Progress in Retinal and Eye Research最新文献

{"title":"Aging, oxidative stress, and cataracts: Therapeutic prospects and translational insights into peroxiredoxin 6","authors":"Eri Kubo ,&nbsp;Bhavana Chhunchha ,&nbsp;Dhirendra P. Singh","doi":"10.1016/j.preteyeres.2026.101444","DOIUrl":"10.1016/j.preteyeres.2026.101444","url":null,"abstract":"<div><div>Selenium-independent peroxiredoxin 6 (Prdx6) is a unique member of the peroxiredoxin family, which protects cells from various stressors by regulating reactive oxygen species (ROS) and maintaining survival signaling. As a multifunctional \"moonlighting\" protein, Prdx6 exhibits glutathione peroxidase (GPx), acidic calcium-independent phospholipase A2, and lysophosphatidylcholine acyltransferase activities, enabling it to reduce ROS. Loss of Prdx6, owing to dysregulation of its transactivator nuclear factor erythroid 2-related factor 2 or aberrant oxidative post-translational modifications from aging or oxidative stress, disrupts cellular homeostasis and triggers inflammatory or non-inflammatory cell death, including apoptosis and pyroptosis. Similar to GPx4, Prdx6 exhibits selenium-independent peroxidase activity and possesses phospholipid hydroperoxide–reducing GPx activity. A novel function of Prdx6 in facilitating selenium utilization was identified recently; that is, it enhances the expression and activity of selenoproteins, especially GPx4, and prevents ferroptosis. Conversely, Prdx6 deficiency reduces selenoprotein levels and promotes ferroptosis. Nevertheless, the molecular mechanisms through which Prdx6 modulates cell death and survival, particularly under aging and oxidative stress conditions contributing to cataractogenesis, remain unclear. In this review, we summarize the current knowledge of Prdx6 regulation and activity during oxidative stress and aging, highlighting its role in inflammatory and non-inflammatory signaling that contributes to eye lens pathology and cataract formation. Additionally, we discuss natural activators and potential therapeutic strategies targeting Prdx6 to extend eye lens health and delay or prevent cataract development. Overall, we conclude that enhancing Prdx6 activity offers a promising strategy to prevent or reverse age-related cataracts.</div></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":"111 ","pages":"Article 101444"},"PeriodicalIF":14.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polypoidal choroidal vasculopathy: In-depth insights and promising future directions","authors":"Zuyi Yang ,&nbsp;Wenfei Zhang ,&nbsp;Xingwang Gu ,&nbsp;Xinyu Zhao ,&nbsp;SriniVas R. Sadda ,&nbsp;Gemmy Cheung ,&nbsp;Adrian Koh ,&nbsp;Anat Loewenstein ,&nbsp;Bing Li ,&nbsp;Chuting Wang ,&nbsp;Jiaqi Zhang ,&nbsp;Jingyuan Yang ,&nbsp;Kehan Jin ,&nbsp;Lihui Meng ,&nbsp;Lulu Chen ,&nbsp;Meiqian He ,&nbsp;Minzhen Yuan ,&nbsp;Mingyue Luo ,&nbsp;Nien Li ,&nbsp;Paisan Ruamviboonsuk ,&nbsp;Youxin Chen","doi":"10.1016/j.preteyeres.2025.101414","DOIUrl":"10.1016/j.preteyeres.2025.101414","url":null,"abstract":"<div><div>Polypoidal choroidal vasculopathy (PCV) is an ocular condition predominantly affecting elderly individuals of Asian descent, characterized by the presence of polypoidal lesions and branching neovascular networks in the sub-retinal pigment epithelium (RPE) space. It has garnered increased attention for its potential differences from neovascular age-related macular degeneration. Genetic studies have identified specific genetic markers associated with PCV. Advances in imaging techniques, particularly optical coherence tomography (OCT) and OCT angiography, have significantly enhanced the diagnosis of PCV and our insight into its unique pathogenesis. Treatment strategies for PCV have evolved, with anti-vascular endothelial growth factor (VEGF) monotherapy becoming the primary treatment, and combination therapies including photodynamic therapy showing promising results. Consideration of targets beyond VEGF and the incorporation of artificial intelligence (AI) based analysis strategies may open the door to more personalized, precise, and effective treatments for patients. This review comprehensively discusses the current knowledge and recent advancements in PCV, including its epidemiology, genetics, biomarkers, pathogenesis, diagnosis, and management. It also highlights the need to explore mechanism underlying the higher prevalence of PCV in pigmented races, clarify the roles of pachychoroid and pachydrusen in PCV pathogenesis, and develop animal models that can better recapitulate the disease's pathological features.</div></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":"110 ","pages":"Article 101414"},"PeriodicalIF":14.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathological mechanism in Fuchs endothelial corneal dystrophy and myotonic dystrophy type 1: more than meets the eye","authors":"Elisa Landi ,&nbsp;Derick G. Wansink ,&nbsp;Vanessa LaPointe ,&nbsp;Hans van Bokhoven ,&nbsp;Alice E. Davidson ,&nbsp;Mor Dickman","doi":"10.1016/j.preteyeres.2025.101418","DOIUrl":"10.1016/j.preteyeres.2025.101418","url":null,"abstract":"<div><div>Fuchs endothelial corneal dystrophy (FECD) is a heritable disorder distinguished by a progressive degeneration of the corneal endothelium. In its late-onset form, FECD has been associated with a trinucleotide repeat (TNR) expansion (CTG18.1) located in an intronic region of the <em>TCF4</em> gene, whose frequency is variable among different ancestry groups. Since its discovery, studies investigating CTG18.1-mediated pathogenesis have steadily increased, yet much concerning the unique and tissue-specific clinical features of the disease, as well as its heritable mode of transmission, remain poorly understood. The field of repeat expansion disorders has greatly informed mechanistic understanding of CTG18.1-mediated FECD. In particular, molecular mechanisms underlying myotonic dystrophy type 1, attributed to a CTG expansion in the 3ˈ UTR of the <em>DMPK</em> gene, have considerably informed the FECD field, despite its stark contrast in terms of multisystemic manifestations and variable age at onset. In this work, we critically discuss the non-mutually shared pathogenic parallelisms existing between the pathologies, as well as the unique molecular signatures exhibited by FECD and DM1, speculating on potential research directions for future investigations. Moreover, we discuss the few studies published over the past decade describing the occurrence of FECD in DM1 patients. Here, we debate possible shared molecular signatures that could explain FECD development as a consequence of a non-coding CTG expansion, irrespective of loci (e.g. <em>DMPK</em> or <em>TCF4</em>), and discuss experimental approaches to explain whether these pathologies share toxic mechanisms that arise from these distinct repeat elements.</div></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":"110 ","pages":"Article 101418"},"PeriodicalIF":14.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145575514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond convolutions and supervised learning with transformers and representation learning for retinal image analysis","authors":"Yue Wu ,&nbsp;Cecilia S. Lee ,&nbsp;Aaron Y. Lee","doi":"10.1016/j.preteyeres.2025.101419","DOIUrl":"10.1016/j.preteyeres.2025.101419","url":null,"abstract":"<div><div>Retinal image analysis has enjoyed groundbreaking advances in the last ten years due to seismic improvements in image analysis techniques from the field of computer vision. Previous reviews in deep learning and artificial intelligence (AI) (Schmidt-Erfurth et al., 2018; Ting et al., 2019) have either focused on supervised learning, where labels are curated or manually created, or concentrated on the application of AI in specific image modalities and retina diseases (Hormel et al., 2021; Li et al., 2024a (<span><span>Hormel et al., 2021</span></span>, <span><span>Li et al., 2024a</span></span>)). In this review, we sought to summarize the advances in the field with the shift towards label-free approaches using representational learning and the emergence of vision transformers as alternatives to convolutional neural networks for image analysis. These advances include semi-supervised learning, self-supervised learning and directly led to the advent of foundation models, vision-language models, and multi-modal models.</div></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":"110 ","pages":"Article 101419"},"PeriodicalIF":14.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surgical management of myopic traction maculopathy; expert perspectives from the myopia society","authors":"Hiroyuki Takahashi ,&nbsp;Richard F. Spaide ,&nbsp;Shu Yen Lee ,&nbsp;Yasushi Ikuno ,&nbsp;Pei-Ting Lu ,&nbsp;Chi-Chun Lai ,&nbsp;Yuxin Fang ,&nbsp;Chui Ming Gemmy Cheung ,&nbsp;Jose M. Ruiz-Moreno ,&nbsp;Kyoko Ohno-Matsui","doi":"10.1016/j.preteyeres.2025.101434","DOIUrl":"10.1016/j.preteyeres.2025.101434","url":null,"abstract":"<div><div>Myopic traction maculopathy (MTM) occurs in approximately 9–34 % of highly myopic eyes and requires surgical treatment to prevent irreversible vision loss due to progression to macular hole (MH) or retinal detachment (RD). While treatment of MTM, which presents with a variety of morphological patterns, shares the common goal of managing the causative tractional tissues on the retina, it is essential to tailor the surgical plan according to the locations of each lesion. Here, we classify MTM into four core lesions: retinoschisis, foveal RD, lamellar MH (LMH), and full-thickness MH (FTMH), and present an algorithm for treatment decision-making. Pars plana vitrectomy (PPV) is a procedure that enables reliable removal of traction-inducing tissues and should be promptly indicated for patients with foveal RD showing progressive vision decline or those with MHRD. Postoperatively, development of macular hole or progression of macular atrophy should be monitored carefully. In recurrent MTM, inadequate membrane peeling is a common cause, requiring wide-field imaging and more intensive intraoperative assessment for residual tissues. Recurrent MTM without FTMH is treated with additional ILM peeling, while recurrence with FTMH is managed surgically using techniques involving ILM flaps, autologous retinal flap, or amniotic membrane transplantation. Macular buckling has also been reported to be effective when used alone or in combination with PPV. Following treatment, long-term follow-up is essential for monitoring both recovery and recurrence. Though further validation through randomized prospective trials is needed, the paradigm for MTM surgery continues to evolve toward preventing persistent vision loss and to optimizing long-term outcomes.</div></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":"110 ","pages":"Article 101434"},"PeriodicalIF":14.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and effectiveness of vital dyes for intraocular surgery","authors":"Mario R. Romano ,&nbsp;Mariantonia Ferrara ,&nbsp;Peter Szurman ,&nbsp;Angelo Spadaro ,&nbsp;Hannah J Levis ,&nbsp;Andrea Govetto ,&nbsp;Tommaso Rossi ,&nbsp;Chiara BM. Platania ,&nbsp;Kai Januschowski ,&nbsp;Claudio Bucolo ,&nbsp;Vito Romano","doi":"10.1016/j.preteyeres.2025.101412","DOIUrl":"10.1016/j.preteyeres.2025.101412","url":null,"abstract":"<div><div>Over the last decade, vital dyes have revolutionized ophthalmic surgery, becoming indispensable tools in many intraocular procedures. These intraocular medical devices enhance visualization, facilitate tissue differentiation and improve surgical precision, ultimately optimizing outcomes. An understanding of their physicochemical properties and staining patterns is crucial for maximizing their benefits and achieving near-histological accuracy. In the recent years, increasing attention has been given to the biocompatibility of intraocular devices to enhance safety and minimise risks. Despite their widespread use, the long-term safety, interactions with intraocular devices, and optimal staining protocols of vital dyes remain insufficiently understood. Addressing these gaps is critical to improving surgical efficacy and patient safety. This review synthesizes recent findings to bridge these knowledge gaps and provide updated clinical insights, offering a comprehensive and detailed analysis of the physicochemical properties, staining mechanisms, and safety profiles of both traditional and newly developed vital dyes. Additionally, it examines how these properties influence surgical efficacy and biocompatibility. We also present an in-depth overview of experimental and clinical studies investigating the potential intraocular toxicity of vital dyes, focusing on crucial and controversial topics, such as surgical risk factors, the interaction between intraocular medical devices and the role of phototoxicity. Drawing on the latest experimental and clinical evidence, we propose updated guidelines to optimise the safe and effective use of vital dyes in intraocular surgery and patients outcomes.</div></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":"110 ","pages":"Article 101412"},"PeriodicalIF":14.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145412271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Femtosecond lasers in ophthalmology: Mechanisms, clinical breakthroughs, and multidisciplinary frontiers","authors":"Wan-Ping Zhang ,&nbsp;Hai-Jun Lv ,&nbsp;An-Peng Pan ,&nbsp;Wan-Xia Zhang ,&nbsp;Xu Shao ,&nbsp;Yong-Zheng Qu ,&nbsp;An-Song Li ,&nbsp;Lin-Hua Chen ,&nbsp;Shao-Qun Zeng ,&nbsp;A-Yong Yu","doi":"10.1016/j.preteyeres.2025.101431","DOIUrl":"10.1016/j.preteyeres.2025.101431","url":null,"abstract":"<div><div>Femtosecond laser (FSL) technology has emerged as a transformative force in ophthalmology, offering unprecedented precision in tissue manipulation with minimal collateral thermal and mechanical damage. This comprehensive review traces the evolution of FSL from its fundamental physical principles to its broad spectrum of clinical applications. We examine its roles in refractive surgery, corneal transplantation, presbyopia correction, cataract surgery, glaucoma management, and pterygium excision, as well as recent advancements in intraocular lens customization and nanopatterning. Beyond established clinical use, we explore emerging frontiers where FSL intersects with optogenetics, two-photon photodynamic therapy, and artificial intelligence-augmented optical coherence tomography. Unresolved challenges, including reactive oxygen species-mediated toxicity, cost limitations, and long-term biosafety, are critically discussed. By integrating mechanistic insights, clinical evidence, and translational prospects, this review highlights the potential of FSL to redefine ophthalmic practice through interdisciplinary innovation and to enable the development of personalized, minimally invasive therapeutic strategies.</div></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":"110 ","pages":"Article 101431"},"PeriodicalIF":14.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative analysis of conjunctival vascular alterations: Applications in ocular and systemic disease detection","authors":"Xuran Duan ,&nbsp;Chaoyu Lei ,&nbsp;Chris Hong Long Lim ,&nbsp;Jianbin Ding ,&nbsp;Jodhbir S. Mehta ,&nbsp;Sayan Basu ,&nbsp;Luke Johnston ,&nbsp;Yujie Ren ,&nbsp;Chen Zhao ,&nbsp;Victor Koh Teck Chang ,&nbsp;Huifang Zhou","doi":"10.1016/j.preteyeres.2025.101416","DOIUrl":"10.1016/j.preteyeres.2025.101416","url":null,"abstract":"<div><div>The conjunctival blood vessels are the only microcirculatory system on the body surface that can be observed non-invasively. Anatomically interconnected with multiple craniofacial circulatory systems, these vessels can indirectly reflect the blood supply to these areas and the overall state of systemic microcirculation. We synthesize findings from 48 studies spanning 2020–2025. Overall, existing research has found that the conjunctival vascular parameters can change in various diseases such as diabetes, cardiovascular diseases, and autoimmune diseases, and may even precede organic lesions. Recent advancements in conjunctival vessel imaging and analysis technologies have enabled the identification and evaluation of various ocular and systemic diseases based on conjunctival vascular parameters. However, existing studies are limited by insufficient sample sizes, covariate interference, limited disease types, a lack of investigation into the underlying mechanisms of conjunctival vascular changes, and inadequate integration with emerging technologies, such as artificial intelligence. Future research should aim to broaden the scope of investigation, delve deeper into the mechanisms governing conjunctival vascular alterations, and integrate artificial intelligence to establish a solid foundation for the clinical application of conjunctival vascular parameters.</div></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":"110 ","pages":"Article 101416"},"PeriodicalIF":14.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145553612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glymphatic transport and ocular diseases","authors":"Xiaowei Wang ,&nbsp;Christine Delle ,&nbsp;Maiken Nedergaard ,&nbsp;Peter Wostyn","doi":"10.1016/j.preteyeres.2025.101433","DOIUrl":"10.1016/j.preteyeres.2025.101433","url":null,"abstract":"<div><div>The high metabolic demand of retinal neurons requires tightly regulated mechanisms to maintain homeostasis and ensure the efficient clearance of metabolic waste and excess water. Recent studies have identified a glymphatic-like system in the rodent eye, and growing evidence supports the existence of a similar pathway in the human eye, facilitating fluid exchange and waste removal. The ocular glymphatic system supports bidirectional flow along the optic nerve - anterograde from the retina and retrograde from the brain.</div><div>In this review, we integrate findings from preclinical models and clinically grounded hypotheses to identify key contributors to glymphatic dysfunction in ocular diseases. These include impaired laminar barrier integrity, pathological perivascular space expansion, aquaporin-4 abnormalities, immature vasculature, and pathological immune activation. Glymphatic impairment has been implicated in murine models of glaucoma, diabetic retinopathy, and ocular manifestations of Alzheimer's disease. Additionally, disrupted glymphatic flow is suspected in papilledema, spaceflight associated neuro-ocular syndrome, and Terson syndrome.</div><div>We further explore novel associations between glymphatic dysfunction and other blinding disorders such as myopic optic neuropathy, age-related macular degeneration, neuromyelitis optica spectrum disorders, and retinal vasculitis. In delineating these mechanistic links, this review provides a conceptual framework to guide future research in glymphatic contributions to ocular diseases.</div></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":"110 ","pages":"Article 101433"},"PeriodicalIF":14.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical histopathology and pathogenesis of macular telangiectasia type 2","authors":"Dimitrios P. Ntentakis ,&nbsp;Anastasia Maria Ntentaki ,&nbsp;Eleni Delavogia ,&nbsp;Gustavo Sakuno ,&nbsp;Victor S.M.C. Corrêa ,&nbsp;Nikolaos E. Efstathiou ,&nbsp;Mary E. Aronow ,&nbsp;Emily Y. Chew ,&nbsp;Joan W. Miller ,&nbsp;Demetrios G. Vavvas","doi":"10.1016/j.preteyeres.2025.101401","DOIUrl":"10.1016/j.preteyeres.2025.101401","url":null,"abstract":"<div><div>Macular telangiectasia type 2 (MacTel) is a rare neurodegenerative retinal disease defined by a unique combination of reduced macular pigment, a characteristic angiographic pattern, and a localized clinical presentation. The condition typically affects the temporal perifovea and leads to progressive visual impairment. No definitive treatment exists. Current management is limited to intravitreal anti-vascular endothelial growth factor (VEGF) injections for end-stage neovascular complications and the recently approved Encelto implant (Neurotech Pharmaceuticals, Inc.), which delivers ciliary neurotrophic factor (CNTF) for neuroprotection.</div><div>To clarify the still enigmatic pathophysiology of MacTel, we conducted a comprehensive review of all human histopathology reports published in English through December 31, 2024. Findings were systematically evaluated with respect to tissue processing techniques, postmortem fixation times, disease stage at last recorded ophthalmologic evaluation, diagnostic certainty, inclusion of control specimens, and the anatomic origin of analyzed retinal sections. This approach aimed to identify histopathologic features most likely to represent core disease mechanisms.</div><div>Each of the features identified as most likely to be pathophysiologically relevant was independently assessed for clinical and histopathologic specificity. These features were then further interpreted in the context of genetic, metabolic, and anatomic associations reported in the literature. Donor demographics, coexisting ocular conditions, and systemic comorbidities were also reviewed to support the development of an integrative hypothesis for MacTel pathogenesis.</div><div>Drawing on this synthesis, we propose a histopathology-informed model of disease pathophysiology and outline a provisional timeline for the contribution of key factors to clinical expression. We also review current neuroprotective strategies and provide targeted recommendations for future therapeutic development and histopathologic research. The conceptual framework developed in this work —grounded in rigorous analysis of the most consistent and methodologically validated histopathologic findings, and interpretation of their mechanistic context— may serve as a model for deciphering rare retinal diseases and for generating focused, hypothesis-driven questions to guide future investigation.</div></div>","PeriodicalId":21159,"journal":{"name":"Progress in Retinal and Eye Research","volume":"110 ","pages":"Article 101401"},"PeriodicalIF":14.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}