 1 (HMGB1) were determined using quantitative real-time polymerase chain reaction and Western blot. In vitro experiments, such as flow cytometry, Western blot, and Electron microscope (TEM) were conducted. The binding interaction was confirmed using dual-luciferase reporter and overexpression/inhibition experiments. cKIAA1462 was knocked down via intravitreal lentiviral injection in diabetic mice, followed by expression level detection, functional analysis and histological assessments.
RESULTS: cKIAA1462 was significantly upregulated under high glucose conditions both in vitro and in vivo (in retinas of diabetic mice). It acted as a molecular sponge for miR-183-5p, increasing the expression of HMGB1. Elevated HMGB1 concurrently impaired autophagic flux (increased p62, decreased autophagosomes) and activated the NLRP3 inflammasome (upregulated NLRP3, ASC, caspase-1), promoting pyroptosis. Silencing cKIAA1462 in vivo restored autophagy, suppressed pyroptosis, improved retinal structure, and enhanced electroretinogram responses in diabetic mice.
CONCLUSION: The cKIAA1462/miR-183-5p/HMGB1 axis plays a critical role in diabetic RPE injury by dual regulation of autophagy and pyroptosis. Targeting this pathway may offer a novel therapeutic strategy for early diabetic retinopathy.

Keywords: Autophagy; Diabetic retinopathy; HMGB1; Pyroptosis; circKIAA1462; microRNA-183-5p

DOI: https://doi.org/10.1186/s12967-026-08560-w

J Ocul Pharmacol Ther. 2026 Jul 24. 10807683261472707

miR-129-5p Modulates the ZEB1/2 Signaling Axis to Suppress Palmitic Acid-Induced Epithelial-Mesenchymal Transition and Barrier Dysfunction in ARPE-19 Cells.

Po-Han Chen, Yuh-Shin Chang, Ying-Hsien Kao, Yun-Ting Lou, Wen-Chuan Wu, Hung-Chi Lai, Yo-Chen Chang.

PURPOSE: Proliferative vitreoretinopathy (PVR) is driven by the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells. While palmitic acid (PA) represents a potent metabolic stressor in the subretinal microenvironment, its impact on the microRNA (miRNA) landscape remains poorly defined. This study investigated the role of miR-129-5p in PA-induced transdifferentiation and evaluated the protective potential of ectopic miR-129-5p mimicry in ARPE-19 cells.
METHODS: Low-passage ARPE-19 cells were challenged with sublethal PA to induce lipotoxic stress. miR-129-5p levels were modulated using synthetic mimics under basal and stressed conditions. EMT progression was tracked using immunofluorescence for tight junction topology and transcription factor nuclear localization, Phalloidin-FITC cytoskeletal F-actin staining, and immunoblotting for hallmark epithelial (E-cadherin) and mesenchymal (α-smooth muscle actin, fibronectin) effectors. Functional shifts were evaluated via wound healing and paracellular macromolecular permeability assays.
RESULTS: PA exposure triggered a myofibroblastic phenotype and significantly depleted the intracellular miR-129-5p pool, accompanied by parallel vesicle-independent extracellular efflux. Under unchallenged baseline, mimic delivery directly suppressed endogenous ZEB1/2 expression. Under lipid stress, miR-129-5p mimicry neutralized transdifferentiation, successfully restoring E-cadherin and counteracting core transcription factor upregulation (ZEB1, ZEB2, and Snail). Morphologically, mimicry prevented pericellular ZO-1 dissolution, suppressed ZEB2 nuclear translocation, and blocked contractile stress fiber assembly. Functionally, maintaining this miRNA node significantly attenuated PA-enhanced cell migration and rescued outer blood-retinal barrier homeostasis by suppressing paracellular macromolecular flux.
CONCLUSIONS: miR-129-5p functions as an essential cell-autonomous posttranscriptional gatekeeper of RPE identity, cytoskeletal architecture, and barrier homeostasis. Targeted modulation of this posttranscriptional network offers a promising pharmacological framework for mitigating lipotoxicity-associated subretinal fibrosis in PVR.

Keywords: ZEB1/2 axis; barrier function; epithelial–mesenchymal transition (EMT); miR-129-5p; palmitic acid; proliferative vitreoretinopathy (PVR); retinal pigment epithelium (RPE)

DOI: https://doi.org/10.1177/10807683261472707