The retina was used as an experimentally accessible tissue because it combines high metabolic demand with tightly regulated interactions among neurons, glia and resident immune cells. Electroretinography, or ERG, provides a quantitative readout of electrical responses from several retinal components. The investigators combined this functional measurement with biochemical assays and immunohistochemistry to ask whether mitochondrial genetic background could modify retinal function, mitochondrial composition and the abundance and localization of STING, a protein involved in innate immune signaling.

The study included mice approximately 2, 10 and 20 months old, while ERG recordings and retinal ATP measurements were restricted to younger animals because of study-design constraints. To isolate mitochondrial genetic effects from nuclear genetic effects, the researchers used mitochondrial–nuclear exchange, or MNX, mice. All animals had a C57BL/6J nuclear genome, but one group carried C57BL/6J mitochondrial DNA and the other carried C3H/HeN mitochondrial DNA.

The two mitochondrial genomes differ by two missense variants: one in a subunit of respiratory-chain complex I and one in a subunit of complex IV. Approximately 113 male and female mice were used across the experiments. Most molecular and imaging groups contained only three or four animals, making the work exploratory and limiting statistical power, particularly for interaction tests and sex-specific analyses.

Western blotting revealed that aging changed the abundance of proteins associated with oxidative phosphorylation, but the pattern varied by mitochondrial background. In mice carrying C3H mitochondrial DNA, the measured complex I subunit NDUFB8 increased between 2 and 10 months and remained elevated at 20 months, while it remained stable in the C57 mitochondrial-DNA group. Complex II showed a similar distinction: SDHB abundance increased progressively across the three ages in the C3H group but did not change in the C57 group.

Complex III declined markedly with age in both backgrounds. Complex IV was lower at 2 months with C3H mitochondrial DNA, increased with age and surpassed the corresponding C57 level by 20 months. The ATP synthase alpha subunit, representing complex V, was also lower at baseline in the C3H group and decreased significantly in both backgrounds by 10 months.

The respiratory-chain pattern is consistent with age-related remodeling rather than a uniform decline in every mitochondrial component. Complex III is a major site of reactive oxygen species production through the Q cycle, making its age-related reduction potentially relevant to oxidative stress. Complex IV rose while complex V fell, a combination that could reflect compensatory maintenance of electron transport when ATP production is constrained.

These remain interpretations rather than demonstrated mechanisms: the investigators did not directly quantify reactive oxygen species, transcriptional feedback, glycolytic reliance or mitochondrial mass. The abundance measurements were normalized to beta-actin, a cytoskeletal protein, and the authors note that accounting directly for changes in mitochondrial abundance would sharpen interpretation of the observed remodeling. ERG measurements at 3 weeks and 2 months showed that retinal function was not uniformly impaired in either mitochondrial background.

Photoreceptor and retinal ganglion-cell responses were broadly comparable, but the b-wave, which reflects bipolar-cell activity modulated by Müller glia, showed an interaction between mitochondrial background and stimulus intensity. C57 mitochondrial-DNA mice had lower b-wave amplitudes than C3H mitochondrial-DNA mice at 3 weeks. The c-wave, which the study used to assess retinal pigment epithelium activity, was higher at 2 months than at 3 weeks regardless of mitochondrial background in the reported comparison, with a significant age difference identified in the C3H group.

Total retinal ATP measured at 8 weeks did not differ significantly between backgrounds, indicating that the respiratory-protein differences did not produce a detectable difference in this bulk ATP measure. A quantitative PCR assay compared amplification of long and short mitochondrial-DNA fragments to estimate mitochondrial-DNA lesions. Lesion burden increased significantly with age in the C57 mitochondrial-DNA group, whereas the C3H group did not show a significant age-related increase.

At 20 months, the C3H group had a lower lesion burden than the C57 group. Because mitochondrial DNA can function as a damage-associated signal when released into the cytosol, this divergence could be relevant to cGAS–STING signaling. The experiment did not, however, directly measure cytosolic mitochondrial DNA, cGAS activity, interferon responses or downstream STING activation.

The proposed connection between accumulated lesions and inflammatory signaling therefore remains unproven in this study. Immunohistochemical analysis showed that microglial STING abundance increased strongly with age in untreated retinas: 20-month-old animals had more STING within microglia than the younger groups. The overall analysis of untreated tissue did not find a significant main effect of mitochondrial background or a significant age-by-background interaction.

A direct comparison nevertheless found a lower STING burden in 20-month-old C3H mitochondrial-DNA mice. Acute elevation of intraocular pressure produced a different pattern. In a mixed-effects analysis that accounted for contralateral eyes from the same animal, treatment, age and an age-by-genotype interaction significantly influenced microglial STING abundance.

Pressure elevation reduced STING abundance in 20-month-old C57 animals relative to their control eyes, while other treatment comparisons did not reach statistical significance. Age was also associated with a change in the intracellular distribution of STING. Colocalization between STING and LAMP1, a lysosomal marker, was lower in 20-month-old mice than in either younger group.

This age effect did not differ significantly by mitochondrial background and was not significantly changed by acute pressure elevation. The imaging result is compatible with altered STING trafficking or lysosomal processing, including possible changes in degradation, but the study did not directly test those mechanisms. It also quantified protein abundance and localization rather than functional pathway activity, so the reduced lysosomal association cannot be interpreted as proof that aged microglia had stronger or weaker STING signaling.

Measurements of interferon responses, additional pathway components, multiple recovery intervals and chronic pressure paradigms would be required to address those questions. Overall, the study identifies coordinated but not necessarily causal changes in retinal metabolism and microglial protein regulation across aging in two mitochondrial–nuclear exchange mouse lines. C3H mitochondrial DNA was associated with age-related increases in complexes I and II, less mitochondrial-DNA damage at 20 months and a different pattern of microglial STING abundance under control and pressure-stressed conditions.

Age increased microglial STING and reduced STING–LAMP1 colocalization across both backgrounds. Important limitations remain: ERG data were unavailable at 10 and 20 months, several cohorts were small, sex effects could not be assessed with adequate power in most experiments, and only one hour of recovery was examined after acute pressure elevation.

Subject of Research: Effects of mitochondrial genetic background on retinal aging, bioenergetics and microglial STING in mice

Article Title: Mitochondrial Genetic Background Shapes Baseline Retinal Function, Age‐Related Bioenergetic Remodeling, and Microglial STING Phenotypes

Article References: Somerville, M. M., Lin, S. S., Ballinger, S. W., & Gross, A. K. (2026). Mitochondrial Genetic Background Shapes Baseline Retinal Function, Age‐Related Bioenergetic Remodeling, and Microglial STING Phenotypes. Aging Cell, 25(10), Article e70771. https://doi.org/10.1111/acel.70771

Image Credits: AI Generated

DOI: 10.1111/acel.70771

Keywords: retinal aging, mitochondrial DNA, oxidative phosphorylation, microglia, STING signaling, mitochondrial damage, electroretinography, mouse model, intracellular pressure, innate immunity, Mitochondrial, Genetic

The clinical stakes are considerable. Systemic cancers can reach the eye through several distinct mechanisms: direct metastatic spread through the bloodstream, immune-mediated paraneoplastic attacks on retinal tissue, infiltration by blood or lymphatic cancers, and toxic side effects of anticancer treatments themselves. The choroid, the vascular layer supplying the outer retina, is particularly vulnerable to hematogenous tumor dissemination because of its rich blood flow. Yet the same imaging findings that suggest malignancy can also appear in inflammatory, infectious, vascular, or degenerative disorders, which is precisely why the authors emphasize that imaging alone rarely establishes a diagnosis. Instead, its principal value lies in raising or lowering suspicion, prioritizing competing diagnoses, and guiding the next appropriate investigation.

The review’s central contribution is the phenotype-to-confirmation framework, which organizes suspicious findings into five categories. The first is the exudative choroidal mass phenotype, characterized by an amelanotic or creamy-yellow choroidal lesion accompanied by subretinal fluid, disturbance of the retinal pigment epithelium, and an altered choroidal contour on optical coherence tomography. This combination should raise suspicion for choroidal metastasis, particularly in older patients or those with known cancer. However, the authors caution that amelanotic melanoma, choroidal hemangioma, inflammatory granuloma, and posterior scleritis remain important alternatives that must be excluded before malignancy is presumed.

The second phenotype involves RPE-choroidal remodeling, marked by multifocal changes in the retinal pigment epithelium, abnormal fundus autofluorescence, subretinal fluid, choroidal thickening, and bilateral or diffuse involvement. This pattern may indicate paraneoplastic choroidopathies, most notably bilateral diffuse uveal melanocytic proliferation, a rare syndrome in which ocular changes can precede detection of an occult carcinoma. In BDUMP, highly suggestive findings include multiple round or oval red patches at the level of the RPE, a characteristic patchy or giraffe-like autofluorescence pattern, and progressive outer-retinal disruption. The differential diagnosis here is broad, encompassing central serous chorioretinopathy, Vogt-Koyanagi-Harada disease, posterior scleritis, and drug-related changes, making pattern recognition and longitudinal follow-up essential.

The third category, the vitreoretinal infiltrative phenotype, may be the most clinically urgent because it frequently masquerades as uveitis. Suspicion for vitreoretinal lymphoma increases in older patients with persistent or recurrent intermediate or posterior uveitis, especially when large vitreous cells form sheets or clumps, vitreous haze appears limited relative to the cellular burden, cystoid macular edema is absent or modest, or OCT reveals hyperreflective deposits in the outer retina or sub-RPE space. A transient or incomplete response to corticosteroids does not exclude lymphoma. When suspicion remains high, the authors recommend coordinated diagnostic vitrectomy with prompt processing for cytology, flow cytometry, interleukin-10 and interleukin-6 measurement, immunoglobulin gene rearrangement analysis, and MYD88 L265P mutation testing. Critically, they note that systemic corticosteroids should be withheld before sampling when clinically safe, because prior treatment can reduce cellular yield, and that a single negative test never excludes lymphoma when the clinical course remains suspicious.

The fourth phenotype, diffuse neuroretinal dysfunction, shifts the diagnostic emphasis from structure to function. Patients may experience photopsia, nyctalopia, and visual field loss that appear wildly disproportionate to what the fundus examination shows. Cancer-associated retinopathy and melanoma-associated retinopathy are the principal paraneoplastic culprits, and electroretinography plays a central role in characterization. Cancer-associated retinopathy typically produces generalized rod-cone or cone-rod dysfunction, while melanoma-associated retinopathy classically yields an electronegative ERG pattern, with a relatively preserved a-wave and reduced b-wave, indicating predominantly bipolar-cell dysfunction. The authors stress that antiretinal antibody testing provides only supportive evidence and should never be treated as a standalone confirmatory test, since antibody positivity is not disease-specific and results vary between laboratories.

The fifth category, the treatment-imprint phenotype, addresses a growing challenge in modern oncology: distinguishing therapy-related ocular toxicity from disease progression. Different drug classes produce recognizable but overlapping patterns. MEK inhibitors may cause bilateral, multifocal, shallow subretinal fluid with limited leakage on fluorescein angiography. Immune checkpoint inhibitors can trigger uveitis, retinal vasculitis, or even a VKH-like phenotype with serous retinal detachment. Radiation therapy produces a delayed microangiopathy with hemorrhages, cotton-wool spots, and macular edema. The authors emphasize that a temporal relationship supports but does not prove causality, and that new choroidal or retinal lesions during treatment should never be automatically attributed to toxicity, since metastatic progression may occur during therapy. Decisions about modifying systemic treatment must be made jointly by ophthalmologist and oncologist.

Beyond the five phenotypes, the review offers a sober assessment of artificial intelligence in this domain. While interpretable multimodal models have demonstrated proof of concept in distinguishing choroidal tumor categories, the authors argue that AI should currently be regarded as a research tool rather than an independent diagnostic system for malignancy-related eye disease. The most plausible near-term role is longitudinal comparison rather than single-image classification: tracking lesion dimensions, subretinal fluid, choroidal thickness, and outer-retinal integrity over time. The obstacles are substantial, including small and imbalanced datasets, inconsistent diagnostic reference standards, variable imaging protocols, and device-related domain shift. Current ophthalmic AI evidence remains far stronger in high-volume diseases such as diabetic retinopathy than in these rare and heterogeneous malignancy-related disorders.

The authors are appropriately candid about their own limitations. The narrative design did not include formal risk-of-bias assessment or quantitative evidence grading, and much of the available evidence derives from retrospective series, small cohorts, and diagnostically striking case reports that may overestimate the apparent specificity of individual imaging patterns. The five phenotypes were developed as an interpretive clinical model and have not been prospectively validated; overlap between them is expected, particularly when metastatic, immune-mediated, vascular, and treatment-related mechanisms coexist in the same patient. The framework should therefore be regarded as a structured aid to clinical suspicion and diagnostic escalation rather than a classification system with established sensitivity, specificity, or predictive value.

Nevertheless, the practical message for clinicians and patients is clear: certain findings should lower the threshold for escalation. A new choroidal mass in an older patient, bilateral multifocal abnormalities unexplained by common retinal disease, recurrent or corticosteroid-resistant inflammation, rapid visual deterioration disproportionate to fundus findings, and new posterior segment abnormalities during anticancer therapy all warrant timely exclusion of mimickers and selection of the most appropriate confirmatory step. The authors call for multicenter onco-ophthalmic registries linking ocular findings with cancer type, treatment exposure, and molecular confirmation, which would allow prospective validation of the phenotypes and establish standardized reporting criteria. Until then, the framework offers something genuinely valuable: a disciplined way to convert an atypical eye examination into the right question, asked at the right time, of the right specialist. In a disease landscape where earlier detection can alter trajectories, the retina may prove to be one of medicine’s most underused diagnostic surfaces.

Subject of Research: Posterior segment imaging patterns as clues to systemic malignancy

Article Title: Posterior segment imaging clues to systemic malignancy: a phenotype-to-confirmation narrative review

Article References: Denda, N., Davidović Terzić, S., Maletin, N., Veljkov, K., Rasković, A., Jovančević, L., & Babović, S. (2026). Posterior segment imaging clues to systemic malignancy: a phenotype-to-confirmation narrative review. Frontiers in Ophthalmology, 6, Article 1917738. https://doi.org/10.3389/fopht.2026.1917738

Image Credits: AI Generated

DOI: 10.3389/fopht.2026.1917738

Keywords: choroidal metastasis, multimodal imaging, posterior segment, systemic malignancy, vitreoretinal lymphoma, paraneoplastic retinopathy, optical coherence tomography, BDUMP, anticancer therapy toxicity, electroretinography, artificial intelligence, onco-ophthalmology

The research, conducted at HOCH Health Ostschweiz in St. Gallen and published in Frontiers in Neuroimaging, revisited a retrospective series of seven consecutive patients diagnosed with AZOOR between 2005 and 2025. The team, led by Scott Tschuppert, Christophe Valmaggia, and Margarita G. Todorova, combined the full arsenal of modern retinal diagnostics—optical coherence tomography, fundus autofluorescence, near-infrared reflectance, fluorescein angiography, visual field testing, and two forms of electroretinography—with a technique called retinal oximetry. The goal was ambitious: to see whether AZOOR leaves a measurable metabolic fingerprint that could distinguish it from retinitis pigmentosa, a hereditary disease it can superficially mimic.

The cohort itself reflects the typical face of AZOOR. Five of the seven patients were women, with a median age of just 28 years and a range spanning 20 to 53. Six patients had symptoms in only one eye at presentation. Their complaints ranged from scotomas and photopsias to reduced visual acuity and color desaturation. Diagnostic delay varied widely, from as little as eight days to as long as 180 days, underscoring how easily this condition slips past initial examination. One patient had a preceding flu-like illness, another later developed thoracic herpes zoster, and one had bilateral congenital aniridia, with AZOOR assigned clinically to a single presenting eye.

On structural imaging, the disease left its mark consistently. Spectral-domain optical coherence tomography revealed disruption or irregularity of the ellipsoid zone—the thin band corresponding to the inner segments of photoreceptors—in every affected eye. Fundus autofluorescence showed patchy hyperautofluorescence, and near-infrared reflectance imaging displayed the trizonal patterns that have become a hallmark of the disorder. Multifocal electroretinography, which maps macular function point by point, detected macular dysfunction in six of seven patients. Full-field electroretinography, by contrast, was abnormal in only five patients and entirely normal in others, confirming that AZOOR is fundamentally a focal, zonal process rather than a uniform degeneration.

The real novelty lay in the oximetry data. The technique relies on a simple physical principle: oxygenated and deoxygenated hemoglobin absorb light differently at different wavelengths. The Oxymap T1 oximeter mounted on a fundus camera captures images simultaneously at 586 nanometers, where absorption is insensitive to oxygen, and at 605 nanometers, where it is oxygen-sensitive. Software then calculates the optical density ratio for each vessel segment, yielding an estimate of hemoglobin oxygen saturation. Measurements were taken in a predefined peripapillary zone, between concentric circles of two and three optic-disc diameters centered on the optic nerve. Complete arterial and venous data were available for eight eye-level measurements from four AZOOR patients, which were compared against an existing institutional dataset of 22 eyes from 15 healthy controls and 42 eyes from 21 retinitis pigmentosa patients.

The numbers told a striking story. Across the AZOOR measurements, mean arteriolar oxygen saturation was 95.2 percent, noticeably below the 99.1 percent seen in healthy controls and the 101.3 percent recorded in the retinitis pigmentosa group. Meanwhile, venular saturation was unremarkable at 67.3 percent, and consequently the arteriovenous difference—a surrogate for how much oxygen the retina actually consumes—was compressed to 27.9 percent, versus roughly 34 to 36 percent in the other groups. Kruskal–Wallis testing across all three groups confirmed significant intergroup differences for arteriolar saturation and the arteriovenous difference, while exploratory pairwise Mann–Whitney comparisons showed that AZOOR was significantly lower than both controls and retinitis pigmentosa on both parameters. Venous saturation, intriguingly, did not differ among the groups at all.

Why does this matter? The comparison with retinitis pigmentosa is the intellectually satisfying part. In that degenerative disease, photoreceptors—especially oxygen-hungry rods—die off progressively. When the tissue’s metabolic demand collapses, less oxygen is extracted from the blood, so vessels carry away oxygen they never delivered, and measured saturation rises. Some retinitis pigmentosa values even exceed 100 percent, a recognized calibration artifact of altered vessel caliber and changed retinal optics rather than true supersaturation. AZOOR shows the opposite pattern: lower arterial saturation despite outer retinal damage. Reduced oxygen consumption alone cannot explain this, because dying photoreceptors should push saturation up, not down. Something else is going on—possibly vascular dysregulation, inflammation-associated vascular change, or disease-related optical effects, though the authors are careful to label all such explanations hypothetical.

This metabolic profile is biologically plausible in the context of an inflammatory disease. In uveitic conditions such as Vogt-Koyanagi-Harada disease and Behçet disease, retinal oxygen metabolism and vascular parameters shift measurably, and occlusive vasculitis can be documented with angiography and optical coherence tomography angiography. The AZOOR pattern is compatible with localized inflammatory or vascular dysregulation—though oximetry measures saturation, not blood flow, so it cannot by itself prove occlusion or reduced perfusion. The researchers emphasize that because oximetry was performed at wildly different disease stages, roughly 15 days after symptom onset in one patient and up to 120 months in another, these findings represent a disease-associated pattern observed during routine follow-up, not evidence of acute inflammatory activity.

The caveats deserve honest acknowledgment. AZOOR is rare, and seven patients is a small sample by any standard; oximetry was available in only four of them because the instrument arrived at the clinic after several patients had completed care. Both eyes of the same individual were analyzed when available, violating statistical independence, and the exploratory comparisons were not corrected for multiple testing. The retinitis pigmentosa and control data came from a separate institutional dataset without a standardized severity classification. The authors themselves frame the p-values as hypothesis-generating rather than confirmatory. A sensitivity analysis excluding the patient with congenital aniridia left the direction of all findings unchanged, which strengthens the signal somewhat, but nobody is claiming a diagnostic threshold yet.

Still, the conceptual advance is real. By adding a metabolic vascular parameter to a phenotyping workflow traditionally built on structure and electrophysiology, the St. Gallen team has sketched what a complete multimodal assessment of AZOOR could look like: arterial, venous, and arteriovenous oxygen metrics layered onto OCT segmentation, wide-field autofluorescence mapping, OCT angiography, adaptive optics imaging, and longitudinal visual field and ERG outcomes. If prospective studies confirm that AZOOR’s low arterial saturation and reduced oxygen extraction persist or evolve in a characteristic way, retinal oximetry could become a practical biomarker for monitoring disease activity and, eventually, for testing treatments in a condition where no controlled therapeutic trial has ever been completed. For a disease discovered more than thirty years ago and still lacking a known cause, a new window on its metabolism is a genuinely exciting development.

Subject of Research: Retinal oxygen saturation measured with oximetry in acute zonal occult outer retinopathy compared with retinitis pigmentosa and healthy controls

Article Title: Distinct retinal oxygenation patterns in acute zonal occult outer retinopathy assessed by multimodal imaging

Article References: Tschuppert, S., Valmaggia, C., & Todorova, M. G. (2026). Distinct retinal oxygenation patterns in acute zonal occult outer retinopathy assessed by multimodal imaging. Frontiers in Neuroimaging, 5, Article 1902215. https://doi.org/10.3389/fnimg.2026.1902215

Image Credits: AI Generated

DOI: 10.3389/fnimg.2026.1902215

Keywords: AZOOR, retinal oximetry, retinitis pigmentosa, oxygen saturation, multimodal imaging, ellipsoid zone, electroretinography, optical coherence tomography, outer retinopathy, retinal metabolism, ophthalmic imaging, autofluorescence

Researchers at the State University of Campinas in Brazil, working with collaborators in Hungary, Switzerland, France and São Paulo, turned to the Townes HbSS mouse, a humanized model of sickle cell anemia in which the animals carry the same single-point mutation in the beta-globin gene that defines the human disease. That mutation, a substitution of valine for glutamic acid at the sixth codon, causes hemoglobin S to polymerize when deoxygenated, deforming red cells into their characteristic crescent shape. The resulting rigidity and membrane alterations drive hemolysis, endothelial dysfunction, vaso-occlusion and ischemia throughout the body, and the retina, with its exceptionally high metabolic demand, is particularly vulnerable to the consequences.

To confirm that the model faithfully reproduced the human condition, the team first characterized the animals’ blood. Compared with C57BL/6J controls, the Townes HbSS mice showed reductions of roughly 58 percent in erythrocyte count, 52 percent in hematocrit and 46 percent in hemoglobin concentration, alongside dramatic elevations in reticulocytes and white blood cells. Markers of hemolysis told a similar story: total, direct and indirect bilirubin levels were all massively increased, consistent with the ongoing destruction of red cells that characterizes sickle cell anemia. These hematological and metabolic signatures confirmed that the experimental group carried the disease phenotype before any retinal analysis began.

The researchers then probed retinal function using electroretinography, a technique that measures the electrical potentials generated between the cornea and the retina in response to flashes of light of varying intensity. Under dark-adapted conditions, which isolate rod photoreceptor activity, the sickle cell mice produced a-wave amplitudes significantly smaller than controls at the highest light intensity tested, and their implicit times were shortened at an intermediate flash strength. Under light-adapted conditions, which emphasize cone and bipolar cell responses, the b-wave implicit time was prolonged in the diseased animals, indicating a delayed signal in the bipolar cell layer. Perhaps most strikingly, the oscillatory potentials, small rhythmic wavelets superimposed on the b-wave that are thought to reflect inner retinal amacrine cell activity, were reduced in amplitude at maximum light intensity, hinting at early damage to the inner retina before gross structural changes appear.

Histological examination of stained retinal sections reinforced this picture of degeneration. Both the sickle cell mice and the aged controls showed some disorganization of the outer nuclear layer, where photoreceptor cell bodies reside, but the Townes HbSS animals also displayed discrete alterations in the inner nuclear layer, suggesting a pathophysiological process distinct from simple aging. Blood vessels were additionally observed within the ganglion cell layer of the sickle cell retinas, a finding the authors interpret as consistent with the vascular remodeling that accompanies the disease. Because the control strain is known to undergo gradual photoreceptor degeneration beginning around six months of age, the team attributes the inner retinal changes in the sickle cell mice specifically to the vaso-occlusion and hypoxia of the disease rather than to time alone.

The centerpiece of the study, however, is the proteomic analysis. Using label-free quantification on an LTQ Orbitrap Velos mass spectrometer coupled to nanoflow liquid chromatography, the researchers mapped the retinal proteome across pooled samples from five sickle cell mice and seven controls. The analysis identified 2,248 proteins in total, of which 163 were detected exclusively in control retinas and 43 only in the sickle cell group. After applying a nominal significance threshold, 268 proteins emerged as differentially expressed: 63 upregulated and 205 downregulated in the diseased retinas. While no individual protein survived correction for false discovery rate, the pattern of change was far from random, and functional enrichment analysis revealed a coherent molecular story.

Among the downregulated proteins, the most heavily enriched pathways were phototransduction, the citric acid cycle and oxidative phosphorylation, the mitochondrial machinery that generates most of the cell’s ATP. Among the upregulated proteins, the enriched pathways included glycolysis, gluconeogenesis and signaling through hypoxia-inducible factor 1, the master transcriptional regulator of the cellular response to low oxygen. This reciprocal pattern, a collapse of oxygen-dependent energy production paired with an activation of hypoxia-adaptive programs, mirrors what has been observed in other proliferative retinopathies such as retinopathy of prematurity, where independent work has shown that mitochondrial respiration declines at the peak of neovascularization and that supplying metabolic substrates can suppress pathological angiogenesis.

Within the phototransduction pathway, several proteins stood out. The Pde6 family, comprising the alpha, beta and gamma subunits of rod phosphodiesterase, was downregulated, as were Cnga1, the alpha subunit of the cyclic nucleotide-gated channel that carries sodium and calcium into the photoreceptor outer segment, and Slc24a1, a sodium-calcium-potassium exchanger that regulates calcium clearance and photoreceptor recovery after light exposure. Mutations in these same genes are known causes of retinitis pigmentosa and congenital stationary night blindness in humans, disorders characterized by progressive photoreceptor degeneration. To verify that the protein-level findings reflected genuine transcriptional changes, the researchers performed quantitative reverse transcription PCR on selected targets, confirming that both Cnga1 and Slc24a1 messenger RNA were also reduced in the sickle cell retinas, in agreement with the proteomic data.

The convergence of proteomic and transcriptomic evidence on the phototransduction cascade carries particular weight because it suggests that the molecular machinery for converting light into neural signals is being dismantled early in the disease process, before the morphological and functional deficits become pronounced. In a single-cell RNA sequencing study of a retinitis pigmentosa model, downregulation of Pde6g, Cnga1 and Slc24a1 was interpreted as a signature of early rod degeneration that precedes clinical manifestations. The sickle cell retina appears to be following a similar trajectory, driven not by genetic mutation of the photoreceptors themselves but by the hypoxic and ischemic environment created by vaso-occlusion in the microvasculature that supplies them.

The clinical implications are sobering. Current treatments for proliferative sickle cell retinopathy, including laser photocoagulation, intravitreal anti-VEGF injections and vitrectomy for advanced complications, are borrowed from other proliferative retinopathies without dedicated prospective trials in the sickle cell context. While anti-VEGF therapy has shown benefit in regressing seafan vessels and improving vision, recent work in a mouse model of retinal vascular disease found that chronic VEGF inhibition failed to rescue the expression of phototransduction-related genes or prevent photoreceptor loss, raising the possibility that vascular-targeted approaches alone may not address the full spectrum of retinal damage in sickle cell disease. By identifying the metabolic and phototransduction pathways that are compromised before overt structural breakdown, this proteomic study provides a molecular foundation for developing biomarkers that could detect sickle cell retinopathy earlier and for designing mechanism-based therapies that protect photoreceptors directly rather than merely pruning abnormal vessels. The authors acknowledge limitations, including the use of the C57BL/6J strain as controls rather than the ideal Townes HbAA comparator and the absence of retinal flat-mount analysis for angiogenesis quantification, but the molecular landscape they have charted offers a starting point for a field that has long lacked one.

Subject of Research: Proteomic analysis of retinal molecular pathways in a humanized mouse model of sickle cell retinopathy

Article Title: Sickle cell retinopathy molecular investigation through proteomic analysis of Townes HbSS mice retinas

Article References: de Castro, J. N. P., Monte, A. R. C., de Oliveira, A. C. R., Acacio, J. D., Rodrigues, T. A. R., Barboni, M. T. S., Liber, A. M. P., Bonci, D. M. O., Ventura, D. F., Costa, F. F., Camargo, A. C. L., & de Melo, M. B. (2026). Sickle cell retinopathy molecular investigation through proteomic analysis of Townes HbSS mice retinas. Experimental Biology and Medicine, 251, Article 11228. https://doi.org/10.3389/ebm.2026.11228

Image Credits: AI Generated

DOI: 10.3389/ebm.2026.11228

Keywords: sickle cell retinopathy, sickle cell disease, proteomics, Townes HbSS mice, phototransduction, oxidative phosphorylation, hypoxia, retinal degeneration, anti-VEGF, electroretinography, biomarkers, retina

The appeal of graphene begins with an almost improbable list of properties packed into a sheet of carbon just one atom thick. The material transmits roughly 97.7 percent of visible light, conducts electricity with carrier mobility exceeding 200,000 square centimeters per volt-second at room temperature, and exhibits a Young’s modulus of approximately 1 terapascal with tensile strength above 130 gigapascals. For a contact lens, that combination is extraordinary. A graphene layer can be transparent enough not to disturb vision, conductive enough to carry sensor signals and antenna currents, and mechanically robust enough to survive the relentless deformation of blinking. Unlike brittle transparent conductors such as indium tin oxide, graphene bends and stretches with the soft hydrogel substrates that modern lenses are made from, making it a natural candidate for embedding electronics directly into the ocular environment.

Beyond mechanics and conductivity, graphene brings a biointerface chemistry that the review’s authors highlight as central to its ocular promise. Its ultra-smooth surface topology minimizes protein adsorption and bacterial adhesion, two processes that plague conventional lenses by causing biofouling, discomfort, and infection risk. The material’s inherent antimicrobial activity operates through multiple mechanisms, including direct contact killing, oxidative stress induction, and disruption of bacterial membranes, offering a built-in defense against the microbial colonization that can lead to corneal ulceration and vision loss. Graphene’s aromatic structure and strong covalent bonding also confer resistance to chemical degradation and enzymatic breakdown under physiological conditions, while its naturally hydrophobic surface can be tuned through functionalization to optimize wettability and tear film stability. In principle, these features combine to reduce inflammation, extend safe wearing times, and create surfaces onto which drugs and recognition molecules can be grafted.

The review is careful to sort the literature by technological maturity, distinguishing conceptual device architectures from laboratory proof-of-concept studies and from experimentally demonstrated prototypes, and the differences are striking. At the most speculative end sit the so-called night-vision lenses. Graphene photodetectors on flexible transparent substrates have indeed demonstrated the ability to detect infrared light, converting infrared photons into electrical signals that could in principle be rendered as visible overlays in the wearer’s field of view. The review’s own schematic of such a device is explicitly labeled conceptual, and no integrated wearable lens system with this capability has been clinically validated. Still, the underlying photodetection physics, demonstrated in broadband graphene devices at room temperature, keeps the idea alive for security, defense, and augmented reality applications far beyond medicine.

More grounded are the proof-of-concept demonstrations of electromagnetic shielding and moisture retention. Laboratory studies of lenses coated with an approximately 5-nanometer graphene film reported an 80 percent reduction in microwave-induced protein denaturation, measured through controlled egg-white exposure experiments, alongside a 30 percent reduction in tear evaporation compared with conventional lenses. The dual function addresses two modern anxieties at once: growing exposure to wireless radiation in digital environments and the persistent problem of dry eye among lens wearers. The authors caution that these results represent demonstrations of material functionality rather than established smart lens products, but they illustrate how a single graphene layer can deliver protective properties that conventional hydrogel materials simply cannot match.

At the prototype level, two applications stand out. The first is transparent electroretinography. An experimentally demonstrated graphene-on-lens electrode system covers the full cornea while remaining highly transparent, enabling comprehensive retinal recordings without visual obstruction. In the reported configuration, the graphene electrodes achieved roughly a threefold improvement in signal-to-noise ratio compared with conventional DTL fiber electrodes, a gain the review attributes to the conformal, intimate contact between the atomically thin electrode and the corneal surface, which reduces movement artifacts and permits extended recording sessions without irritation. The second flagship prototype is a wireless intraocular pressure sensor for glaucoma management. Built around graphene nanowall strain gauges with a reported sensitivity of approximately 42,250 parts per million per millimeter of mercury, the lens detects the tiny corneal curvature changes caused by pressure fluctuations and transmits the data wirelessly via a near-field communication antenna. Validation in rabbit eyes demonstrated accurate pressure measurement with minimal tissue response, placing the technology firmly in the preclinical category but marking it as one of the field’s most translationally advanced achievements.

Biosensing extends the vision further into personalized medicine. A proof-of-concept graphene field-effect transistor functionalized with anti-cortisol antibodies has detected tear cortisol at a limit of detection of approximately 10 picograms per milliliter, with smartphone-compatible NFC readout envisioned for routine self-monitoring of stress hormones. Tear-based glucose sensing follows a similar logic, exploiting graphene’s vast surface area and tunable chemistry to immobilize glucose-specific enzymes for non-invasive diabetes surveillance. Drug delivery rounds out the application landscape: graphene oxide laden lenses have been investigated for the controlled release of timolol, cyclosporine, bimatoprost, antibiotics, anti-inflammatory agents, and growth factors, with release profiles that can respond to stimuli such as pH, temperature, or enzymatic activity. By delivering therapeutics directly to ocular tissues, such systems could improve efficacy while minimizing systemic side effects, and graphene’s photodynamic potential, generating reactive oxygen species under light exposure, adds yet another therapeutic modality for treating infections and neovascularization.

Turning these concepts into manufacturable devices is where the field confronts its hardest engineering trade-offs. Chemical vapor deposition produces the highest-quality monolayer graphene, grown on copper foil at around 1000 degrees Celsius in a methane and hydrogen atmosphere, but transferring that fragile film onto a curved, soft lens requires polymer-assisted wet transfer, careful etching, and meticulous rinsing, with costs estimated at roughly five dollars per lens. Solution-phase processing using graphene oxide is cheaper and compatible with existing lens manufacturing, but sacrifices film quality and electrical performance. Patterning strategies, including layer-by-layer assembly, electrochemical deposition, inkjet printing of graphene inks, and direct laser interference patterning at 355 nanometers, allow researchers to write sensors, antennas, and circuits onto curved surfaces, while hydrogel incorporation and microcontact printing embed graphene into the lens bulk. Even the assembly sequence matters: a representative workflow positions a graphene monolayer on a poly(methyl methacrylate) intermediate that serves as both transfer scaffold and dielectric buffer before final cast-molding into pHEMA hydrogel at 70 degrees Celsius.

Safety and regulatory hurdles may prove even more formidable than the engineering. Graphene’s impermeability, so useful for moisture retention, threatens to choke off the oxygen transmission that corneal health demands, prompting proposed solutions such as focused ion beam or laser drilling of 50-nanometer pores to restore permeability above 30 barrer. Heat dissipation is another concern, with temperature rises of 2 to 3 degrees Celsius observed under 2.4 gigahertz exposure, motivating micro-heat-spreader grids beneath the graphene layer. Delamination after roughly 30 days of wear, driven by weak graphene-hydrogel adhesion under the mechanical stress of blinking, may be addressed by silanizing the lens surface with 3-aminopropyl-triethoxysilane to create covalent bonds. More fundamentally, the toxicology remains unsettled: pristine graphene generally shows low short-term cytotoxicity toward corneal cells, but graphene oxide can induce oxidative stress and membrane damage, some studies report DNA strand breaks and mitochondrial damage in human corneal epithelial cell lines under prolonged exposure, and tear film enzymes such as peroxidases and lysozymes may partially degrade functionalized graphene into bioactive products whose in vivo toxicity is largely uncharacterized. No longitudinal human trials of embedded graphene lenses exist, and no graphene-enhanced contact lens has yet received regulatory approval, although the FDA and EMA have issued draft guidelines for nanomaterials in medical devices.

The review’s authors close with a sober but optimistic outlook for 2025 to 2030. Future platforms may combine graphene with other two-dimensional materials such as molybdenum disulfide or hexagonal boron nitride to build heterostructures capable of multimodal biosensing of glucose, lactate, cytokines, and cortisol, while micro-scale graphene supercapacitors and energy-harvesting modules could free lenses from external power, and artificial intelligence could interpret sensor signals in real time on the lens itself. Modular designs with interchangeable sensing and therapeutic units, harmonized ISO testing protocols for nanoparticle shedding and chronic exposure, and roll-to-roll manufacturing on copper-nickel foils to slash costs all feature in the proposed roadmap. For now, the authors conclude, graphene-based contact lenses remain a promising but technically and translationally immature technology, one whose success will be decided not only in the materials laboratory but in standardized toxicology, scalable manufacturing, and the slow, exacting work of proving that a sheet of carbon one atom thick can live safely on the human eye for years at a time.

Subject of Research: Graphene-integrated contact lenses for ocular biosensing, drug delivery, and antimicrobial protection

Article Title: Graphene-integrated contact lenses for ocular sensing, drug delivery, and antimicrobial protection

Article References: Shaker, L. M., Alamiery, A., & Hussien, N. A. (2026). Graphene-integrated contact lenses for ocular sensing, drug delivery, and antimicrobial protection. Discover Chemistry, 3(1), Article 481. https://doi.org/10.1007/s44371-026-00894-0

Image Credits: AI Generated

DOI: 10.1007/s44371-026-00894-0

Keywords: graphene, contact lenses, smart lenses, biosensors, drug delivery, antimicrobial, intraocular pressure, glaucoma, electroretinography, biocompatibility, chemical vapor deposition, wearable electronics

The team, led by first authors Dogan Can Kirman and Ashley A. Rowe under the senior guidance of Katherine J. Wert and Rafael L. Ufret-Vincenty, generated mice lacking Herc3 using CRISPR-Cas9 genome editing. Herc3 encodes an E3 ubiquitin ligase, a molecular tagger that marks misfolded or damaged proteins for destruction by the proteasome, the cell’s waste-disposal complex. Without it, protein quality control collapses, and cells — especially metabolically demanding neurons like photoreceptors — accumulate toxic debris. The researchers had previously noticed a hint that female mutants fared worse; this study was designed to test that suspicion rigorously, tracking retinal anatomy, function, and gene expression in male and female animals as they aged.

The structural evidence was unambiguous. By 15 months of age, optical coherence tomography, a non-invasive imaging technique that cross-sections the living retina, revealed significantly accelerated thinning of the outer retina in females compared with males. Histological examination confirmed the finding, showing that the outer nuclear layer — the densely packed band containing the cell bodies of rod and cone photoreceptors — was markedly thinner in females, with a statistical significance of P = 0.0013. In plain terms, the females were losing the very cells that capture light. Fundus photography, which images the interior surface of the eye, told a parallel story: aging females accumulated significantly more bright spots on the retina, a feature the authors link to subretinal microglia, the resident immune cells of the nervous system. Greater spot accumulation, statistically significant at 14 to 16 months, pointed to amplified neuroimmune activation in female eyes.

Function tracked structure. Electroretinography, which measures the electrical responses of retinal cells to flashes of light under dark-adapted (scotopic) conditions, showed significantly weakened responses in female mutants at 12 and 16 months of age. Because scotopic responses primarily reflect rod photoreceptor activity, the results indicate that the females’ dim-light vision was deteriorating measurably faster than the males’. Together, the imaging, histology, and electrophysiology establish that female sex is associated with accelerated degeneration across every level of analysis — from molecules to tissue architecture to behaviorally relevant visual function.

The most striking insights, however, came from the molecular level. The team performed bulk RNA sequencing on neuroretinas from young, pre-degenerative mice, just 8 to 10 weeks old, when the retina still looks structurally normal. Even at this early stage, female mutants carried a distinct transcriptional fingerprint: 143 genes were differentially expressed relative to males, with 90 downregulated and 53 upregulated. The upregulated networks were dominated by mitochondrial energy metabolism, protein translation, RNA processing, and genome maintenance — pathways that, when cranked up in a young tissue, signal compensatory stress rather than vigor. The female retinas were essentially working overtime, burning extra metabolic and proteostatic resources to keep pace with the damage caused by Herc3 loss.

Meanwhile, the downregulated genes told the complementary half of the story. Pathways governing extracellular matrix organization, structural tissue development, lipid and hormone metabolism, and baseline inflammatory regulation were quieter in the young female retinas. The extracellular matrix provides the scaffolding that holds retinal cells in place and supports their survival, so its early suppression suggests that female tissue maintenance and structural integrity were already compromised before any thinning could be seen. In the authors’ interpretation, the young female retina exists in a more vulnerable state: higher metabolic and proteostatic demand running on a weaker structural foundation. Over time, that chronic imbalance culminates in homeostatic breakdown.

The late-stage molecular profile confirmed this trajectory. In aging mutants at 14 to 16 months, degenerating female retinas showed heightened expression of neuroinflammatory and microglial activation markers, including Aif1, Cd68, Itgam, Ccl5, and Il23a. They also displayed signs of proteostatic failure, with elevated Casp4, Tnfrsf10b, and Tnfrsf1a — genes associated with inflammatory cell-death pathways — alongside disruption of autophagy, the cell’s recycling system, marked by changes in Atg12. Perhaps most tellingly, the females lost expression of Nrl, a master transcription factor that defines photoreceptor identity. The loss of a cell’s core identity program is a hallmark of terminal degeneration, indicating that female photoreceptors were not merely stressed but actively dying and dedifferentiating.

What drives this female-specific vulnerability? The researchers turned to sex hormones for an answer. They compared ovariectomized Herc3-deficient females — animals whose ovaries had been removed, eliminating the primary source of estrogen and other ovarian hormones — with intact female mutants. The transcriptomic differences between these groups supported a role for female sex hormones in heightening susceptibility to retinal degeneration and microglial activation. This finding is provocative because it inverts a common assumption: rather than protecting the retina, ovarian hormones appear to amplify the damage when protein quality control fails, at least in this model. The authors caution that the data establish an association and a role for hormones in susceptibility, and the precise hormonal mechanisms remain to be worked out.

The broader significance of the study extends well beyond ophthalmology. Retinal degeneration is increasingly studied as a window into neurodegeneration generally, because the retina is accessible, imageable, and mechanistically akin to brain tissue. Many neurodegenerative and retinal diseases — from Alzheimer’s and Parkinson’s to age-related macular degeneration — show sex-biased prevalence or severity, yet the biological reasons remain poorly understood, and females have historically been understudied in neuroscience research. By establishing Herc3-deficient mice as a robust model of sex-dependent retinal neurodegeneration, the UT Southwestern team has created a platform for dissecting those mechanisms and, critically, for testing interventions at the right stage of disease in the right sex.

The study also carries a practical message about therapeutic timing. Because the female-specific molecular signature appears in young, pre-degenerative retinas, it defines an early, phase-specific therapeutic window — a period when boosting tissue maintenance, easing metabolic load, or supporting proteostasis might prevent the later cascade of inflammation and cell death. Conversely, the late-stage profile of neuroinflammation, autophagic failure, and photoreceptor loss suggests that once disease is established, different targets would be needed. The authors argue that distinct, sex-specific therapeutic windows should be developed for male and female patients, a conclusion that aligns with a growing movement in precision medicine to treat biological sex as a fundamental variable rather than a nuisance factor. For the millions of people — disproportionately women in many retinal diseases — facing progressive vision loss, the finding that the female retina carries a measurable molecular vulnerability from early life is both a warning and a roadmap: the damage begins long before symptoms, and that hidden early phase may be exactly where treatment can succeed.

Subject of Research: Sex-dependent retinal neurodegeneration in Herc3-deficient mice

Article Title: Female sex accelerates retinal neurodegeneration in Herc3-deficient mice

Article References: Kirman, D. C., Rowe, A. A., Kumar, A., Xing, C., Turpin, E. R., Ulker-Yilmazer, G., Aredo, B., Wert, K. J., & Ufret-Vincenty, R. L. (2026). Female sex accelerates retinal neurodegeneration in Herc3-deficient mice. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00999-2

Image Credits: AI Generated

DOI: 10.1186/s13293-026-00999-2

Keywords: Herc3, retinal degeneration, sexual dimorphism, ubiquitin-proteasome system, neuroinflammation, microglia, photoreceptors, sex hormones, CRISPR-Cas9, RNA sequencing, electroretinography, ovariectomy