Kun Liu

Diabetic retinopathy features early glial stress and neurovascular dysfunction, yet Müller glial programs linking inflammatory cues to oxidative injury remain unclear. We identify a spatially clustered interferon-stimulated gene 15 (ISG15) ⁺ Müller glial subtype expanded in streptozotocin-induced diabetic mice. High glucose alone did not increase basal free ISG15 or detectable ISGylation (ISG15-dependent protein modification) in primary Müller glia, whereas conditioned medium from high glucose–exposed microglia induced both, recapitulated by IFN-β and attenuated by type I interferon receptor 1 inhibition. In vivo, Ifnb1 RNAscope signals were associated with microglia, retinal Ifnb1 expression increased in diabetic retinas, and microglial depletion reduced Ifnb1 expression and limited the expansion of ISG15 ⁺ Müller glia. Müller glia–specific Isg15 deletion preserved blood–retinal barrier integrity, reduced acellular capillaries and Evans blue leakage, and mitigated oxidative stress, lipid peroxidation, and glutathione redox imbalance. Loss of ISG15 or disruption of ISGylation blunted interferon-driven oxidative stress in Müller glia and reduced Müller glia–conditioned medium–dependent endothelial migration and tube formation. Mechanistically, IFN-β promoted peroxiredoxin 6 (PRDX6) ISGylation and proteasome-dependent degradation without altering Prdx6 transcripts. Thus, microglial IFN-β promotes an ISG15 ⁺ Müller glial subtype that compromises antioxidant defense and promotes early barrier injury in diabetic retinopathy.

Tractional retinal detachment caused by fibroproliferative membrane formation is a vision-threatening complication of proliferative diabetic retinopathy (PDR). Müller cells can acquire myofibroblast-like features during retinal fibroproliferative remodeling, yet the metabolic mechanisms governing these phenotypic changes remain poorly understood. Here, we report that lactate is a metabolic regulator of myofibroblast-like remodeling in Müller cells. Metabolomic profiling revealed elevated vitreous lactate levels in patients with PDR. Consistently, lactate concentrations were increased in the vitreous and retinal tissues of diabetic rats, whereas high-glucose exposure promoted lactate accumulation in primary Müller cells. Increased lactate availability enhanced Müller cell proliferative activity and migration, as well as the expression of myofibroblast-associated proteins, including α-smooth muscle actin, smooth muscle protein 22, and collagen I, whereas oxamate, an inhibitor of lactate dehydrogenase, attenuated these responses. Lactylome profiling and molecular validation revealed K186 of methyl-CpG-binding domain protein 2 (MBD2) as a functionally relevant lactylation site. RNA sequencing of high-glucose-treated Müller cells expressing MBD2-K186R versus MBD2-WT revealed reduced YAP1 expression in the K186R group, suggesting that YAP1 is a downstream effector of MBD2 K186 lactylation. Mechanistically, increased lactate availability enhanced MBD2 K186 lactylation and YAP1 activation, as evidenced by reduced inhibitory phosphorylation of YAP1 and increased nuclear accumulation of YAP1. MBD2 K186R attenuated YAP1 activation and myofibroblast-like changes, whereas YAP1 overexpression partially reversed these effects. Collectively, these findings reveal a lactate–MBD2 K186 lactylation–YAP1 signaling axis that promotes myofibroblast-like remodeling of Müller cells and may contribute to fibroproliferative pathology in PDR.

Atrial fibrillation (AF), a common cardiac arrhythmia, presents significant challenges for early detection and management due to its asymptomatic and paroxysmal characteristics. In this study, we introduce the RetiAF score, a multimodal foundation-model-based biomarker derived from retinal fundus images for early detection of AF. We identified that the RetiAF score demonstrated a robust performance across multi-ethnic, multi-center datasets, achieving AUROCs of 0.8610 and 0.8019 on the UK Biobank (UKBB) development and internal testing datasets, and an AUROC of 0.7803 on an external dataset acquired in Shanghai, China. In addition, we identified that the RetiAF score consistently outperformed the traditional risk scores such as CHARGE-AF (AUROC: 0.7553) and C₂HEST (AUROC: 0.7246) for the UKBB internal testing dataset. Multivariable logistic regression and propensity score analyses further demonstrated that the RetiAF score was independently associated with AF risk (p < 0.001). When stratified by higher C₂HEST scores (≥3), the RetiAF score achieved an AUROC of 0.9619, highlighting its potential for identifying high-risk patients before the clinical onset of AF. The multimodal hybrid version of RetiAF (Hybrid_RetiAF) score, which incorporated clinical features (e.g., Age, BMI, etc) into the deep learning model, further enhanced predictive performance and achieved AUROCs of 0.8924 and 0.8381 on the UKBB Cohorts. As a secondary exploratory analysis, we evaluated whether RetiAF-derived scores were associated with chronic ischemic heart disease in UKBB, suggesting shared cardio-retinal risk information. These findings underscore the potentials of non-invasive retinal imaging as a scalable tool for AF and cardiovascular risk assessment, offering a promising alternative for large-scale screenings and personalized interventions.

Aims: To evaluate the association between continuous glucose monitoring (CGM)‐derived glycaemic variability indicators and early microvascular changes of the retina and choroid in nondiabetic individuals. Materials and Methods: Community‐based individuals at high risk for type 2 diabetes (T2DM) underwent detailed assessments including oral glucose tolerance tests (OGTT), CGM and ophthalmic imaging including optical coherence tomography angiography (OCTA). Based on the mean amplitude of glycaemic excursions (MAGE), 338 OGTT‐confirmed nondiabetic participants were categorized as having normal glucose fluctuation (NGF) or abnormal glucose fluctuation (AGF). Between‐group differences in foveal avascular zone (FAZ), blood flow density and thickness in retina and choroid were analysed. Multiple linear regression analysis was used to analyse the correlation between CGM metrics and blood flow density in retina and choroid. Results: Compared with the NGF group (265 eyes from 265 participants), the AGF group (73 eyes from 73 participants) showed lower retinal blood flow density in the central ( p = 0.007) and parafoveal temporal ( p = 0.003) regions of the superficial layer and in the parafoveal temporal ( p = 0.014) and parafoveal superior ( p = 0.005) regions of the deep layer. In the choroid, the volume area ratio of large vessels (CVV/a) was reduced, whereas the choroidal vascular index (CVI) was increased in the AGF group. Choroidal thickness was decreased among individuals with AGF. CGM metrics such as MAGE and coefficient of variation (CV) were negatively correlated with the retinal and choroidal blood flow density. Conclusions: Increased glycaemic variability even in nondiabetic adults is associated with reduced blood flow density and decreased choroidal thickness. Trial Registration: ClinicalTrials.gov NCT03811470

As individuals age, the influence of lifestyle on health becomes increasingly evident. Notably, alcohol consumption has drawn particular attention due to its potential role in the development of age-related diseases [1]. Targeted intervention in later life addressing this factor could improve overall public health outcomes. Age-related macular degeneration (AMD) is a leading cause of vision […]

AIM: To investigate the potential impact of lipidaemic and clinical factors on the development of proliferative vitreoretinopathy (PVR) following uncomplicated primary rhegmatogenous retinal detachment (RRD) surgery in nondiabetic individuals. METHODS: This was a retrospective, single-center, case-control study of consecutive patients who underwent primary RRD surgery. The study group comprised 145 patients who developed PVR within 3y of follow-up, while the control group comprised 161 patients with RRD who did not develop PVR. Cox regression analysis was utilized to identify independent associations between various risk markers and the occurrence of PVR. RESULTS: The mean age of patients was 52.31y (SD=13.29), and 54.25% (n=166) were male. The median time to PVR formation after surgery was 150d. Multivariate Cox regression indicated that cigarette smoking status [hazard ratio (HR): 0.43, 95% confidence interval (CI): 0.31-0.60, P<0.001], retinal detachment (RD) not involving the macula (HR: 0.52, 95%CI: 0.37-0.73, P<0.001), apolipoprotein A1 (ApoA1; HR: 1.01, 95%CI: 1.01-1.02, P<0.001) and apolipoprotein E (ApoE; HR: 3.81, 95%CI: 1.64-8.85, P=0.002) were independent predictors of PVR. CONCLUSION: Apart from macular involvement and smoking, the lipidaemic factors ApoA1 and ApoE are risk factors of PVR after primary RRD surgery.

Background: To evaluate the association between continuous glucose monitoring (CGM)-derived glycemic variability indicators and early microvascular changes of the retina and choroid in nondiabetic individuals.Methods: Community-based individuals at high risk for type 2 diabetes (T2DM) underwent detailed assessments including oral glucose tolerance tests (OGTT), CGM, and ophthalmic imaging including optical coherence tomography angiography (OCTA). Based on the mean amplitude of glycemic excursions (MAGE), 338 OGTT-confirmed nondiabetic participants were categorized as having normal glucose fluctuation (NGF) or abnormal glucose fluctuation (AGF). Between-group differences in foveal avascular zone (FAZ), blood flow density, and thickness in retina and choroid were analyzed. Multiple linear regression analysis was used to analyze the correlation between CGM metrics and blood flow density in retina and choroid.Findings: Compared with the NGF group (264 eyes from 264 participants), the AGF group (74 eyes from 74 participants) showed lower retinal blood flow density in the central (P=0.001) and parafoveal nasal (P=0.022) regions of the superficial layer, and in the parafoveal superior region of the deep layer (P<0.001). In the choroid, the volume area ratio of large vessels (CVV/a) was reduced, whereas the choroidal vascular index (CVI) was increased in the AGF group. Choroidal thickness was decrease in all regions among individuals with AGF. CGM metrics such as MAGE and coefficient of variation (CV) were negatively correlated with the retinal and choroidal blood flow density.Interpretation: Increased glycemic variability even in nondiabetic adults is associated with reduced blood flow density and decreased choroidal thickness.

To develop diffusion-based fundus fluorescein angiography (DiFFA), a noninvasive method for generating high-quality FFA images from color fundus (CF) photographs using diffusion models, addressing the limitations of invasive FFA examinations in detecting diabetic microvascular complications. DiFFA was trained on paired CF and FFA images from 4032 patients across 3 hospitals, with external validation using 2000 CF images from the UK Biobank. Four systematic evaluations were conducted: (1) objective image quality assessment using the mean absolute error, peak signal-to-noise ratio, structural similarity index measure, and Fréchet inception distance metrics, (2) subjective authenticity evaluation by ophthalmologists, (3) diagnostic efficiency assessment, and (4) automated classification accuracy for diabetic retinopathy and diabetic kidney disease using VGG16 with and without synthetic FFA images. DiFFA achieved strong objective performance (mean absolute error, 109.25,; peak signal-to-noise ratio, 27.677; Fréchet inception distance, 38.466; structural similarity index measure, 0.694). Ophthalmologists showed limited ability to distinguish synthetic from real FFA images (area under the curve, 0.52 ± 0.06 for junior ophthalmologists and 0.57 ± 0.05 for senior ophthalmologists), with no significant quality score differences (P > 0.05). Combining synthetic FFA with CF images improved automated classification, achieving an area under the curve of 0.933 for diabetic retinopathy and 0.849 for diabetic kidney disease internally, compared with 0.891 and 0.792 using CF photographs alone. External validation confirmed improvements (diabetic retinopathy, 0.858 to 0.879; diabetic kidney disease, 0.731 to 0.814). DiFFA successfully generates clinically authentic FFA images from non-invasive CF photographs, enhancing diagnostic accuracy while overcoming the invasiveness limitations of traditional FFA examinations. Diffusion-based fundus fluorescein angiography enables noninvasive early detection of diabetic microvascular complications, improving patient compliance and diagnostic accessibility while reducing examination risks in diabetes screening and monitoring.