Therapeutic potential of curcumin in ophthalmic diseases: mechanisms and clinical applications

Abstract

Ocular diseases impacting both the front and back segments of the eye are major contributors to worldwide vision loss. Curcumin, extracted from the rhizome of Curcuma longa, is a lipophilic polyphenol whose broad pharmacologic profile, including antioxidant, anti-inflammatory, antimutagenic, antimicrobial, and antineoplastic, renders it an attractive prospect for ocular therapeutics. However, much of the existing research primarily focuses on the general mechanisms of curcumin in the human body, with a lack of comprehensive reviews specifically addressing its mechanisms in ophthalmic diseases. Therefore, this review aims to explore curcumin’s therapeutic potential in ophthalmic disorders and examine its mechanisms of action in terms of its anti-inflammatory, antioxidant, anti-angiogenic, neuroprotective roles, and antibacterial effects. The influence of curcumin on a range of ocular diseases, including age-related macular degeneration, diabetic retinopathy, glaucoma, cataracts, dry eye disease, pterygium, and uveitis, was also discussed. An analysis of preclinical and clinical studies conducted over the past 5 years suggested that curcumin holds promise as a therapeutic agent for various eye disorders. Furthermore, the review addressed the challenges faced in the clinical translation of curcumin in ophthalmology, such as issues related to dosage, formulation, and long-term safety. Despite curcumin’s promising efficacy in preclinical models, several hurdles remain in its clinical application, highlighting the need for further research to facilitate its broader use in ophthalmic treatment.

Introduction

Ophthalmic diseases, such as cataracts, diabetic retinopathy (DR), glaucoma, age-related macular degeneration (AMD), and uveitis, are primary causes of vision impairment and blindness around the world [1, 2]. Despite the progress in pharmacological and surgical treatments [3, 4], many of these disorders remain difficult to manage due to their complex pathophysiology, which often involves oxidative stress, chronic inflammation, and abnormal angiogenesis [5]. Consequently, there is an increasing interest in exploring natural compounds with multi-target therapeutic potential that could complement and enhance existing treatment options.

Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione], a polyphenol derived from the rhizomes of C. longa (turmeric), has been a cornerstone of Ayurvedic and traditional Chinese medicine for centuries in the treatment of inflammatory disorders [6]. As the most extensively studied of the three primary curcuminoids (including demethoxycurcumin and bisdemethoxycurcumin) [7], curcumin exhibits diverse pharmacological properties, such as potent anti-inflammatory, anti-angiogenic, antioxidant, and neuroprotective effects [8–10]. Extensive preclinical research has shown curcumin’s potential in addressing the pathological mechanisms underlying various ocular diseases, including inhibiting vascular endothelial growth factor (VEGF) in DR [11], reducing oxidative damage in cataracts, and protecting retinal ganglion cells in glaucoma [12]. Furthermore, curcumin’s ability to modulate key signaling pathways, such as nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), and mitogen-activated protein kinase (MAPK) [13], suggests a promising role in ocular therapeutics.

This review aims to comprehensively evaluate the mechanisms through which curcumin exerts its beneficial effects in various ophthalmic diseases, evaluates preclinical and clinical evidence supporting its use, and discusses future perspectives for its integration into ocular therapy. By synthesizing current knowledge, this paper aims to highlight curcumin’s potential as a complementary or adjunctive treatment for eye disorders, while addressing existing challenges in its clinical application.

Mechanisms of action in ophthalmic diseases

Anti-inflammatory effects

During the inflammatory process, a variety of inflammatory mediators are produced by immune cells, including macrophages, dendritic cells, and T lymphocytes [14]. Among these mediators, pro-inflammatory cytokines play crucial roles in immune responses, with major representatives being tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-6, IL-12, IL-8, as well as monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) [15, 16]. These cytokines can activate inflammatory signaling cascades in a positive feedback loop. The janus kinase/signal transducer and activator of transcription (JAK/STAT), NF-κB, and MAPK pathways, which are critical for the inflammatory response in immune cells, play particularly significant roles in diseases such as DR, macular edema, and glaucoma [17]. Recent studies have increasingly explored curcumin’s potential as an immunomodulatory compound for immune regulation. Extensive preclinical and clinical research has demonstrated its anti-inflammatory effects in multiple inflammatory disorders, including glomerulonephritis, osteoarthritis, rheumatoid arthritis, pancreatitis, ulcerative colitis, and bronchitis [18]. In ophthalmic diseases, Chen et al. [19] reported that curcumin attenuated hyperosmotic stress-induced IL-1β overexpression in corneal epithelial cells by modulating the p38 MAPK, JNK, and NF-κB signaling pathways, suggesting its therapeutic value for dry eye disease (DED) management. Ultraviolet B (UVB) exposure significantly increased IL-6 and IL-8 production and activated both MAPK and NF-κB signaling pathways in limbal epithelial cells. However, curcumin treatment significantly suppressed these UVB-induced inflammatory responses, including cytokine release and pathway activation [20]. Curcumin has been shown to suppress MAP kinases, such as c-Jun N-terminal kinase (JNK), AK strain transforming (Akt), and extracellular signal-regulated kinase (ERK) [21], which phosphorylate IκB for subsequent degradation, thereby preventing NF-κB activation [22]. Lee et al. [23] demonstrated that curcumin treatment led to a decrease in the expression of inflammatory mediators such as IL-6, IL-8, MCP-1, and ICAM-1 at both the mRNA and protein levels in patients with Graves’ orbitopathy. It also suppressed IL-1β–mediated phosphorylation of Erk, Akt, JNK, and NF-κB p65 proteins. In addition to curcumin, both demethoxycurcumin and bisdemethoxycurcumin effectively reduce inflammatory cytokines. According to Kasetsuwan’s [24] study, like curcumin, demethoxycurcumin and bisdemethoxycurcumin also exhibit significant anti-inflammatory effects, reducing levels of proinflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-17 A, matrix metalloproteinase-9 (MMP-9), and ICAM-1 mRNA under hyperosmotic conditions compared to untreated controls. Therefore, the immunomodulatory effects of curcumin arise from its ability to interact with a broad range of immune cells. Additionally, curcumin could reduce the production of pro-inflammatory mediators like MCP-1, ICAM-1, IL-1, and IL-8 by targeting key signaling and transcription factors, including JAKs/STATs, NF-κB, and MAPKs (Fig. 1A).

Fig. 1.

Potential mechanisms of action of curcumin in terms of its anti-inflammatory (A), antioxidant (B), anti-angiogenic (C), neuroprotective (D), and antibacterial (E) roles in ophthalmic diseases

Antioxidant properties

Oxidative stress is a common pathological factor in many ophthalmic diseases [2]. Reactive oxygen species (ROS), such as hydroxyl radicals (OH·), superoxide anions (O₂⁻), and hydrogen peroxide (H₂O₂), induce oxidative damage to essential biomolecules including membrane lipids, functional proteins, and genetic material, ultimately resulting in cellular impairment and apoptosis [2]. Curcumin is a natural antioxidant that has been shown to effectively scavenge ROS through multiple mechanisms. It may modulate antioxidant enzyme activity to neutralize free radicals. Gao et al. [25] demonstrated that curcumin attenuated selenite-induced cataracts by enhancing the activities of glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD), while decreasing intracellular ROS levels. The therapeutic effects were further attributed to its capacity to protect ocular cells from oxidative damage and potentially suppress ROS-generating enzymes like cyclooxygenase-2 (COX-2). The COX-2 pathway catalyzes the oxidation of 5-Hydroxy-eicosatetraenoic acid (S form) (5 S-HETE), a product of 5-lipoxygenase (5-LOX), forming a di-endoperoxide and 5-Hydroxy-prostaglandin H2 (5-OH-PGH2), which is equivalent to prostaglandin H2 (PGH2) in the COX-2 pathway [26]. This process may subsequently trigger the generation of multiple pro-inflammatory factors and ROS. By inhibiting the COX-2 pathway, curcumin can effectively reduce the generation of these harmful substances, thus alleviating oxidative stress and inflammation in ocular tissues [27]. Due to its lipophilic nature, curcumin exhibits free radical-scavenging activity through hydrogen atom donation. This hydrogen-donating property is a key mechanism through which curcumin scavenges ROS and reactive nitrogen species (RNS) [28]. Specifically, curcumin can decrease the activity of inducible nitric oxide synthase (iNOS) in murine macrophages [29]. The iNOS enzyme catalyzes the generation of nitric oxide (NO) during inflammatory responses, and excessive NO production can contribute to oxidative stress and tissue damage [30]. By reducing iNOS activity, curcumin helps to lower the levels of NO and its reactive derivatives, thus mitigating oxidative stress and inflammation [18]. Moreover, curcumin can also modulate the expression of Nrf2, a crucial cellular defense mechanism against oxidative stress [31]. The transcription factor Nrf2 regulates the expression of antioxidant response element (ARE)-dependent genes, including heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), and glutathione S-transferase (GST) [32]. For instance, in an animal model of AMD, curcumin treatment upregulated the Nrf2 pathway in retinal pigment epithelium (RPE), resulting in reduced oxidative stress and improved retinal function [33]. Therefore, by modulating the Nrf2 pathway, curcumin can provide long-term protection against oxidative stress-induced damage in ophthalmic diseases (Fig. 1B).

Anti-angiogenic effects

Abnormal angiogenesis is a hallmark of several ophthalmic diseases, such as AMD, DR, and immune keratitis [34]. VEGF serves as a principal regulator of neovascularization, stimulating endothelial cell proliferation, motility, and viability [35]. Excessive VEGF expression drives pathological angiogenesis characterized by vascular hyperpermeability and hemorrhage, contributing to vision-impairing complications [36]. Curcumin effectively suppresses both VEGF production and signaling through multiple pathways. It can downregulate the transcription of VEGF genes by interfering with the activity of transcription factors like hypoxia-inducible factor-1α (HIF-1α) [27]. Additionally, curcumin can block the VEGF receptor (VEGFR) signaling pathway, preventing the downstream activation of pro-angiogenic cascades [37]. In a mouse model of oxygen-induced retinopathy, administration of curcumolide, a unique sesquiterpenoid derived from curcuma, significantly reduced retinal neovascularization [38]. This was achieved by suppressing VEGF expression, inhibiting VEGFR2-mediated signaling, and blocking key downstream protein kinases of VEGFR2. Kuo et al. [39] demonstrated that hexahydrocurcumin, a compound derived from curcumin through catalytic hydrogenation, can be effectively administered via subconjunctival injection. This approach significantly reduced both basic fibroblast growth factor (bFGF) and VEGF expression in experimental rats, thereby effectively inhibiting gene-induced corneal neovascularization. Thus, the anti-angiogenic effects of curcumin offer a potential therapeutic strategy to prevent and treat angiogenesis-related ophthalmic diseases (Fig. 1C).

Neuroprotective roles

Neurodegenerative ocular diseases, such as glaucoma, optic neuritis, and ischemic retinopathies, involve progressive damage to retinal ganglion cells (RGCs) and other neuronal structures, ultimately leading to irreversible blindness [40]. RGC loss represents a shared pathological manifestation across multiple optic neuropathies, ultimately resulting in progressive visual impairment and potential blindness. Curcumin has exhibited neuroprotective effects on RGCs through multiple mechanisms. For instance, Burugula et al. [41] demonstrated that curcumin attenuated staurosporine-mediated amacrine cell and RGC loss by increasing the expression of NF-κB. In optic nerve crush models, significant loss of RGC, thinning of retinal layers, and optic nerve damage were observed. However, curcumin administration demonstrated effectively counteracted retinal degeneration, preventing alterations in the apoptotic cascade, MAPK, and small ubiquitin-like modifier 1 (SUMO-1) pathways, this therapeutic intervention preserved RGC viability and maintained normal histological architecture by stabilizing critical protein degradation mechanisms [42].

The progressive photoreceptor degeneration characteristic of retinitis pigmentosa has been shown to be ameliorated by curcumin treatment in preclinical rodent studies, with demonstrated neuroprotective outcomes. For example, curcumin treatment significantly reduced retinal degeneration, leading to an improvement in visual function in retinal degeneration 1 mice. Additionally, curcumin inhibited the activation of microglia, as well as the secretion of matrix metalloproteinases and chemokines in the retina [43]. Thus, curcumin as a promising therapeutic candidate for neurodegenerative pathologies including retinitis pigmentosa. Its observed neuroprotective effects appear to be mediated through suppression of microglia-derived oxidative stress. In both BV-2 microglia and a high intraocular pressure animal model, curcumin pre-treatment increased cell viability, while significantly reducing intracellular ROS levels and apoptosis [44]. Therefore, curcumin exerts neuroprotective actions via multiple mechanisms, making it a promising therapeutic agent for these conditions (Fig. 1D).

Antibacterial effects

Curcumin’s antibacterial properties are particularly significant in ophthalmic applications, especially in combating ocular surface infections. Its antimicrobial action results from the synergistic interaction of multiple mechanisms, making it less likely to induce bacterial resistance [45]. As an amphiphilic molecule, curcumin intercalates into the phospholipid bilayer of bacterial cell membranes through hydrophobic interactions, disrupting their structure and increasing membrane permeability. This leads to leakage of crucial intracellular components, such as potassium ions (K⁺), ATP, and nucleic acids, dissipating the proton motive force and ultimately causing bacterial cell death [45]. Studies have shown that curcumin significantly damages the cell membranes of common ocular pathogens like Staphylococcus aureus and Pseudomonas aeruginosa [46]. Biofilms are protective communities of bacteria adhering to surfaces and encased in a self-produced extracellular polymeric matrix, which play a key role in chronic infections and treatment failures [47]. Curcumin effectively inhibits bacterial adhesion and quorum-sensing mechanisms, disrupting biofilm formation in S. aureus and P. aeruginosa isolates [48]. Additionally, curcumin’s redox activity induces excessive ROS accumulation within bacterial cells, further inhibiting bacterial growth or inducing cell death [49]. This multi-targeted antibacterial profile positions curcumin as a promising candidate for treating ocular bacterial infections, especially those caused by drug-resistant strains or biofilm-forming bacteria (Fig. 1E). However, most supporting evidence comes from in vitro studies, with direct experimental and clinical research on ocular infections remaining limited.

Applications in specific ophthalmic disorders

Due to its multi-faceted pharmacological properties, curcumin has shown promise in addressing a variety of ophthalmic conditions, such as AMD, DR, glaucoma, cataracts, DED, pterygium, and uveitis (Fig. 2).

Fig. 2.

Application of curcumin in ophthalmic diseases. This diagram illustrates the application of curcumin in ophthalmic diseases, covering preclinical and clinical studies. Preclinically, oral administration of curcumin is explored using models like rats. Clinically, it involves oral routes and ocular-related interventions

Age-related macular degeneration

AMD ranks among the principal drivers of blindness in the global aging population [50]. As a bioactive compound with potent anti-inflammatory and free radical-scavenging activities, curcumin has emerged as a promising candidate for AMD intervention [51]. Alsoudi et al. [52] suggested that the use of curcumin-based nutritional supplements was associated with a lower incidence of AMD and slower progression to advanced stages. The pathogenesis of AMD involves inflammation, oxidative stress, and degeneration of the RPE [53, 54]. Oxidative stress drives the accumulation of misfolded proteins and aberrant lipids within RPE cells, triggering inflammatory responses and cell apoptosis. Using a hydrogen peroxide-induced AMD model, Zhu et al. [55] demonstrated curcumin’s antioxidant properties through significant reduction of free radicals and modulation of oxidative stress markers including SOD, malondialdehyde (MDA), and glutathione (GSH). These effects correlated with decreased apoptotic activity and improved retinal pigment epithelial cell survival. In experimental models of light-induced retinal degeneration mimicking AMD pathogenesis, curcumin treatment effectively suppressed NF-κB activation and attenuated the expression of pro-inflammatory genes [56]. These findings demonstrated curcumin’s multi-target therapeutic potential in AMD, showing reproducible protective effects across diverse experimental systems. Notably, curcumin administration induces the expression of endogenous cytoprotective factors, including the antioxidant enzyme heme oxygenase-1 [57] and the master regulator Nrf2, which coordinately enhance cellular defense mechanisms against AMD-related pathology [58]. Choroidal neovascularization is a common characteristic in the late stages of AMD, often resulting in rapid vision loss. Curcumin has been shown to prevent pathological choroidal neovascularization by suppressing the activity of HIF-1α [59] and the expression of VEGF [60]. In summary, curcumin demonstrates therapeutic promise for AMD by simultaneously targeting oxidative damage, inflammatory pathways, and abnormal blood vessel growth.

Diabetic retinopathy

Diabetic retinopathy is a severe microvascular complication of diabetes mellitus, whose growing prevalence parallels the global rise in diabetes cases [61]. As a leading cause of preventable blindness worldwide, the pathogenesis of DR involves synergistic oxidative stress and inflammatory pathways, with upregulated mediators including IL-1β, NF-κB, and TNF-α contributing to retinal damage. Experimental studies using diabetic rodent models have consistently revealed curcumin’s multimodal retinal protective effects. Kowluru et al. [62] reported that dietary curcumin supplementation (0.05%) significantly boosted retinal antioxidant defenses while suppressing key inflammatory mediators including NF-κB and IL-1β. Complementary findings by Gupta et al. [63] established curcumin’s vascular protective capacity, demonstrating prevention of endothelial cell degeneration and restoration of capillary basement membrane integrity through coordinated modulation of oxidative stress markers, pro-inflammatory cytokines, and TNF-α signaling pathways. Abnormal angiogenesis, driven by elevated levels of VEGF, is a hallmark of proliferative DR. Curcumin inhibits VEGF expression and signaling [63]. It also reduces the migration of retinal endothelial cells suppressed by stromal cell-derived factor-1 (SDF-1), thereby preventing abnormal neovascularization [11]. These anti-angiogenic effects of curcumin may help reduce retinal neovascularization and associated complications. Curcumin therapy in diabetic rats significantly reduced blood glucose, alleviated oxidative stress, reduced retinal edema, and improved retinal damage. It further improved Nrf2 pathway regulation and inhibited key pathways involved in diabetic retinal damage, such as the advanced glycation end-products (AGEs) - receptor for advanced glycation end-products (RAGE) and the extracellular matrix (ECM)-receptor pathways, outperforming insulin alone [33]. Overall, curcumin can alleviate early diabetic retinal injury and, when used in combination with antihyperglycemic treatments, may enhance therapeutic outcomes in managing diabetic complications.

Glaucoma

Glaucoma, a neurodegenerative disorder responsible for permanent blindness globally, involves progressive optic neuropathy and RGC degeneration [63]. In an ex vivo model of optic nerve injury, significant retinal layer thinning and pronounced apoptosis of RGCs were observed. However, treatment with curcumin effectively prevented changes in the apoptotic cascade and MAPK signaling pathways, thereby maintaining RGC viability and retinal thickness [64]. Buccarello et al. [65] also indicated that curcumin was able to reduce RGC loss in rodent models of optic nerve transection (ONT). The pathogenesis of glaucoma involves elevated intraocular pressure (IOP), oxidative stress, inflammation, and neurodegeneration. Elevated IOP in glaucoma results from dysfunction in aqueous humor outflow mechanisms, particularly through the trabecular meshwork and uveoscleral routes. In a rodent model of elevated IOP, curcumin reduced intracellular ROS levels and mitigated RGC apoptosis triggered by oxidative stress. Specifically, curcumin treatment downregulated pro-apoptotic mediators, such as caspase-3 (CASP3) and Bcl-2-associated X protein (Bax), while simultaneously promoting the anti-apoptotic protein Bcl-2 [44]. Cheng et al. [66] showed that latanoprost-curcumin nanoparticle formulations effectively reduced oxidative stress-induced damage and IOP in trabecular meshwork cells by lowering the expression of inflammation-related genes, mitochondrial ROS production, and apoptosis levels. Inflammation and oxidative stress are key drivers of glaucoma progression. Curcumin reduced mitofusin 2 levels, increased Nrf2 expression, and alleviated retinal ischemia/reperfusion (I/R) injury by modulating the antioxidant system in animal models of open-angle glaucoma [67].

Cataracts

Cataracts, a prevalent eye condition that typically develops slowly and may affect one or both eyes, are marked by lens clouding, leading to vision impairment [68]. Endogenous antioxidants are vital for maintaining antioxidant balance. In hyperglycemia, the interaction between glycated sugar molecules and antioxidant enzymes is thought to cause their inactivation, which contributes to the onset of diabetic complications [69]. In a selenium-induced cataract model, the activities of SOD, CAT, GSH-Px, and GSH were significantly reduced. However, curcumin pretreatment helped restore the normal levels of these antioxidants [70, 71]. Furthermore, curcumin prevented the formation of ROS and reduced lipid peroxidation products, thereby delaying cataract formation. Thus, curcumin could reverse the depletion of antioxidant enzymes, decrease ROS levels. Calcium ion (Ca²⁺) homeostasis is essential for maintaining lens transparency. Curcumin has been shown to decrease Ca²⁺ levels in the lens by enhancing the activity of Ca²⁺ ATPase, thus preventing cataract formation [72]. The eye lens is made up of lens fibers that are densely packed with crystallin proteins, which are categorized into three types: α, β, and γ. These proteins are essential for preserving the lens’s structural integrity. However, lens opacity can occur when these proteins aggregate excessively [73]. Following the onset of diabetes, crystallin protein levels increase, and curcumin administration was found to reduce these levels in the lens [73]. In a separate study using a selenium-induced cataract model, curcumin did not show significant therapeutic effects on cataract formation but exhibited strong preventive properties [74]. Specifically, selenium administration alone caused a notable elevation in both α and β crystallin levels. Curcumin administered simultaneously with or 24 h after selenium exposure had no impact on crystallin levels. But, prophylactic curcumin administration (24 h pre-selenium exposure) maintained physiological levels of both crystallin proteins and Hsp70 protein, demonstrating remarkable protective efficacy. The aldehyde 4-hydroxy-2-trans-nonenal (4-HNE), a byproduct of lipid peroxidation, is known to contribute to cataract formation. Subcutaneous administration of curcumin in animals promotes the production of GST isoenzymes, which help conjugate 4-HNE with glutathione, effectively detoxifying 4-HNE and neutralizing its harmful effects [75]. Similarly, curcumin has been shown to suppress the accumulation of sorbitol, a sugar alcohol that can lead to osmotic stress and cataract formation [76]. Suryanarayana et al. [77] indicated that a 0.002% concentration of curcumin exerted antioxidant and antiglycation effects, increased oxidative stress, promoted AGE formation, and enhanced protein aggregation, thereby delaying the onset and maturation of galactose-induced cataracts in rats. However, at concentrations of 0.01% and above, curcumin appeared to lose its beneficial effects. These findings suggest that the therapeutic benefits of curcumin on cataracts may be concentration-dependent. Preclinical studies have consistently demonstrated its efficacy in various cataract models. Additional rigorous clinical studies are required to establish curcumin’s efficacy and safety profile for cataract treatment in human patients.

Dry eye disease

The DED is a chronic multifactorial disorder of the tears, which is major characterized by chronic inflammation and oxidative stress of the ocular surface, leading to symptoms such as dryness, irritation, and redness [78]. Muz et al. [79] administered a formulation of curcumin, lutein/zeaxanthin, and vitamin D3 orally to a rat model with benzalkonium chloride-induced DED for 4 weeks. The results showed significant improvements in tear breakup time, tear volume, and tear film integrity, along with a reduction in overall inflammation. Additionally, the formulation restored protective tear proteins such as Mucin 1 (MUC1), MUC4, and MUC5AC and alleviated oxidative stress by boosting antioxidant levels. In clinical practice, a once-daily supplement combining lutein, zeaxanthin isomers, curcumin, and vitamin D3 has been shown to enhance tear volume, quality, and stability in patients with DED, while significantly reducing ocular surface inflammation and damage, offering a promising complement to standard artificial tears [80]. The results robustly demonstrated that the synergistic combination of curcumin with complementary agents exerts pleiotropic therapeutic effects in DED, addressing multiple pathophysiological pathways simultaneously. Current clinical applications of curcumin for DED primarily involve oral administration. Kapil et al. [81] also demonstrated that oral bio-enhanced curcumin serves as an effective and safe supplementary therapy for individuals with mild to moderate DED. Their findings revealed that this form of curcumin notably increased tear meniscus height, enhanced tear film stability, boosted tear volume, diminished bulbar redness, and thickened the lipid layer. Benzalkonium chloride exacerbates DED by inducing inflammation, oxidative stress, and cells apoptosis. In contrast, curcumin could ameliorate benzalkonium chloride-induced DED in mice by modulating key pathways and suppressing pro-inflammatory/apoptotic mediators, notably restoring goblet cells, reducing corneal damage, and inhibiting TNFα, IL6, and CASP3 [82]. Collectively, these findings establish curcumin as a pleiotropic therapeutic agent capable of simultaneously modulating the interconnected inflammatory, apoptotic, and oxidative pathways underlying DED pathogenesis.

Pterygium

Pterygium is a fibrovascular tissue that extends onto the cornea, with surgical excision being the primary treatment [83]. However, the high recurrence rate makes this approach controversial. Zhang et al. [84] found that 20 ~ 80 µmol L^–1 curcumin exerted significant anti-proliferative and pro-apoptotic effects on human pterygium fibroblasts in culture in a dose- and time-dependent manner, offering a potential approach to prevent recurrence following pterygium surgery. Lu et al. [85] also shown that treating pterygium cells with 80 µmol L^–1 curcumin for 48 h significantly inhibited cell proliferation by inducing the apoptosis of human pterygium fibroblasts and suppressing VEGF expression. Additionally, aqueous extracts of curcumin could offer a potential solution for preventing corneal scarring following pterygium surgical excision [86]. Chao et al. [20] developed a simple, eco-friendly, and cost-effective method to synthesize curcumin-stabilized silver nanoparticles, creating a formulation suitable for the development of eye drops intended for the in vivo treatment of human pterygium. However, additional in vivo and in vitro studies remain necessary to comprehensively assess the efficacy and safety of this innovative compound. Therefore, curcumin shows promise as a new therapeutic agent for pterygium treatment in the future.

Uveitis

Uveitis encompasses a spectrum of sight-threatening intraocular inflammatory conditions primarily involving the uveal tract, often progressing to permanent vision loss [87]. Given its anti-inflammatory and antioxidant capacities, Curcumin has been widely explored in ophthalmic diseases. In recent years, curcumin-based composites have garnered significant attention in uveitis research for their enhanced therapeutic potential. Cao et al. [88] showed that curcumin conjugated with polyvinylpyrrolidone nanoparticles effectively treated experimental autoimmune uveitis (EAU) by improving retinal vessel perfusion, enhancing tomographic images, and reducing blood-retinal barrier leakage. These benefits likely stem from reducing oxidative stress, preventing apoptosis in hydrogen peroxide-treated human authenticated RPE (ARPE-19) cells, and promoting a shift from M1 to M2 polarization in lipopolysaccharide (LPS)-induced human microglial cells. The Fe-curcumin nanozyme was successfully fabricated through a facile synthesis protocol, forming a stable coordination complex between curcumin molecules and ferric ions, which could decrease the production of ROS and the expression levels of inflammatory mediators including IL-17, TNF-α, and IFN-γ. Moreover, the Fe-curcumin nanozyme effectively suppressed the expansion of both Th1 and Th17 lymphocyte populations [89]. Tang et al. [90] showed that hyaluronic acid-curcumin nanoparticles, via cluster of differentiation 44 (CD44) targeting and Keap1/Nrf2/HO-1 activation, curb oxidative damage, dampen inflammation, and rescue retinal microvasculature in experimental uveitis. Long-term adjunctive treatment with a curcumin-phosphatidylcholine complex (1 tablet daily) in juvenile idiopathic arthritis-associated uveitis patients showed clinically meaningful reductions in low-grade anterior chamber inflammation while maintaining excellent tolerability over 12 months of observation [91]. Allegri et al. [92] reported the effectiveness of the curcumin-phosphatidylcholine complex in treating recurrent anterior uveitis of various etiologies, including autoimmune, herpetic, and other forms of uveitis. In summary, these studies indicate that curcumin-based composites may offer a novel and effective approach for the safe treatment of uveitis.

Clinical studies and trials in the past 5 years

Preclinical studies

Preclinical studies have extensively demonstrated curcumin’s therapeutic potential across various ophthalmic disease models (Table 1). In AMD models, curcumin was shown to activate autophagy [93], while its prodrug, curcumin diethyl disuccinate, proved to be more potent than curcumin itself in counteracting oxidative stress [94]. In addition, the curcumin metabolite, hexahydrocurcumin, exhibited protective effects against blue light-induced RPE damage [95]. In experimental model of DR, curcumin alleviated disease progression by promoting RPE survival, maintaining tight junction integrity, enhancing retinoid isomerase activity, inhibiting RPE senescence, and suppressing neovascularization [96]. Diabetic rats treated with curcumin showed reduced pro-inflammatory cytokines, oxidative stress markers, and VEGF expression in the vitreous microenvironment [97]. Building on these antioxidative and anti-inflammatory themes, nanotechnology-enabled formulations extend curcumin’s reach. Fe-curcumin nanozymes mitigated oxidative injury, cellular senescence, and inflammation by modulating p53-dependent pathways in a neonatal rat model of sodium selenite-induced oxidative-stress cataract [98]. Moreover, curcumin-laden double-headed nanoparticles, in combination with long-acting injectable insulin, significantly slowed diabetic cataract and retinopathy progression in rodent models, improving hepatic function and peripheral glucose control while preventing diabetic ocular complications [99].

Table 1.

Preclinical studies of curcumin in ophthalmic diseases

No	Disease model	Experimental model	Formulation	Key actions and targets	Ref.
1	AMD	RPE cells	Curcumin	Activated autophagy	[86]
2	AMD	authenticated retinal pigment epithelium ARPE-19 cells	Curcumin prodrug curcumin diethyl disuccinate	Reduced oxidative stress	[87]
3	AMD	ARPE-19 human RPE cells and mouse primary RPE cells to blue light	Curcumin metabolite hexahydrocurcumin	Promoted autophagy, reduced oxidative stress and endoplasmic reticulum stress	[88]
4	DR	ARPE-19 cells line	Curcumin	Promoted RPE survival, TJ integrity, retinoid isomerase activity, RPE senescence inhibition, and neovascularization	[89]
5	DR	Spontaneously diabetic torii rats	Curcumin	Alleviated inflammation and oxidative stress	[90]
6	age-related cataracts	Sodium selenite-induced oxidative stress cataract model in neonatal rats	Fe-curcumin nanozymes	Mitigated oxidative injury, cellular senescence, and inflammation by modulating p53-dependent pathways	[91]
7	diabetic cataracts	Diabetes eye disease mice	curcumin-laden double-headed nanoparticles combined with injectable basal insulin	Prevented diabetic cataracts and retinopathy	[92]
8	Posterior capsule opacification	human lens epithelial cell lines	Curcumin	Suppressed TGF-β2-induced malignant changes in lens epithelial cells by targeting KCNQ1OT1/miR-377-3p/COL1A2 axis	[93]
9	Posterior capsule opacification	human lens epithelial cell lines	Curcumin	Protected LECs against TGF-β2-induced enhancement on the proliferation, migration, invasion and EMT process by regulating FGF7/ZEB1 axis	[94]
10	DED	Benzalkonium chloride -induced dry eye disease in mice	Curcumin	Reduced corneal damage, restored goblet cells, and suppressed IL6, TNFα, and CASP3	[75]
11	DED	In vitro cultured keratinocytes derived from human pterygium explants	Curcumin-silver nanoparticle	Decreased viable cells of keratinocytes derived from human pterygium	[95]
12	Uveitis	H2O2-induced human retinal pigment epithelial cell line	Polyvinylpyrrolidone-curcumin nanoparticles	Mitigated oxidative stress and attenuating macrophage/microglia-elicited inflammation	[81]
13	EAU	EAU model rats	Fe-curcumin nanozyme	Inhibit inflammatory reactions and scavenge ROS	[82]
14	EAU	ARPE-19 human RPE cells and EAU mice	Hyaluronic acid-curcumin nanoparticles	Targeted the CD44 receptor and activate the Keap1/Nrf2/HO-1 signaling pathway	[83]

Curcumin’s impact on posterior capsule opacification (PCO), a common complication following cataract surgery, was equally promising. For example, curcumin abolished transforming growth factor beta 2 (TGF-β2)-induced malignant transformation of lens epithelial cells by disrupting the KCNQ1OT1/miR-377-3p/collagen type I alpha 2 chain (COL1A2) signaling axis [100]. Additionally, curcumin protected lens epithelial cells (LECs) from the TGF-β2-induced enhancement of proliferation, migration, invasion, and epithelial-mesenchymal transition [101]. Curcumin ameliorated benzalkonium chloride-induced DED in mice [82]. Additionally, the treatment with curcumin-silver nanoparticles reduced the number of viable cells in keratinocytes derived from human pterygium explants [102]. Polyvinylpyrrolidone-curcumin nanoparticles alleviated the clinical and pathological progression of EAU in rats by reducing oxidative stress and attenuating inflammation induced by macrophages and microglia [88]. Similarly, Fe-curcumin nanozyme as a nanodrug could inhibit inflammatory reactions and scavenge ROS in the treatment of EAU in rats [89]. Moreover, hyaluronic acid-curcumin nanoparticles prevented the progression of EAU by targeting the CD44 receptor and activating the Keap1/Nrf2/HO-1 signaling pathway [93]. These consistent findings across diverse ophthalmic disease models provide strong rationale for the clinical translation of curcumin-based therapies. However, they also highlight the need for improved formulations to enhance ocular penetration and retention, paving the way for more effective treatments in the future.

Human clinical trials

Clinical trials, while still limited in number, are beginning to validate curcumin’s therapeutic potential in eye diseases (Table 2). For instance, a study comparing curcumin-based nutritional supplements with intravitreal injections (IVIs) of anti-VEGF for treating neovascular AMD found the oral curcumin supplement to be a safe and effective alternative [60]. Similarly, curcumin-piperine has been shown to improve oxidative stress and reduce creatinine levels in patients with DR [103]. In cases of non-proliferative DR, a combination of Curcuma longa and Boswellia serrata has helped maintain baseline central macular thickness (CMT) and best-corrected visual acuity (BCVA) over time [104]. Additionally, Oral bio-enhanced curcumin is a safe and effective therapy for mild-to-moderate DED, significantly improving tear-film stability, lipid-layer thickness, and tear meniscus height while alleviating bulbar hyperemia [81]. Adjunctive therapy with a curcumin-phosphatidylcholine complex, administered as one tablet per day over the course of one year, improved mild chronic anterior chamber flare in patients with juvenile idiopathic arthritis-associated uveitis [91]. In autoimmune uveitis, a phospholipidic-curcumin complex has been shown to reduce both the number and intensity of relapses in patients with HLA-B27-related uveitis [105]. Moreover, a new oral curcumin formulation has demonstrated effectiveness in improving mean BCVA and reducing CMT in patients with acute non-infectious uveitis macular edema [106]. However, most trials to date face common limitations including small sample sizes, short follow-up periods, and variability in formulation quality. The emerging clinical data, while promising, emphasizes the need for larger, well-controlled multicenter trials with standardized preparations.

Table 2.

Clinical trials of curcumin in ophthalmic diseases

No.	Condition	Formulation	Sample size	Key actions and targets	Ref.
1	AMD	Oral administration of a curcumin-based nutritional supplement vehiculated by enterosoma-I®	n = 42 (18 treated/24 controls)	Improved median best-corrected visual acuity and reduced the total number of injections	[53]
2	DR	Curcumin-piperine supplementation	n = 56 (27 treated/29 controls)	increased the activities of CAT and SOD, and decreased the levels of MDA and creatinine	[96]
3	DR	Curcuma Longa and Boswellia Serrata Combination	n = 61 (49 treated/12 controls)	Maintained baseline BCVA and CMT values	[97]
4	DED	oral bio-enhanced curcumin	n = 40	Improved the tear film stability, Lipid Layer Thickness, and Tear Meniscus Height, and reduced the bulbar redness	[98]
5	Juvenile idiopathic arthritis-associated uveitis	oral curcumin-phosphatidylcholine complex	n = 27	Improved mild chronic anterior chamber flare	[84]
6	HLA-B27-associated autoimmune uveitis	oral phospholipidic-curcumin complex	n = 60	Decreased the number and intensity of HLA-B27-related autoimmune uveitis relapses	[99]
7	Acute non-infectious uveitis	oral curcumin formulation	n = 26	Improved in mean BCVA and decreased CMT	[100]

Challenges in clinical translation

Despite the promising preclinical and clinical findings, several challenges remain in translating curcumin-based therapies into widespread clinical use for ophthalmic diseases. While curcumin has demonstrated therapeutic potential in a variety of eye conditions, its low bioavailability and unclear mechanisms of action hinder its widespread application. Traditional curcumin formulations often face issues with poor ocular penetration and retention, which can reduce their effectiveness. The development of novel formulations, such as nanoformulations and curcumin complexes, has shown promise in overcoming these barriers [28, 90, 98, 99, 102], but the ideal concentration and delivery system for sustained ocular exposure remain unclear. Rodent experiments rarely exceed a few weeks or months, whereas the longest human follow-up to date extends only to 12 months [105, 106]. Although short-duration studies report encouraging efficacy and only mild, transient adverse events, robust evidence on chronic exposure is still missing, especially for lifelong or decades-long ocular diseases.

In conclusion, while curcumin-based therapies for ophthalmic diseases are still in their early stages, the potential for these treatments is vast. The development of advanced drug delivery systems, exploration of synergistic effects with other therapies, and the need for large-scale clinical trials are key areas for future research. By addressing the challenges of formulation, dosage, and long-term safety, curcumin could emerge as a valuable therapeutic option in the management of various eye diseases, offering patients a safe, effective, and non-invasive alternative to traditional treatments.

Novel drug delivery systems for ophthalmic applications

Despite its significant therapeutic potential, the clinical application of curcumin in ophthalmology is limited by its physicochemical properties, including its predominant keto-enol form in polar solvents, high hydrophobicity, low chemical stability, and poor bioavailability [28]. However, advanced drug delivery systems are designed to overcome these barriers by enhancing solubility, improving corneal permeability, prolonging ocular residence time, and enabling targeted delivery, thereby maximizing the therapeutic efficacy of curcumin.

Nanoformulations encapsulate curcumin within nanoscale carriers, effectively increasing its solubility and leveraging the small size of nanoparticles to enhance tissue penetration [107]. Nanostructured lipid carriers (NLCs), a second-generation lipid-based nanoparticle system, offer enhanced drug loading capacity, improved solubility, stability, controlled release, and superior permeation properties, making them promising vehicles for ocular drug delivery [108]. For instance, Nirbhavane et al. [109] developed NLCs encapsulating curcumin, naringenin, and alpha-lactalbumin for sustained and targeted ocular delivery in DR management. The optimized formulation, delivered as a topical eye drop, significantly reduced vitreous VEGF levels and restored normal retinal morphology in diabetic rats after 4 weeks of treatment. Lakhani et al. [110] also formulated, optimized, and evaluated curcumin-loaded NLCs, demonstrating enhanced drug permeation across the corneal barrier while maintaining safety. The polyvinylpyrrolidone (PVP)-curcumin nanoparticles, a type of conjugate composed of the hydrophilic polymer PVP and natural curcumin, were reported to relieve clinical and pathological progression, improved perfusion and tomographic manifestations of retinal vessels, and reduced blood–retinal barrier leakage in EAU rats, possibly through the mitigation of oxidative stress and attenuation of macrophage/microglia-elicited inflammation [88] Hydrogels offer a strategic solution for enhancing the ocular residence time of curcumin. Engineered to adhere to the mucin layer of the cornea and conjunctiva, these formulations resist rapid clearance caused by tear flow and blinking, thereby sustaining drug availability at the ocular surface [111]. For example, a lignin-based hydrogel, which has been shown to effectively deliver bioactive compounds such as curcumin, naringenin, and α-lactalbumin directly to the retina, targeting key pathological mechanisms of DR and exhibiting significant anti-inflammatory effects in experimental models [112]. This approach is particularly beneficial for treating chronic anterior segment diseases, where extended drug exposure is essential.

In conclusion, the clinical translation of curcumin in ophthalmology is no longer hindered by its physicochemical properties, thanks to innovative drug delivery technologies. These formulations not only enhance curcumin’s therapeutic potential but also pave the way for more effective and sustained treatments for various ocular conditions.

Conclusion

Curcumin, a natural polyphenol derived from the turmeric plant, has demonstrated significant therapeutic potential in the field of ophthalmology, particularly in treating various eye diseases, including AMD, DR, glaucoma, cataracts, DED, pterygium, and uveitis. Its antioxidant, anti-inflammatory, anti-angiogenic, and antibacterial properties have been well-documented in preclinical studies, where it has shown to mitigate disease progression, reduce oxidative stress, and protect retinal and lens cells. Although novel formulations, such as nanoformulations and curcumin complexes, have significantly improved its bioavailability and ocular penetration, enhancing its clinical relevance. However, challenges related to formulation, dosage optimization, and long-term safety remain. Future research should not only focus on refining delivery systems for curcumin but also expand to include its natural analogs, demethoxycurcumin and bisdemethoxycurcumin. A critical direction will be the comparative evaluation of the relative potency, bioavailability, and specific mechanisms of demethoxycurcumin and bisdemethoxycurcumin against curcumin. Such studies may reveal whether these analogs, individually or in combination, offer superior efficacy or more favorable pharmacokinetic profiles, potentially leading to more effective and targeted ophthalmic therapies. With continued progress in these areas, curcumin could emerge as a valuable addition to the ophthalmic therapeutic arsenal, offering a safe, effective, and non-invasive treatment alternative for patients.

Abbreviations

4-HNE

4-Hydroxy-2-trans-nonenal

5-LOX

5-Lipoxygenase

5-OH-PGH2

5-Hydroxy-prostaglandin H2

5S-HETE

5-Hydroxy-eicosatetraenoic acid

AGEs

Advanced glycation end-products

Akt

AK strain transforming

AMD

Age-related macular degeneration

ARE

Antioxidant response element

ARPE-19

Adult retinal pigment epithelium 19

Bax

Bcl-2-associated X protein

bFGF

Basic fibroblast growth facto

Ca²⁺

Calcium ion

CASP3

Caspase-3

CAT

Catalase

CD44

Cluster of differentiation 44

CMT

Central macular thickness

COL1A2

Collagen type I alpha 2 chain

COX-2

Cyclooxygenase-2

DED

Dry eye disease

DR

Diabetic retinopathy

EAU

Experimental autoimmune uveitis

ECM

Extracellular matrix

ERK

Extracellular signal-regulated kinase

GSH

Glutathione

GSH-Px

Glutathione peroxidase

GST

Glutathione S-transferase

H₂O₂

Hydrogen peroxide

HIF-1α

Hypoxia-inducible factor-1α

HO-1

Heme oxygenase-1

I/R

Ischemia/Reperfusion

ICAM-1

Intercellular adhesion molecule-1

IFN- γ

Interferon- γ

IL-1β

Interleukin-1β

iNOS

Inducible nitric oxide synthase

IOP

Intraocular pressure

IVIs

Intravitreal injections

JAK/STAT

Janus kinase/Signal transducer and activator of transcription

JNK

c-Jun N-terminal kinase

LECs

lens epithelial cells

LPS

lipopolysaccharide

MAPK

Mitogen-activated protein kinase

MCP-1

Monocyte chemoattractant protein-1

MDA

Malondialdehyde

MMP-9

Matrix metalloproteinase-9

MUC1

Mucin 1

NF-κB

Nuclear factor-κB

NO

Nitric oxide

NQO1

NAD(P)H quinone dehydrogenase 1

Nrf2

Nuclear factor erythroid 2-related factor 2

O₂⁻

Superoxide anions

OH

Hydroxyl radicals

ONT

Optic nerve transection

PCO

Posterior capsule opacification

PGH2

Prostaglandin H2

RAGE

Receptor for advanced glycation end-products

RGCs

Retinal ganglion cells

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

RPE

Retinal pigment epithelium

SDF-1

Stromal cell-derived factor-1

SOD

Superoxide dismutase

SUMO-1

Small ubiquitin-like modifier 1

TGF-β2

Transforming growth factor beta 2

TNF-α

Tumor necrosis factor-α

UVB

Ultraviolet B

VEGF

Vascular endothelial growth factor

VEGFR

VEGF receptor

Author contributions

Kangning Wang and Tian Tian conceived the idea for the work and wrote the original manuscript, revised, edited the manuscript and delivered it. Shizhou Cheng and Goujin Zuo modified and edited the manuscript. Zijian Chen, Xue He, and Yi Xiang participated in the design and revision of the picture and table in attachment. All authors agreed to be accountable for the content of the work and approved the final version for publication.

Funding

No relevant funding was received for this study.

Data availability

All figures and tables are original and are not taken from other publications. Data sharing is not applicable to this article, as no new data were created or analyzed in this study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors agreed to publish this review.

Competing interests

The authors declare no conflict of interest.