Research progress on glycolytic reprogramming in ophthalmic diseases

Abstract

The retina is one of the most energy-demanding tissues in the human body. Retinal energy metabolism is primarily dominated by aerobic glycolysis, with more than 80% of the glucose consumed being converted to lactic acid. As a highly energy-consuming tissue, the metabolic characteristics of the retina, especially aerobic glycolysis, are essential for maintaining retinal cell function during normal physiological processes. However, in disease states, this metabolic balance is disrupted, leading to a range of pathological changes. There is currently growing evidence that metabolic reprogramming is a pathological cause of diseases such as retinal degeneration, uveal melanoma, and glaucoma. This article reviews the mechanisms involved in metabolic reprogramming in ocular diseases and describes relevant therapeutic targets. Despite the many advances, the regulatory mechanisms of metabolic reprogramming in ophthalmic diseases still need to be thoroughly investigated, and new therapeutic strategies are expected to be developed based on this in the future.

Introduction

Under normal aerobic conditions, intracellular pyruvate enters the mitochondria and participates in the tricarboxylic acid cycle (TCA), generating adenosine triphosphate (ATP) through oxidative phosphorylation. Under low or no aerobic conditions, pyruvate is directly reduced to lactate through glycolysis to generate energy (Rabinowitz & Enerbäck, 2020). In 1921, German scientist Otto Warburg made a groundbreaking discovery: even under sufficient oxygen, cancer cells preferentially utilize glycolysis to obtain most of their energy. This type of glycolysis under aerobic conditions is called the “Warburg effect”, also known as metabolic reprogramming (Warburg, 1956). Notably, metabolic reprogramming is a hallmark of malignancy first recognized a century ago and has since become a focal point in cancer research. In some cases, reprogrammed metabolic activities can be exploited to diagnose, monitor, and treat cancer. Consequently, several metabolic inhibitors designed to target key pathways of metabolic activity have entered clinical trials (Hu et al., 2024).

The retina is unique as the only non-proliferative tissue capable of sustained aerobic glycolysis (Wubben et al., 2017). Recent studies reveal that many ophthalmic diseases are linked to metabolic reprogramming, suggesting that related pathway proteins could serve as therapeutic targets. This article reviews recent advances, explores the role of metabolic reprogramming in ophthalmic diseases, and lays the groundwork for developing new strategies to target metabolic pathways therapeutically.

Survey Methodology

This review is primarily aimed at:

• 1.Ophthalmology researchers: to provide new perspectives on metabolic regulation in disease mechanisms.
• 2.Clinicians: to analyse advances in translational medicine such as stem cell therapy and gene editing.
• 3.Molecular biologists: to explore the molecular pathways of epigenetic-metabolic interactions.
• 4.Drug developers: Evaluate the therapeutic potential of targeting metabolic enzymes or reprogramming technologies.

Literature Search Strategies

• 1.Databases and Search Engines
  • •International databases: PubMed, Web of Science, ScienceDirect, Cell Press, Nature Portfolio.
  • •Chinese databases: China Knowledge Network (CNKI) (Fig. 1).
• 2Search Keywords

  Core subject terms Combined search formula (example)

  • •Metabolic reprogramming: metabolic reprogramming, metabolic remodeling, Warburg effect, glycolysis.
  • •Ocular Diseases: ocular diseases, age-related macular degeneration (AMD), glaucoma, diabetic retinopathy, retinal degeneration, macular degeneration, glaucoma, retinitis pigmentosa.
  • •Techniques/mechanisms: epigenetic regulation, stem cell therapy, gene therapy, cell reprogramming, epigenetic modifications, oxidative stress.

  (metabolic reprogramming OR metabolic remodeling) AND (ocular diseases OR AMD OR glaucoma)

• 3.Time Frame

  From January 2015 to March 2025, with priority given to the inclusion of high—impact studies from the last 5 years (post—2020), e.g., Nature, Cell series of journals, Science Translational Medicine, etc.

• 4.Inclusion and exclusion criteria

  Inclusion Criteria

  • •Study type: basic research (e.g., animal models, cellular experiments), preclinical trials, clinical trials, reviews and Meta-analyses.
  • •Relevance: Explicitly explore the mechanism of action or therapeutic application of metabolic reprogramming in ophthalmic diseases, e.g., the association of metabolic pathways such as enhanced glycolysis with retinopathy. Application of reprogramming techniques (e.g., cellular reprogramming, epigenetic interventions) in vision restoration.
  • •Language: English and Chinese literature.

  Exclusion criteria

  • •Not related to ophthalmic diseases (e.g., only discussing cancer metabolism).
  • •Purely clinical observational studies that do not address metabolic mechanisms or therapeutic strategies.
  • •Low-quality evidence: preprints that have not been peer-reviewed (unless the content is groundbreaking), replicated studies, or case reports with too small a sample size.

Figure 1. PRISMA 2020 flow diagram for new systematic reviews which included searches of databases, registers and other sources.

Academic literature indexed in PubMed, Web of Science, ScienceDirect, and China National Knowledge Infrastructure (CNKI) was retrieved.

Metabolic reprogramming

The Warburg effect is described as a reprogramming of cancer cell metabolism, whereby cells utilize more glucose than normal cells and redirect it toward anabolic processes such as lipid, RNA/DNA synthesis, and nicotinamide adenine dinucleotide phosphate (NADPH) generation, leading to incomplete glucose oxidation despite oxygen availability (Warburg, 1956). Intriguingly, Warburg noted that the retina was the only non-proliferative tissue capable of aerobic glycolysis, and subsequent studies revealed that this phenomenon is localized specifically to photoreceptors. Photoreceptors must continually regenerate their outer segment (OS) membranes, a process that demands not only catabolic energy production but also anabolic synthesis of lipids, proteins, and nucleic acids (Xu, Zhao & Kang, 2024). Glucose is transported from the choroidal vasculature to photoreceptors (PRs) via the retinal pigment epithelium (RPE). Whereas RPE cells rely primarily on oxidative phosphorylation. In contrast, photoreceptor cells are more dependent on glycolysis. During aerobic glycolysis in photoreceptors, glucose is converted to lactate, which is transported to RPE cells. There, lactate is converted to pyruvate via lactate dehydrogenase (LDH), fueling mitochondrial oxidative phosphorylation (Kanow et al., 2017) (Fig. 2). Notably, Rods shuttle glucose into the pentose phosphate pathway (PPP) to synthesize new membranes and facilitate OS generation (Zhang et al., 2016). Critically, Photoreceptor cell death is the ultimate cause of vision loss in many retinal disorders (Zhang et al., 2016; Fisher & Ferrington, 2018). Thus, disruption of this metabolic balance between the outer retina and the retinal pigment epithelium can lead to photoreceptor outer segment dysplasia or even photoreceptor death, ultimately causing visual impairment. Remarkably, in many retinal diseases, the balance between the RPE and photoreceptor cells is disrupted. As a result, the RPE increases its dependence on glycolysis for energy production, using more of the available glucose to meet its own metabolic needs. This metabolic shift makes less glucose available to photoreceptors, whose ability to regenerate the outer segments is compromised due to insufficient energy and other biosynthetic raw materials (Fig. 2). Hexokinase 2 (HK2), pyruvate kinase muscle isoform 2 (PKM2), and lactate dehydrogenase A (LDHA) are central isoforms regulating aerobic glycolysis and lactate production in PRs. Among these, HK2, the first key glycolytic enzyme, is predominantly expressed in PRs. Studies demonstrate that optic rod cell-specific deletion of Hk2 reduces aerobic glycolysis and increases oxidative phosphorylation (OXPHOS) (Petit et al., 2018). Pyruvate kinase (PK), the final glycolytic enzyme, converts phosphoenolpyruvate (PEP) and adenosine diphosphate (ADP) to pyruvate and ATP. Meanwhile, LDHA catalyzes the conversion of pyruvate to lactate in the last step of aerobic glycolysis. Strikingly, in vivo electroporation of LDHA or PKM2 expression reduces OS length (Chinchore et al., 2017). Furthermore, similar to HK2 and PKM2, LDHA is preferentially expressed in PRs, consistent with the spatial organization of aerobic glycolysis in the retina (Casson et al., 2016; Weh et al., 2020). These enzymes represent critical targets for metabolic reprogramming and its role in disease. Collectively, these findings suggest that targeting these enzymes may offer novel therapeutic strategies to reprogram metabolism and halt disease progression.

Figure 2. Schematic diagram of glucose metabolism of the RPE and photoreceptors in the RPE-retinal ecosystem.

Normal Vision: Under normal physiological conditions, normal glucose metabolism of the RPE and photoreceptors in the RPE-retinal ecosystem leads to normal vision; Vsion Dysfunction: Metabolic dysfunc-tion of the RPE and photoreceptors in the RPE-retinal ecosystem. Abbreviations: GLU, glucose; RPE, retinal pigment epithelium; PR, photoreceptor; TCA, tricarboxylic acid cycle; G-6-P, glu-cose-6-phosphate; PEP, phosphoenolpyruvate; HK2, hexokinase2; PKM2, pyruvate kinase mus-cle isoform 2; LDHA, lactate dehydrogenase A. Figure support was provided by figdraw.com.

Retinal degeneration

Age-related macular degeneration

Age-related macular degeneration (AMD) is a progressive retinal disease that is the leading cause of vision impairment. It accounts for approximately 6% to 9% of global legal blindness, especially in people over 50 years of age (Fleckenstein, Schmitz-Valckenberg & Chakravarthy, 2024). The pathogenesis of AMD is complex and involves multiple factors such as genetics, environment, and metabolism. Dysfunction and degeneration of RPE cells are considered to be the core pathogenesis of AMD. The advanced stages of AMD are categorized as atrophic (dry) and exudative (wet) (Guymer & Campbell, 2023). Dry AMD is characterized by progressive RPE atrophy, leading to degeneration of photoreceptor cells and causing central vision loss. In wet AMD, abnormal proliferation of choroidal neovascularization (CNV) crosses the retina, leading to hemorrhage, leakage, and scar formation, further impairing visual function (Fabre et al., 2022).

A key feature of dry AMD is the loss of RPE and photoreceptors. Fisher & Ferrington (2018) analyzed human donor tissues and demonstrated that mitochondrial damage in the RPE acts as a key driver of dry AMD pathology. Using diverse experimental approaches, their work revealed that RPE primary cultures from AMD donors exhibited disrupted mitochondrial structure, reduced mitochondrial number and mass, altered mitochondrial protein expression, and increased mitochondrial DNA damage—all correlating with disease severity (Fisher & Ferrington, 2018). Critically, prior studies indicate that RPE cells predominantly rely on oxidative phosphorylation to meet energy demands (Kanow et al., 2017). However, research by Golestaneh et al. (2017) showed that RPE cells in AMD patients rely on glycolysis as the main source of ATP rather than oxidative phosphorylation.

When mitochondrial dysfunction occurs, these cells shift to aerobic glycolysis to sustain energy production. This metabolic adaptation reduces the availability of glucose for photoreceptors, which themselves depend on glycolysis for survival. Notably, rod photoreceptors secrete a cone survival factor that enhances glucose uptake by cone cells, establishing a metabolic interdependence between rods and cones. Consequently, rod degeneration precedes cone loss (Curcio, Medeiros & Millican, 1996). Given the macula’s high density of metabolically demanding cone photoreceptors, it is likely that RPE and photoreceptor death occurs preferentially in this region, explaining why macular degeneration is a hallmark of advanced AMD.

Neovascular AMD (nAMD) accounts for more than 90% of vision loss due to AMD disease, and although anti-vascular endothelial growth factor (VEGF) injections have become the first-line treatment to improve angiogenesis (Pugazhendhi et al., 2021), there are still patients who are incurable due to subretinal fibrosis (SF) (Zhang et al., 2025). Growing evidence implicates RPE cell epithelial-mesenchymal transition (EMT) as critical to SF pathogenesis in nAMD (Zhou et al., 2020). Ma et al. (2024b) found downregulation of mitochondria-associated metabolism and downregulation of carnitine palmitoyltransferase 1A (CPT1A) expression in retinal pigment epithelial cells using single-cell sequencing in a mouse nAMD model. Their findings suggest a bidirectional relationship between metabolic dysfunction and fibrosis: metabolic alterations drive fibrotic progression, while fibrosis exacerbates metabolic imbalance. Specifically, TGFβ signaling activation reprograms RPE metabolism, shifting from mitochondrial oxidative phosphorylation to glycolysis via ERK-dependent downregulation of CPT1A and other key metabolic enzymes. As CPT1A is the rate-limiting enzyme for mitochondrial fatty acid oxidation, its suppression blocks fatty acid entry into mitochondria, forcing cells into a glycolytic state reminiscent of the Warburg effect. This metabolic shift not only enables rapid ATP production to fuel EMT and extracellular matrix (ECM) deposition during fibrosis but also generates glycolytic byproducts like serine and glycine, which directly support collagen synthesis. Central to this metabolic rewiring is the mitochondrial pyruvate dehydrogenase complex (PDC), whose activity is tightly regulated by post-translational modifications. Phosphorylation of PDC’s E1α subunit (PDHE1α) by pyruvate dehydrogenase kinases (PDK1–4) inhibits PDC, diverting pyruvate away from mitochondrial oxidation (Park et al., 2018). Supporting this mechanism, Kim et al. (2024) demonstrated that PDK4-mediated PDHE1α phosphorylation dramatically increases in RPE cells within 24 h of laser-induced CNV in mice, shunting metabolism toward aerobic glycolysis. Consequently, accumulated glycolytic intermediates provide energy and biosynthetic precursors for cell proliferation and inflammation, propelling CNV progression. Critically, Pdk4 knockout mice exhibit significantly smaller CNV lesions, highlighting PDK4 inhibition as a promising therapeutic strategy for nAMD.

In AMD, elevated levels of cytokines such as TNFα, TGF-β2, IL-6, and IL-1β in the RPE/choroid complex drive chronic inflammation, contributing to tissue injury, oxidative stress, fibrosis, and necrosis (Lee et al., 2021). Hansman et al. (2024) found that TNFα, TGF-β2, IL-1β, and cytokine mixtures significantly elevated lactate production, glucose consumption, and extracellular acidification rates in ARPE-19 cells, primary human RPE cells (from donor eyes), and rat retinal explants, while also modulating glycolytic gene expression. These findings strongly implicate inflammatory cytokines in promoting AMD progression through metabolic reprogramming. Beyond cytokines, excessive homocysteine (Hcy) disrupts RPE structure and barrier function, promotes experimental CNV in mice (Ibrahim et al., 2016), and upregulates retinal hypoxia-inducible factor 1α (HIF-1α) and VEGF levels (Tawfik et al., 2014), thereby enhancing angiogenic potential in retinal endothelial cells both in vitro and in vivo (Mohamed et al., 2017). Further supporting this metabolic link, Samra et al. (2023) revealed that HHcy induces a Warburg-like glycolytic shift in RPE cells by upregulating glycolytic enzymes (e.g., hexokinase 1 and lactate dehydrogenase), leading in cellular dysfunction and pathological CNV. Collectively, these studies establish metabolic reprogramming as a central pathogenic mechanism in AMD. Targeting these metabolic pathways may unlock novel therapeutic strategies to mitigate AMD progression.

Retinitis pigmentosa

Retinitis pigmentosa (RP) is an inherited retinal disease caused by mutations in several genes, leading to progressive degeneration of photoreceptors and eventual blindness (Vingolo et al., 2024). In healthy photoreceptors, the OS rely on NADPH—produced by the PPP—to synthesize phospholipids, a critical process for maintaining their structure and function. However, in RP, one of the earliest pathological hallmarks is abnormal rod photoreceptor OS development. Mutations in the phosphodiesterase-6 (PDE6) gene, a key regulator of photoreceptor signaling, are among the most common causes of autosomal recessive RP (Wu et al., 2016). To explore potential therapeutic strategies, Zhang et al. (2016). Knocked out the sirt6 gene in Pde6-mutant mice; they demonstrated that sirt6 knockout preserved OS integrity, restored retinal layer morphology, and improved photoreceptor function. Mechanistically, inhibition of the sirt6 gene was shown to enhance glycolysis by upregulating glycolysis-related transcription factors, modulating enzyme kinetics, and increasing metabolic intermediate levels, thereby shifting cellular metabolism toward glycolytic flux.

RP is characterized by the primary degeneration of rod photoreceptors, followed by the subsequent loss of cone photoreceptors (Verbakel et al., 2018). Since approximately 10% of photoreceptor OS are phagocytosed by RPE cells daily, photoreceptors require efficient membrane synthesis to sustain their structural integrity. Notably, aerobic glycolysis has been proposed as being critical for supporting their membrane biosynthesis (Rajala, 2020). PKM2, which catalyzes the final step of glycolysis (conversion of PEP to pyruvate), is highly expressed in both rod and cone photoreceptors (Weh et al., 2020). Zhang et al. (2020) found that photoreceptor function could be rescued by PKM2 knockdown. This apparent contradiction may arise from PKM2’s dual roles: its knockdown might restore glucose homeostasis by enhancing catabolic ATP production or by modulating metabolic coupling between RPE cells and photoreceptors, thereby shifting photoreceptors toward a pro-survival anabolic state. Further supporting this metabolic interplay, Rajala et al. (2018a) demonstrated that conditional knockdown of PKM2 in mouse rod photoreceptors led to the accumulation of glycolytic intermediates, reduced dark-adapted a- and b-wave amplitudes on electroretinography (ERG), and impaired rod function via metabolic flux analysis. Consistently, TUNEL staining revealed an increase in cell death in the retinal outer nuclear layer, indicating PKM2 loss exacerbates rod degeneration. In a parallel study published the same year, Rajala et al. (2018b) conditionally knocked out PKM2 in cone photoreceptors, observing age-dependent cone dysfunction—manifested as decreased visual b-wave amplitude, altered flicker ERG responses, cone cell loss, and OS shortening. These phenotypes correlated with the downregulation of glycolysis-, PPP-, and fatty acid biosynthesis-related genes. Strikingly, subretinal PKM2 injection partially rescued OS shortening (Chinchore et al., 2017) underscoring PKM2’s essential role in cone anabolism. Expanding on these findings, Zhu et al. (2021) reported that blue light exposure upregulated PKM2 expression in the 661W cone cell line, triggering oxidative stress and apoptosis. However, pretreatment with the PKM2 inhibitor shikonin reduced apoptosis and mitigated oxidative stress. Conversely, Wubben et al. (2020) later showed in 2020 that the PKM2 activator ML-265 regulated metabolism and suppressed apoptosis, highlighting PKM2’s context-dependent effects. Collectively, these studies establish PKM2 as a pivotal regulator of photoreceptor homeostasis, influencing metabolic reprogramming, survival, and retinal degeneration progression. Targeting PKM2-mediated pathways thus represents a promising therapeutic strategy for retinal diseases.

Diabetic retinopathy

Diabetic retinopathy (DR) is the leading cause of visual impairment and blindness in people of working age. Metabolic reprogramming plays a key role in the DR process. In DR, persistent hyperglycemia induces mitochondrial dysfunction in RPE cells, triggering a glycolytic shift and excessive lactate production, which exacerbates photoreceptor degeneration (Yumnamcha et al., 2020). Notably, under physiological conditions, photoreceptors export lactate to fuel RPE cells and Müller glial cells. However, in DR, pathological accumulation of lactate and glutamate in Müller cells and neuronal microenvironments induces retinal excitotoxicity and photoreceptor damage (Li & Puro, 2002). Furthermore, Müller cell dysfunction disrupts neurovascular interactions, compromising retinal homeostasis (Newman, 2013). Metabolic reprogramming also impairs endothelial cell barrier function, accelerating DR progression by destabilizing vascular integrity (Trudeau et al., 2010; Madsen-Bouterse et al., 2010). Targeting endothelial metabolism, Han et al. (2024) demonstrated that tSRNA-1599 suppresses angiogenesis by modulating HK2 expression, altering glycolytic flux and metabolite dynamics. Central to DR pathogenesis, HIF-1α amplifies glycolysis, exacerbating oxidative stress and neurodegeneration, particularly in photoreceptors (Li et al., 2020a; Min et al., 2021). Counteracting this cascade, Chen et al. (2024) showed that WNT inhibitory factor 1 (WIF1) mitigates photoreceptor damage by suppressing the Wnt/β-catenin–HIF-1α–GLUT1 axis, thereby reducing oxidative stress and preserving retinal neurons. Compounding these metabolic disruptions, high glucose and cytokines synergistically inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. While GAPDH suppression forces a metabolic shift toward oxidative phosphorylation to meet energy demands, this adaptation risks oxidative stress and mitochondrial dysfunction (Shivashankar, Lim & Acosta, 2021). Emerging evidence also implicates microglial metabolic reprogramming in DR inflammation. Using multi-omics approaches, Lv et al. (2022) identified activated microglia as key drivers of early retinal inflammation, with their metabolic rewiring fueling pro-inflammatory responses (Cai, Xia & Zhang, 2024). Notably, STF31 treatment reprograms inflamed microglia toward oxidative phosphorylation by blocking GLUT1-mediated glucose uptake, highlighting therapeutic potential.

Collectively, DR progression hinges on metabolic crosstalk among photoreceptors, RPE, Müller cells, endothelium, and microglia, orchestrated by oxidative stress, inflammation, and mitochondrial failure. Deciphering these mechanisms offers promise for developing targeted therapies to halt DR progression and preserve vision.

Uveal melanoma

Uveal melanoma (UM), an aggressive intraocular malignancy arising from melanocytes, exhibits high metastatic potential even after successful primary tumor treatment with radiation or surgery. It is concerning that the median age at diagnosis for patients with metastatic UM is approximately 61–65 years, and the 10-year mortality rate is extremely high, approaching 100% (Smit et al., 2020; Rantala et al., 2022). As a hallmark feature of cancer, metabolic reprogramming involves alterations in key pathways in UM. Peng et al. (2018) utilized TCGA pan-cancer data (including UM) to classify tumor samples into different metabolic expression subtypes through transcriptomic analysis. Their study revealed that upregulation of genes related to glycolysis, the tricarboxylic acid cycle, and energy metabolism constitutes a specific subtype pattern in UM and other cancer types, which is associated with poor patient prognosis at the pan-cancer level. Consistent with this, UM with monosomy 3 may have higher glucose uptake potential, accumulate more 18F-FDG, and show up as abnormal radioactive foci on PET/CT images (Weidmann et al., 2017). This suggests that glycolytic activity is elevated in UM tumors (Cohen et al., 2018). Critically, higher total glycolytic activity correlates with poorer median overall survival (Han, Schug & Aplin, 2021). Whereas glycogen metabolism is suppressed, particularly in highly metastatic monosomy 3 UM (Vardanyan et al., 2020). These metabolic adaptations likely drive UM pathogenesis and metastasis.

Hypoxia, a key microenvironmental feature of UM, fuels malignant progression by stabilizing HIF-1α (Zhao et al., 2022). HIF-1α promotes tumor growth and metastasis by upregulating pro-angiogenic genes (e.g., VEGF, ANGPTL4) (Hu et al., 2021), and rewiring tumor metabolism (de Heer, Jalving & Harris, 2020). Notably, BNIP3—a hypoxia-inducible stress sensor regulated by HIF-1α—modulates energy metabolism in UM cells (Yao et al., 2022). Under hypoxia, BNIP3 enhances mitochondrial respiration and ATP production while suppressing glycolysis (reduced glucose uptake/lactate output) (Sun et al., 2024). Mechanistically, BNIP3 acts as a mitophagy receptor, binding LC3 to clear dysfunctional mitochondria under hypoxia (Panigrahi et al., 2020). This mitochondrial optimization reduces mitochondrial ROS (mtROS), which destabilizes HIF-1α, thereby inhibiting its transcriptional activation of glycolytic genes and perpetuating metabolic adaptation.

BRCA1-associated protein 1 (BAP1), a tumor suppressor gene located on chromosome 3p21.1, is frequently deleted in metastatic UM (Carbone et al., 2020). Approximately 30%–40% of primary UM cases exhibit BAP1 mutations, while more than 80% of UM cases with distant metastasis exhibit BAP1 mutations (Field et al., 2018). Recent studies have shown that loss of BAP1 in cancer cells results in critical changes in cellular metabolism (Han et al., 2021). BAP1-deficient UM tumors exhibit hyperactive OXPHOS (Han, Schug & Aplin, 2021). Han et al. (2022) additionally, they reported upregulated PDC components and pyruvate dehydrogenase kinase 1 (PDHK1) in these tumors. Mechanistically, PDHK1-mediated phosphorylation of PDH diverts pyruvate toward glycolysis, and PDHK1 inhibition suppresses UM cell growth, validating metabolic targeting as a therapeutic strategy.

Metabolic reprogramming, particularly abnormal glycolysis, is a characteristic hallmark of uveal melanoma (UM) and an important prognostic indicator. Hindso et al. (2025) found that glycolysis parameters measured by ¹⁸F-FDG PET/CT (metabolic tumor volume, MTV; total lesion glycolysis, TLG) measured by ¹⁸F-FDG PET/CT outperform AJCC staging in predicting survival in metastatic UM, indicating that elevated glycolysis levels are associated with poor prognosis. Similarly, Guo et al. (2023) established a glycolysis-related gene signature (GRGS) comprising genes such as ISG20 and MET, which accurately predicts prognosis and is associated with immune infiltration and mutations (e.g., BAP1, SF3B1). These findings highlight that metabolic rewiring not only drives the pathogenesis of UM but also provides quantifiable indicators for prognosis. Targeting these pathways may offer new therapeutic avenues for high-risk patients. For example, quercetin inhibits glycolysis in UM cells (Tura et al., 2024), while lactate, as a key metabolic regulator, reshapes the metabolic profile of UM cells through distinct mechanisms (Longhitano et al., 2022). Abnormal glycolysis serves as both a critical prognostic biomarker and a therapeutic target, reflecting tumor aggressiveness and providing avenues for intervention.

Glaucoma

Glaucoma is an optic neuropathy in which the main risk factors are elevated intraocular pressure (IOP) and reduced ocular perfusion. High IOP leads to damage of retinal ganglion cell (RGC) axons, manifesting in pathological features such as optic nerve head cupping and excessive deposition of ECM in the lamina cribrosa (Kang & Tanna, 2021). Damaged axons release a range of signaling molecules, including cytokines and growth factors, which activate surrounding cells into a state of repair and regeneration. This process, however, may inadvertently drive fibrosis: excessive ECM deposition results in the activation of fibroblasts within the ECM, laying the groundwork for fibrosis (Liu et al., 2018). Notably, mitochondrial dysfunction and impaired cellular respiration/metabolism in fibroblasts are hallmark features of fibrosis (Li et al., 2020b). Building on this, Kamel et al. (2020) demonstrated metabolic reprogramming in glaucomatous lamina cribrosa (LC) cells. Compared to normal LC cells, glaucomatous LC cells exhibit decreased OXPHOS and increased glycolysis. Specifically, monocarboxylate transporter 1 (MCT1) and MCT4—responsible for intra- and extracellular lactate transport (Pucino, Cucchi & Mauro, 2018)—are significantly upregulated in glaucomatous LC cells at both mRNA and protein levels. Additionally, enzymes involved in one-carbon and glutamine metabolism are elevated. Enhanced glycolysis rapidly generates ATP, fueling the proliferation and migration of fibrosis-associated cells and ECM synthesis, thereby promoting fibrotic progression. Previous studies have linked MCT4 upregulation to keloid fibroblasts (Okuno et al., 2018), where MCT4 co-localizes with cell surface glycoproteins that induce ECM metalloproteinases (Payen et al., 2020). Critically, the acidic microenvironment caused by elevated lactate may impair matrix metalloproteinase activity, disrupting the balance between ECM degradation and synthesis. This imbalance exacerbates ECM accumulation and accelerates fibrosis. Collectively, these findings suggest that persistent fibrotic injury in the LC arises from metabolic reprogramming; thus, future studies should evaluate whether targeting these metabolic pathways represents a viable therapeutic strategy.

Dry eye disease

Dry eye disease (DED) is a multifactorial disorder characterized by tear film instability, hyperosmolarity, and ocular surface inflammation (Britten-Jones et al., 2024). In China, the prevalence of DED ranges from 5% to 50%, while the incidence is as high as 31.4% (Song et al., 2018). Central to this pathology are mitochondrial respiration and glycolysis, the primary metabolic pathways for ATP production essential to normal corneal endothelial cell function (Greiner et al., 2015). Notably, monocytes infiltrating the ocular surface differentiate into inflammation-associated M1 macrophages, a process recapitulated in murine models where DED is induced by desiccation stress (You et al., 2015). Recent insights from tear metabolic profiling in DED patients revealed that tear film rupture triggers abnormal glycolysis, marked by TCA cycle overexpression (Jiang et al., 2020). Building on this, Han et al. (2023) demonstrated that hyperosmotic stress mediates glycolytic reprogramming in ocular surface epithelial cells, specifically via microenvironment-driven lactate accumulation and macrophage pyroptosis, which exacerbate DED-associated inflammation. Clinical data corroborate these findings: DED patients exhibit significantly elevated IL-1β levels in tear fluid and upregulated pyroptosis- and glycolysis-related genes in ocular surface epithelial cells. Similarly, in murine DED models, glycolysis and pyroptosis-driven inflammation are enhanced. Mechanistically, co-culture experiments revealed that hyperosmotic stress induces glycolytic reprogramming in human corneal epithelial cells (HCECs), subsequently triggering macrophage cell death. Conversely, inhibiting HCEC glycolysis suppresses this effect. Collectively, these studies highlight glycolysis-dependent cell death as a key driver of DED pathogenesis, positioning glycolytic pathway regulators as potential therapeutic targets.

Graves’ orbitopathy

Thyroid-associated ophthalmopathy (TAO), also known as Graves’ ophthalmopathy or thyroid ophthalmopathy, is the most common extra-thyroidal manifestation of Graves’ disease (GD) (Lee & Kahaly, 2023) and is closely linked to oxidative stress. Recent studies suggest that oxidative stress plays a critical role in the pathogenesis of TAO. During oxidative stress, mitochondria produce excess free radicals and oxidants, disrupting the cellular redox balance. This imbalance can damage mitochondrial membranes and DNA, impairing the function of ocular tissues in TAO patients (Ma et al., 2024b). Notably, orbital fibroblasts (OFs) mediate most of these pathological changes in response to inflammatory or metabolic stimuli (Łacheta et al., 2019). Importantly, TAO OFs exhibit significant oxidative stress (Lanzolla, Marcocci & Marinò, 2020). Interestingly, in proliferating cells—particularly tumor cells—the glycolytic pathway is known to dominate. Ma et al. (2020) demonstrated that TAO OFs similarly exhibit enhanced glycolysis. Their experiments revealed that the PDK inhibitor dichloroacetic acid (DCA) suppresses TAO OF proliferation, reduces lactate production, and increases oxygen consumption. Furthermore, knockdown of PDK2—overexpressed in TAO OFs—replicated these effects, confirming its role in driving glycolytic activity. Enhanced glycolysis promotes cell proliferation, and proliferating cells may leverage this metabolic shift to bolster antioxidant defenses, thereby mitigating oxidative stress. Building on this, Ma et al. (2022) found that switching OFs from OXPHOS to glycolysis reduces reactive oxygen species (ROS) production, which enhances resistance to ferroptosis. Collectively, these findings underscore the pivotal role of glycolysis in TAO pathogenesis, highlighting glycolytic pathway components as potential therapeutic targets. Further research is needed to elucidate the detailed mechanisms by which glycolysis influences ocular disease progression.

Myopia

Myopia is a highly prevalent eye disorder worldwide, with adult prevalence rates reaching 10–30% in many countries. In regions of East and Southeast Asia, prevalence among young populations is strikingly higher, exceeding 80–90% (Modjtahedi et al., 2018). Myopia is characterized by excessive elongation of the ocular axial length (AL) and vitreous chamber depth (VCD), which shifts the focal point of light in front of the retina. This refractive error triggers abnormal visual signaling, prompting the retina to release tonic signaling molecules. These molecules propagate to the choroid and sclera, driving pathological scleral remodeling through aberrant metabolic processes (Baird et al., 2020). Mechanistically, Feng et al. (2024) analyzed retinal tissues in guinea pigs with form-deprivation myopia (FDM) and observed upregulation of key glycolytic rate-limiting enzymes in the FDM group. Specifically, LDH activity and lactate levels were significantly elevated compared to controls. The authors proposed that heightened glycolysis in the retina may meet the energy demands of rapid ocular elongation, while lactate could also mediate protein lactylation modifications. Extending these findings to the sclera, Lin et al. (2024) reported increased glycolysis-related enzymes and lactate in murine sclera, with PKM2 overexpression inducing myopia-like features, including AL elongation and reduced refractive power. Together, these studies suggest that metabolic reprogramming—particularly glycolytic activation—contributes to myopia progression, though deeper investigations are needed to identify clinically translatable therapeutic targets. Supporting this hypothesis, the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) suppressed FDM development in guinea pigs, demonstrating that scleral glycolysis promotes myopia, while its inhibition alleviate the condition. These collective findings underscore glycolysis reprogramming as a critical driver of myopia, offering potential targets for prevention and treatment, while advancing our understanding of its molecular and cellular mechanisms.

Conclusions

In conclusion, our comprehensive analysis underscores the pivotal role of metabolic reprogramming in driving the progression of various ocular diseases, including AMD, RP, DR, UM, glaucoma, DED, TAO, and myopia. Across these conditions, aberrant shifts in metabolic pathways, particularly glycolysis and mitochondrial dysfunction, emerge as key pathogenic drivers, exacerbating tissue damage and inflammation. The interplay between mitochondrial dysfunction, oxidative stress, and inflammation creates a self-perpetuating cycle that destabilizes retinal homeostasis, accelerates fibrosis, and promotes neurodegeneration. Crucially, the metabolic crosstalk between retinal cells—such as photoreceptors, RPE, and Müller glia—highlights the interdependence of energy substrate availability, redox balance, and structural integrity in maintaining visual function. Targeting these metabolic alterations presents a promising therapeutic avenue to mitigate disease progression and preserve vision. For example, lactate plays a key role in metabolic regulation in the retina by activating the GPR81 receptor, promoting the survival of retinal ganglion cells, optimizing the energy metabolism of Müller cells, and reducing lactate release. These effects clearly indicate that the lactate/GPR81 signaling axis may be a potential therapeutic target. Future research should focus on elucidating the intricate molecular mechanisms underlying metabolic reprogramming in ocular diseases, exploring the potential of metabolic modulators as therapeutic agents, and developing personalized strategies to restore metabolic balance in affected tissues. Additionally, cellular metabolism is an interconnected network. In addition to glycolysis, which is the focus of this article, the reprogramming of amino acid metabolism (such as glutamine metabolism) and lipid metabolism (such as fatty acid metabolism) also plays a key role in various physiological and pathological processes and is increasingly attracting attention in the field of ophthalmology. Future research urgently needs to explore the interactions and synergistic/antagonistic effects of these different metabolic pathways in the disease-specific microenvironment of the eye, which will lay the foundation for developing more effective metabolic intervention therapies.

Supplemental Information

Supplemental Information 2. Metabolic reprogramming of RPE (AMD), photoreceptors (RP), microglia/RPE (DR), uveal melanoma (UM), lamina cribrosa (glaucoma), corneal endothelium (DED), orbital fibroblasts (TAO) and retina/sclera (myopia).

Image Creation Software: figdraw

Funding Statement

This study was supported by the Shandong Provincial Key Research and Development Programme (2021LCZX09), the Shandong Provincial Natural Science Foundation (ZR2021LZY045), the Shandong Provincial Medico-Health Science and Technology Project (202307021729), and the Shandong Provincial Traditional Chinese Medicine Science and Technology Project (NO. Q-2023015). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.