Search Results (817)

Objectives: This study aims to compare the imaging performance of spectral-domain optical coherence tomography (SD-OCT) and swept-source OCT (SS-OCT) in the early postoperative assessment of patients undergoing vitreoretinal surgery with intraocular gas or air tamponade. Methods: Seventeen eyes of 17 patients who underwent pars plana vitrectomy with either sulfur hexafluoride (SF₆, 20%) or air tamponade were prospectively enrolled. All patients underwent OCT imaging on postoperative day 1 using both the SD-OCT system and the SS-OCT platform, without pharmacological mydriasis. Images were independently evaluated by two experienced ophthalmologists based on the ability to delineate four prespecified anatomical layers: inner retinal layers, ellipsoid zone (EZ), retinal pigment epithelium (RPE) and choroid. Images were classified as adequate quality if two or more of these structures were identifiable. Results: SS-OCT provided adequate-quality images in all 17 eyes (100%), with complete visualization of the inner retinal layers, EZ, RPE, and choroid in 15 eyes (88.2%). In contrast, SD-OCT yielded adequate-quality images in only three of 17 eyes (17.6%), demonstrating marked signal attenuation, interface artifacts, and inability to resolve deeper retinal structures in most cases. No difference in imaging performance was observed between SF₆ and air tamponade subgroups. Conclusions: SS-OCT demonstrates markedly superior imaging performance in gas-filled eyes on postoperative day 1 compared to SD-OCT, primarily attributable to its longer wavelength, reduced sensitivity roll-off, and superior penetration through optically challenging media. These findings suggest that SS-OCT may offer meaningful advantages for early postoperative monitoring following vitreoretinal surgery with tamponade; confirmation in larger prospective cohorts with clinical-outcome correlation is warranted before it can be recommended as the preferred modality. Full article

Background: Regional heterogeneity of the macula and peripheral retinas contributes to the differences in retinal physiology, metabolic demand and susceptibility to macular diseases such as age-related macular degeneration (AMD), diabetic macular oedema (DME) and Macular telangiectasia type 2 (MacTel). Extracellular vesicles (EVs) released from the retinal pigment epithelium (RPE)-choroid are increasingly recognised as mediators of extracellular communication and correlate with the molecular biological states of their tissue of origin. However, regional variation in EV composition in human RPE-Choroid tissues remains poorly characterised. Methods: Human macular and peripheral RPE-choroid explants from non-diseased donor eyes (n = 4) were cultured ex vivo using a transwell system. EV and EV-depleted conditioned media were collected by differential ultracentrifugation, respectively. EVs were characterised by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Proteomic profiling was performed using LC-MS/MS followed by multivariate, pathway, and differential expression analyses. Results: TEM and NTA confirmed the presence of vesicle-like particles in a 119–140 nm size range, indicating small EVs in both regions. Proteomic analysis demonstrated a region-associated separation between the macular and peripheral samples in both EV proteome and EV-depleted soluble secretome datasets. GO enrichment analysis revealed that macular EV proteomes were enriched for wound healing, cell–substrate adhesion, and focal adhesion-related terms with a high abundance of integrin and annexin family members, whereas peripheral EV proteomes were enriched for retinoid- and vitamin-binding terms. In the EV-depleted soluble secretome, macular-enriched proteins were associated with actin binding and extracellular matrix-related terms, while peripheral-enriched proteins were correlated with RNA localisation and nuclear compartment terms. Comparative analysis identified EV-specific, secretome-specific, and shared extracellular protein pools. Several EV-specific markers and membrane proteins such as annexins and integrins, showed a relatively high enrichment in macular EV proteomes, whereas CD63 is more abundant in peripheral EV proteomes. In contrast, EV-depleted soluble secretome contains cytokine- and ligand-associated proteins, including MIF, SPP1, and IL6, which may suggest that EVs and soluble secreted proteins represent partially distinct extracellular signalling compartments. Conclusions: Human macular and peripheral RPE-choroid explants released secretory proteins in a regional differentiated manner, supported by PLS-DA and GO enrichment analyses of both EV proteomes and EV-depleted soluble secretome. Further analysis of the EV proteomes may show that such differences were also able to be reflected in protein categories such as EV-specific markers, mitochondrial and membrane proteins. These findings provide a foundation for future investigations into the role of EV-mediated communication in macular diseases and may support the development of region-specific extracellular biomarkers and therapeutic targets. Full article

Purpose: To describe the morphological and functional features of two patients phenotypically and genotypically diagnosed with Best disease and autosomal dominant drusen (BD-ADD) using multimodal imaging. It is hypothesized that the concurrent presence of pathogenic mutations in both BEST1 and EFEMP1 genes is associated with a phenotype that may exhibit characteristic features of both diseases potentially revealing further additive effects on retinal function or structure. The data are compared with those from a patient with genetically confirmed ADD. Methods: The patients received a full ophthalmological investigation, including fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (SD-OCT) and polarization-sensitive optical coherence tomography (PS-OCT). Genetic analysis of DNA samples was performed by targeted whole-exome sequencing. Results: Macular SD-OCT demonstrated a thickened retinal pigment epithelium (RPE)-Bruch’s membrane complex corresponding to macular drusen-like deposits in both ADD and BD-ADD cases. In contrast to isolated ADD, BD-ADD showed small hyperautofluorescent dots originating in hyperreflective photoreceptor debris at or above the RPE on FAF imaging. FAF further showed large hyperautofluorescent spots corresponding to sub-RPE drusen in both ADD and BD-ADD. The tissue-specific contrast of PS-OCT imaging allowed identification of the RPE within the macular lesion, structural changes of the subretinal material and incipient scar formation. Genetic analysis identified pathogenic mutations in both the BEST1 and the EFEMP1 gene in both BD-ADD cases. Conclusions: The characteristic morphological and functional features of both diseases are evident in the patients with the BD-ADD dual genotype. The coexistence of two independent autosomal dominant disorders provides an illustrative opportunity to inform our understanding of BEST1- and EFEMP1-mediated retinal disease. Full article

Diabetic retinopathy (DR) is a leading cause of vision loss, yet its systemic proteomic mediators remain largely elusive. This study aimed to identify causal plasma proteins, map their cell-type-specific localization in the retina, and experimentally validate their expression under disease-relevant stress. We conducted a proteome-wide association study (PWAS) integrating UK Biobank plasma pQTL data (N = 53,022) with DR GWAS summary statistics. Causal relationships were inferred utilizing summary-data-based Mendelian randomization (SMR) and Bayesian colocalization. Prioritized candidates were mapped to the Human and Mouse Retina Cell Atlases via single-nucleus RNA sequencing (snRNA-seq). Finally, to substantiate the computational findings, in vitro validation of COL4A1 was performed in ARPE-19 cells cultured under hyperglycemic conditions utilizing quantitative real-time PCR (qPCR) and transcriptomic dataset re-analysis. The PWAS identified 26 proteins significantly associated with DR. Subsequent causal inference prioritized 12 high-confidence candidates, including GSTT2B, COL4A1, PAM, and GALNT3. Notably, GSTT2B emerged as a Tier-1 protective causal protein (Z = −3.609; P_SMR = 1.22 × 10⁻⁴). snRNA-seq mapping revealed that GSTT2B is robustly expressed in Müller glia and the retinal pigment epithelium (RPE), whereas COL4A1 is prominently enriched in vascular compartments. These specific expression signatures exhibited partial conservation across species with notable cell-type specific variations. Crucially, in vitro validation confirmed that COL4A1 mRNA expression is significantly upregulated under high-glucose stress. Furthermore, druggability analysis highlighted actionable targets, identifying GSTT2B as a highly probable causal mediator and COL4A1 as a prioritized candidate for structural intervention. This study provides robust genetic, single-cell, and experimental evidence implicating specific plasma proteins in DR pathogenesis. The identification of GSTT2B-mediated protective pathways and the hyperglycemia-induced upregulation of COL4A1 offer a high-resolution molecular atlas to guide drug repositioning and precision therapeutic strategies. Full article

Purpose: To describe the long-term, multimodal follow-up and multidisciplinary evaluation of two pediatric patients with CDH3-related retinopathy, discussing the genotypic and phenotypic spectrum of this rare cadherinopathy. Design: Retrospective observational case series. Methods: Two unrelated children with early-onset macular dystrophy and congenital hypotrichosis underwent a comprehensive ophthalmic examination, including spectral-domain optical coherence tomography (SD-OCT), blue-light fundus autofluorescence (BAF), microperimetry, and full-field electroretinography (ffERG), combined with dermatologic assessment and exome sequencing. Follow-up extended over 4 years in Patient 1 and 15 years in Patient 2. Results: Both patients showed sharply demarcated posterior pole chorioretinal atrophy with preservation of the peripheral retina and stable best-corrected visual acuity throughout follow-up. Microperimetry documented localized sensitivity loss with limited progression. SD-OCT revealed persistent ellipsoid zone disruption, retinal pigment epithelium atrophy, and outer retinal tubulations. Dermatologic evaluation confirmed congenital hypotrichosis without nail abnormalities; one patient exhibited mild fifth finger clinodactyly. Genetic testing identified the following two distinct homozygous CDH3 variants: a splice-site mutation (c.160+1G>A) and a frameshift insertion (c.1837dup, p.(Asp613Glyfs*4)). Conclusions:CDH3 retinopathy presents with a characteristic multimodal imaging pattern of localized macular atrophy and slow functional decline associated with congenital hypotrichosis. A comprehensive multidisciplinary approach was essential for the correct diagnosis and a better and more thorough definition of the clinical presentation. Detailed long-term follow-up supports the hypothesis of retinal pigment epithelium dysfunction or maldevelopment rather than widespread retinal degeneration. Recognition of this phenotype is critical for accurate diagnosis, genetic counseling, and future gene-therapy strategies targeting the preserved peripheral retina. Full article

Background/Objectives: Age-related macular degeneration (AMD) is a leading cause of irreversible visual impairment in aging populations. While effective treatments exist for neovascular AMD and, more recently, geographic atrophy, no widely accepted therapy prevents disease progression in earlier stages. Photobiomodulation (PBM) has emerged as a potential approach to modulate retinal metabolism. This review examines the biological mechanisms proposed to explain PBM effects and explores how mitochondrial physiology may support a bioenergetic framework linking these mechanisms to retinal function in AMD. Methods: We conducted a targeted review of experimental and clinical literature addressing photobiomodulation, mitochondrial function, and retinal metabolism in AMD. Results: Experimental studies indicate that PBM may influence mitochondrial activity through multiple mechanisms, including modulation of cytochrome c oxidase, nitric oxide photodissociation, and redox signaling pathways. However, the diversity of mechanisms and variability of clinical outcomes suggest that the biological basis of PBM remains incompletely understood. Emerging insights from mitochondrial physiology, including the debated concept of local thermal microenvironments, support interpreting PBM effects as modulation of mitochondrial bioenergetics rather than isolated molecular pathways. Conclusions: We propose a conceptual framework in which PBM responses are governed by the interaction between a dose-dependent bioenergetic window and the mitochondrial functional reserve of retinal cells. Within this model, therapeutic effects are most likely when PBM is delivered within an optimal range of stimulation and in retinal tissues where mitochondrial dysfunction remains partially reversible. This framework may help explain variability across studies and support more rational use of PBM in early and intermediate AMD. Full article

Retinal diseases such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) are major causes of visual impairment and are closely associated with oxidative stress, inflammation, vascular dysfunction, and metabolic imbalance. Increasing evidence suggests that gut microbiota also contributes to retinal homeostasis, supporting the emerging concept of the gut–eye axis. In this context, dietary anthocyanins—with blueberry anthocyanins serving as a primary representative model—have attracted attention as potential adjunctive nutritional modulators of ocular health. However, their biological effects are strongly influenced by their limited bioavailability and extensive gastrointestinal metabolism. The objective of this review is to analyze the gastrointestinal fate of dietary anthocyanins and to discuss how their absorption, enzymatic transformation, and microbial biotransformation may influence ocular protection through the gut–eye axis. The review summarizes current knowledge regarding anthocyanin stability in the oral cavity, stomach, small intestine, and colon, as well as the formation of circulating phenolic metabolites generated by the host and through microbial metabolism. In addition, the molecular mechanisms through which anthocyanins and their metabolites may support retinal health are examined, including antioxidant, anti-inflammatory, vasoprotective, and neuroprotective actions. Overall, dietary anthocyanins, illustrated through the rich profile of blueberries, represent promising adjunctive compounds for supporting ocular health, although further clinical and mechanistic studies are still required. Full article

Background and Clinical Significance: Biallelic pathogenic variants in the PCARE gene (photoreceptor cilium actin regulator), also known as C2orf71 (chromosome 2 open reading frame 71), are typically associated with retinitis pigmentosa type 54 (RP54) and, less frequently, with cone–rod dystrophy (CORD23). Case Presentation: A 52-year-old man presented with an eight-year history of progressive visual loss, without photophobia or nyctalopia. He underwent a comprehensive ophthalmological evaluation, including multimodal retinal imaging, automated perimetry, and full electrophysiological testing, in accordance with International Society for Clinical Electrophysiology of Vision (ISCEV)’s standards. Genetic testing was performed using next-generation sequencing (NGS) with an inherited retinal dystrophy gene panel, and findings were confirmed by Sanger sequencing. Clinical examination revealed bilateral macular atrophy with minimal foveal sparing and a central scotoma. Optical coherence tomography (OCT) showed disruption of the outer retinal layers and retinal pigment epithelium (RPE) abnormalities. Fundus autofluorescence (FAF) demonstrated central hypoautofluorescence surrounded by a hyperautofluorescent ring. Electrophysiological testing revealed severely reduced rod- and cone- mediated responses on full-field electroretinography (ERG), absent pattern ERG responses, and markedly reduced multifocal ERG responses, indicating widespread retinal dysfunction with significant macular involvement. Genetic analysis identified a homozygous pathogenic nonsense variant in PCARE [c.3289C>T; p.(Gln1097*)], confirming the diagnosis of an autosomal recessive inherited retinal dystrophy. Conclusions: Biallelic PCARE variants can cause late-onset severe retinal dystrophy, with predominant macular involvement and cone–rod dysfunction. Given its phenotypic overlap with other inherited retinal diseases, accurate diagnosis requires the integration of multimodal retinal imaging, electrophysiological testing, and comprehensive genetic analysis. Full article

RPE65, an isomerohydrolase expressed in retinal pigment epithelium (RPE), is critical for the visual cycle. More than 115 missense variants of the RPE65 gene have been associated with Leber’s congenital amaurosis (LCA), a severe childhood retinal dystrophy. Due to high genetic heterogeneity, the variant-specific pathogenic mechanisms remain largely uncharacterized. In this study we focus on an LCA patient carrying compound heterozygous RPE65 variants (c.200T > G, c.430T > C), aiming to dissect the mechanistic/functional basis of mutated protein-driven retinal degeneration and evaluate gene therapy-mediated restoration using patient-specific hiPSCs-RPE (iRPE). Transient overexpression of wild-type/mutant RPE65 in HEK293T cells showed both variants markedly destabilize the RPE65 protein through the autophagosome–lysosome degradation pathway and its isomerohydrolase activity required for the retinoid visual cycle. We further established a patient-specific iRPE platform suitable for enzymatic activity analysis. Characterization of patient-specific iRPE cells revealed those compound heterozygous variants did not compromise iRPE morphology, most gene expression, or core canonical physiological features of iRPE. However, they significantly downregulate endogenous RPE65 protein abundance and dampen enzymatic function. Subsequently, we delivered RPE65 via adeno-associated viral (AAV) vectors driven by either the ubiquitous CMV promoter or RPE-specific VMD2 promoter into patient iRPE to validate therapeutic potency, and verified that exogenous RPE65 supplementation effectively restores deficient isomerohydrolase activity in this disease model. Collectively, this work elucidates the variant-specific pathogenesis of RPE65-associated LCA and preliminarily assesses the efficacy of gene augmentation, providing preclinical experimental evidence to support the referral of this patient for clinical RPE65 gene replacement therapy. Full article

Objectives: This study aimed to develop curcumin nanoparticles (Cur@PCL-PEG-MF/cRGDfc) with retinal-targeting capability and to evaluate their biological effects and pharmacological mechanisms in vitro. Methods: After synthesis of the carrier framework, metformin (MF) and cRGDfc were conjugated to the carrier material using the carbodiimide method and Michael addition reaction, respectively. Subsequently, self-assembled nanoparticles were formed from the carrier and curcumin under specific conditions. The materials were characterized by spectroscopy, chromatography, elemental analysis, energy-dispersive spectroscopy and X-ray diffraction. The efficacy of the formulation was evaluated in two cell lines, ARPE-19 and HUVEC-T1. In addition, the pharmacological mechanism was explored using transcriptome sequencing as a complementary approach. Key Findings: Self-assembled nanoparticles were successfully prepared by combining the two modified carrier materials, PCL-PEG-MF and PCL-PEG-cRGDfc, with curcumin. The nanoparticles exhibited an encapsulation efficiency of 78.09%, a particle size of 162.33 nm, and a zeta potential of −23.28 mV and displayed a spherical morphology. They showed sustained release in simulated physiological conditions and stronger affinity for ARPE-19 cells under oxidative stress. Nearly 100% of the nanoparticles were internalized by the cells, which was accompanied by reduced ROS and LDH release and decreased DNA fragmentation. In addition, the nanoparticles inhibited neovascularization by reducing VEGF-A release, thereby potentially protecting the retina in macular degeneration and reducing choroidal hemorrhage. Further analyses showed that curcumin and its nanoformulations significantly reduced the expression of inflammatory factors such as IL-1β and IL-18, lowered the protein levels of Caspase-1, GSDMD-N, and NLRP3, and increased AMPK levels. Conclusions: Using PCL-PEG as the carrier framework, MF and cRGDfc were conjugated to construct a curcumin-loaded nanoparticle with retinal-targeting capability. This nanoparticle, characterized by a small particle size, sustained release, and targeted delivery to retinal pigment epithelium (RPE) cells under oxidative stress, alleviated oxidative stress-induced damage. Its therapeutic effect may be mediated, at least in part, by interference with the AMPK/mTOR pathway and activation of the NLRP3/Caspase-1/GSDMD pathway. Full article

Oxidative stress is a major contributor to the development of age-related macular degeneration (AMD), and excessive oxidative stress can induce retinal pigment epithelium (RPE) dysfunction, apoptosis, and retinal degeneration. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) is a major enzymatic source of reactive oxygen species (ROS); however, its mechanistic role in sodium iodate (NaIO₃)-induced oxidative injury remains unclear. Tetrahydrocurcumin (THC), the major metabolite of curcumin, exhibits potent antioxidant and cytoprotective activities, but its protective effects against AMD-associated retinal degeneration have not been fully elucidated. In the present study, we investigated whether THC protects against NaIO₃-induced ROS-mediated apoptosis in RPE cells through regulation of NOX2 signaling. In vitro, THC significantly attenuated NaIO₃-induced cytotoxicity and prevented apoptosis by suppressing hydrogen peroxide (H₂O₂) production and intracellular ROS accumulation in ARPE-19 cells. THC also preserved mitochondrial membrane potential by inhibiting the Src/p47^phox/NOX2 signaling pathway and subsequently attenuated mitochondria-mediated apoptotic signaling. Furthermore, THC markedly reduced the expression of apoptotic proteins, including Bax, cleaved caspase-3, and cleaved PARP, concomitantly with suppression of Ras/Raf/MEK/ERK signaling. Mechanistically, treatment with the selective NOX2 inhibitor GSK2795039 significantly attenuated NaIO₃-induced ROS accumulation and mitochondrial depolarization, while co-treatment with THC further enhanced these protective effects. In vivo, THC ameliorated NaIO₃-induced retinal structural abnormalities by preserving the outer nuclear layer (ONL), reducing caspase-3 expression, and improving pupillary light responses in mice. Collectively, these findings demonstrate that THC protects against NaIO₃-induced retinal degeneration through suppressing NOX2-dependent oxidative stress and downstream Ras/Raf/MEK/ERK-mediated apoptotic signaling, highlighting its potential as a therapeutic candidate for AMD and other oxidative stress-related retinal disorders. Full article

Purpose: This study aimed to validate a deep learning algorithm for automated segmentation and quantitative assessment of the ellipsoid zone (EZ) and the retinal pigment epithelium (RPE)–Bruch’s membrane (BM) complex in healthy eyes and geographic atrophy (GA) eyes. Methods: In this retrospective study, spectral-domain optical coherence tomography (SD-OCT) volume scans from 30 healthy eyes and 30 eyes with GA were analyzed. An NMI-Outer Retina Analyzer was used to segment the inner EZ, inner RPE, and outer BM. Average thicknesses of the EZ-RPE, EZ-BM, and RPE-BM were calculated from volumes and across nine ETDRS sectors. Manual segmentations were corrected by two masked expert graders and compared using intraclass correlation coefficients (ICCs). Dice coefficients (DCs), Pearson correlation coefficients, and absolute thickness differences were used to assess agreement between automated and manual segmentation. Heat maps were generated to visualize thickness. Results: Thirty healthy eyes and thirty GA eyes were included in the analysis. Mean EZ-RPE, EZ-BM, and RPE-BM thicknesses were 47.55 ± 6.75 µm, 69.49 ± 6.92 µm, and 21.94 ± 3.46 µm, respectively, in the healthy eyes and 15.65 ± 11.09 µm, 39.18 ± 23.28 µm, and 23.52 ± 16.21 µm, respectively, in GA eyes. The model demonstrated high segmentation accuracy, with a mean DC of 0.998 in healthy eyes and 0.995–0.998 in GA eyes. In healthy eyes, differences between automated and manual measurements were minimal (1.42 ± 3.39 μm (2.98%) for EZ-RPE, 1.31 ± 3.18 μm (1.88%) for EZ-BM, and 0.67 ± 1.71 μm (3.05%) for RPE-BM), all within 1.88–3.05% of the gold standard (manual corrections). In contrast, GA eyes showed greater variability (mean differences of 3.61 ± 8.62 μm (23.06%) for EZ-RPE, 4.28 ± 11.34 μm (10.92%) for EZ-BM, and 4.4 ± 10.45 μm (18.71%) for RPE-BM). Heat maps revealed increased variability in the junctional zone surrounding the atrophy. Automated and manual measurements showed strong correlations across all sectors in GA eyes (r = 0.97 for EZ-BM, 0.96 for EZ-RPE, and 0.89 for RPE-BM). Conclusions: The NMI-ORA enables accurate, automated segmentation and quantification of outer retinal layers, with performance comparable to that of expert graders. Full article

Fucoidan, a sulfated polysaccharide, is known for its beneficial bioactive effects, for example antioxidant, anti-inflammatory, and vascular modulatory effects. Such a bioactive compound may also be useful for treating neurodegenerative diseases like age-related macular degeneration (AMD). Our research focuses on AMD-related pathomechanisms using primary porcine retinal pigment epithelium (RPE) cells in vitro and zebrafish (Danio rerio) models in vivo. We tested the bioactivity of a commercially available fucoidan (FVs) from bladderwrack with regard to pathomechanisms of AMD. We performed multiplex assays, RT-qPCR and fluorescence-based assays for the formation of nitric oxide (DAF-FM assay) and reactive oxygen species (DCF-DA assay) to analyze angiogenesis-related chemokines and pro-inflammatory cytokines as well as protection against oxidative stress and inflammatory insult. Our results showed that FVs significantly reduced the secretion of pro-angiogenic vascular endothelial growth factor A (VEGF-A) and follistatin as well as the pro-inflammatory cytokines interleukin 8 (IL-8) after lipopolysaccharide (LPS) and polyinosinic/polycytidylic acid (PIC) induction. Interleukin 6 (IL-6) was also reduced in the supernatant of the RPE cells. Additionally, in zebrafish, fucoidan decreased the production of NO and ROS. Gene expression of zebrafish embryos revealed anti-inflammatory effects by suppressing pro-inflammatory genes and significantly downregulating, e.g., interleukin 1 beta (IL-1β). These findings indicate modulation of oxidative stress, inflammatory responses, and VEGF secretion of the used FVs. This study demonstrates that fucoidan possesses AMD-relevant bioactivities in vitro and in vivo, suggesting fucoidan warrants further investigation in AMD-related research and related pathological mechanisms. Full article

Photoreceptor (PR) degeneration is a shared pathological feature of multiple blinding retinal diseases. This narrative review examines the mechanisms underlying PR vulnerability to ferroptosis-associated lipid-peroxidation injury, with emphasis on three interconnected features: the marked enrichment of docosahexaenoic acid (DHA) and other polyunsaturated fatty acids (PUFAs) in PR outer-segment disc membranes; the chronically high metabolic demand of PRs and the specialized spatial organization of their mitochondria; and retinal pigment epithelium (RPE)–PR metabolic coupling, including outer-segment renewal and phagocytic turnover, glucose transport and lactate shuttling, and visual-cycle–related all-trans-retinal (atRAL) clearance and bisretinoid accumulation. We also summarize antioxidant defense systems centered on the cystine/glutamate antiporter (xCT)–glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis and mitochondrial GPX4 (mtGPX4), which restricts iron-dependent lipid peroxidation in PRs. We propose that highly oxidizable membrane phospholipid substrates, mitochondrial homeostatic imbalance, and impaired RPE–PR metabolic coupling may collectively shape PR susceptibility to ferroptosis-associated injury. From a therapeutic perspective, this framework supports multitarget strategies designed to interrupt lipid-peroxidation propagation, stabilize mitochondrial redox homeostasis and quality-control mechanisms, and restore RPE–PR metabolic support and local iron-buffering capacity. Full article