Literature search strategy

A comprehensive and structured literature search was conducted to identify relevant studies examining the role of cholesterol and lipid metabolism in ocular diseases. Electronic databases including Scopus, Web of Science, and Google Scholar were systematically searched for articles published between January 2000 and June 2025. This time frame was selected to capture foundational mechanistic studies as well as recent advances in molecular pathways, clinical associations, and emerging therapies.

Search terms were developed using a combination of Medical Subject Headings (MeSH) and free-text keywords related to cholesterol biology and eye diseases. Core search terms included cholesterol, lipid metabolism, lipoproteins, LDL, HDL, dyslipidemia, mevalonate pathway, SREBP, ABCA1, oxidative stress, and inflammation, combined with ocular-related terms such as AMD, diabetic retinopathy, retinal vascular disease, cataract, and glaucoma. Boolean operators (AND and OR) were applied to refine searches.

Original research articles, clinical studies, systematic reviews, and meta-analyses published in English within the specified period were included. Reference lists of eligible articles were manually screened to identify additional relevant studies, with emphasis placed on recent publications (2018–2025) to ensure contemporary clinical and translational relevance.

General functions of cholesterol

Lipid composition affects membrane characteristics, and cholesterol plays an important role in this process by regulating membrane fluidity and permeability while also inducing the development of coexisting phases and domains in the membrane. Cholesterol molecules are dispersed between the phospholipid bilayer, regulating membrane fluidity and permeability [14]. Furthermore, cholesterol promotes the synthesis of complex membrane microdomains known as lipid rafts, which play important roles in cell signaling and membrane trafficking [11].

Cholesterol not only serves as a molecule of regulation itself but also forms the backbone of all steroid hormones and vitamin D analogs. Cholesterol is also required for the synthesis of steroid hormones such as cortisol, aldosterone, and sex hormones such as progesterone, estrogen, and testosterone [15]. Cholesterol serves as an obligatory precursor for steroid hormone production in steroidogenic tissues, such as the adrenal glands, gonads, placenta, and brain. Regardless of the tissue of origin or the steroid hormone to be produced, steroidogenesis is initiated by the cleavage of the cholesterol side chain to produce pregnenolone. The protein catalyzing this reaction, P-450 side chain cleavage (P450scc/CYP11A1) enzyme, is located in the inner mitochondrial membrane [16]. These hormones are involved in many of the body’s physiological processes, including response to stress, electrolyte balance, and sexual growth and reproduction [15, 16].

Neurosteroids are steroids that are produced in the brain itself. They are multifunctional lipids with effects mediated by ion-gated neurotransmitter receptors rather than typical steroid hormone nuclear receptors. In addition to modulating receptor activation, particular neurosteroids are known to regulate myelination, neuroprotection, and axon and dendritic development. Furthermore, cholesterol acts as a precursor to the production of bile acids, which aid in fat digestion and absorption [17].

Regulation of cholesterol levels

Dietary cholesterol is absorbed by intestinal enterocytes, whereas cholesterol synthesized in the liver can link to lipoproteins to create protein-lipid complexes, which are subsequently released into the bloodstream and transported to cells. In humans, enterocytes excrete roughly 25% of excess cholesterol straight into feces, with the remainder returning to the liver via reverse cholesterol transport (RCT) and excreted as bile. Only a small amount of cholesterol is reabsorbed and returned to the free cholesterol (FC) pool [18]. The mammalian body maintains cholesterol balance using a highly regulated system that ensures homeostasis.

The three-sterol regulatory element-binding proteins, SREBP1a, SREBP1c, and SREBP2, play critical roles in a variety of physiological and pathological processes, including fatty acid synthesis, endoplasmic reticulum (ER) stress, apoptosis, and autophagy, indicating their central role in lipid metabolism and synthesis [19]. SREBP cleavage-activating protein (SCAP), an ER membrane protein, is essential for controlling SREBP activity because it transports SREBPs from the ER to the Golgi apparatus, where proteases cleave SREBP and release its N-terminal domain. Once liberated, this N-terminal domain enters the nucleus and triggers the transcription of important lipogenic genes such as HMG-CoA reductase, HMG-CoA synthase, fatty acid synthase, and glycerol-3-phosphateacyltransferase [20].

SREBP-2 is particularly important among SREBPs because it acts as a liver-specific transcription factor, strictly regulating cholesterol homeostasis by modulating genes involved in cholesterol production and uptake [21]. In contrast, SREBP1c is the major transcription factor responsible for controlling hepatic de novo lipogenesis, particularly in response to insulin signaling. SREBP1c is originally generated as an inactive precursor anchored in the ER membrane; with insulin stimulation, it is proteolytically activated via the ER-to-Golgi trafficking pathway, which is also dependent on SCAP [22]. SCAP acts as a chaperone protein, promoting trafficking and permitting the proteolytic cleavage of SREBP, allowing its active domain to enter the nucleus and regulate lipogenic gene expression. When SCAP is suppressed, the activation process is disturbed, leading to decreased expression of enzymes involved in triglyceride and fatty acid synthesis, and hence reduced de novo lipogenesis [20, 22]. When intracellular cholesterol levels are low, SREBP-2 activates genes that control cholesterol synthesis, absorption, and conversion to bile acids. As cellular cholesterol levels rise, SREBP-2 activity decreases, limiting cholesterol formation and boosting its excretion from the body [23].

HMG-CoA reductase is regulated not just at the transcriptional level but also by post-translational mechanisms. When cholesterol levels in the ER rise, HMG-CoA reductase binds directly to cholesterol and the ER membrane-anchored ubiquitin ligase gp78, causing its destruction. This binding causes polyubiquitination of HMG-CoA reductase, which is then degraded via the 26S proteasome pathway. In contrast, when ER cholesterol levels are low, HMG-CoA reductase turnover is dramatically reduced due to decreased polyubiquitination and limited proteasome destruction [24]. Statins, the most often prescribed type of cholesterol-lowering medications, work by indirectly activating the SREBP regulatory system. They operate by competitively inhibiting HMG-CoA reductase, reducing ER cholesterol levels. This decrease in ER cholesterol induces SCAP-dependent activation of SREBPs, which increases the transcription of target genes involved in cholesterol absorption and synthesis. As a result, LDL receptor (LDLR) expression on the cell surface rises, resulting in better clearance of LDL particles from the circulation [25].

Impact of cholesterol on health

Lipoproteins, made up of unesterified cholesterol, TG, phospholipids, and proteins, circulate in the blood. There are five forms of lipoproteins: chylomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), LDL, and high-density lipoproteins (HDL) [26]. Each has a role in delivering cholesterol and TG to various tissues. Cholesterol is required for optimal cellular function. However, abnormal cholesterol levels are closely associated with cardiovascular disease. LDL, also known as “bad cholesterol”, is a significant contributor to atherosclerosis, coronary artery disease, and stroke. In contrast, HDL or “good cholesterol” is linked to a lower risk of cardiovascular disease. A higher HDL/LDL ratio is thought to be a more reliable indicator of cardiovascular health than TC alone [27] (Figure 1).

Figure 1

Different types of cholesterol and their health implications. The figure delineates the pathways of dietary and endogenous cholesterol through the systemic lipoprotein transport system, highlighting the specific roles and pathological associations of various lipoproteins within the body

Excessive cholesterol, particularly free intracellular cholesterol, may be harmful. It builds up in cell organelles such as the plasma membrane, mitochondria, and ER. High cholesterol levels in macrophages enhance Fas ligand expression on the cell surface, causing mitochondrial death via the pro-apoptotic protein Bax. This promotes plaque instability in atherosclerosis. The cholesterol-induced cell death pathway involves either plasma membrane or ER stress, with the latter causing ER calcium depletion and activation of the unfolded protein response, which promotes cell death [28]. Free cholesterol can also crystallize inside cells, increasing toxicity and causing macrophage death. This mechanism increases the destabilization of atherosclerotic plaques, which can contribute to acute cardiovascular events [29]. Thus, maintaining cholesterol homeostasis is critical for preventing cardiovascular disease.

Cholesterol is an important structural component of cellular membranes, and recent diabetes research has shown that cholesterol levels in adipocytes, skeletal muscle fibers, and pancreatic β cells have a major impact on insulin sensitivity and secretion [30]. As a result, disturbances in cellular cholesterol homeostasis are increasingly thought to have a role in the development of type 2 diabetes (T2D). Recent clinical trials have found that patients with genetic variants that alter cholesterol metabolism are more likely to develop T2D. Furthermore, a series of recent studies in both animal models and human patients have shown that insulin-stimulated glucose uptake is inversely associated with plasma membrane cholesterol level, implying that increased membrane cholesterol reduces insulin action [31].

Cholesterol is essential for hormone synthesis, energy production, and cellular membrane integrity. However, excessive buildup in the body, particularly in organs and the bloodstream, is linked to an elevated risk of a variety of disorders, among them cancer [32]. Research has demonstrated that high cholesterol levels lead to cancer cell malignancy and progression [33, 34]. Mevalonate, a precursor in cholesterol production, increases breast cancer cell proliferation in both in vitro and in vivo studies [35, 36]. Additionally, estrogen receptor-positive breast cancer tissues contain higher levels of 27-hydroxycholesterol, a cholesterol metabolite, than normal tissues [37]. Disruption of cholesterol metabolism and its structural involvement in cell membranes, particularly lipid rafts, is a possible therapeutic target in cancer treatment [38]. Statins and other cholesterol-lowering medications have been studied for their chemoprotective properties. Statins block HMG-CoA reductase, a crucial enzyme in the mevalonate pathway, hence lowering cholesterol synthesis [39]. This inhibition also has an effect on downstream products that are necessary for cell growth and signaling. Although clinical trials have had conflicting outcomes, numerous research highlight statins’ anticancer potential due to their pleiotropic properties. These include decreased protein prenylation, decreased tumor cell proliferation and migration, suppression of Ras signaling, and induction of apoptosis via Akt inactivation and mTOR downregulation [40].

While cholesterol is required for regular cellular processes such as steroid and vitamin D₃ synthesis, its dysregulation has been linked to cancer development [41]. As a result, targeting cholesterol synthesis and metabolism, notably with statins, may provide intriguing pathways for cancer therapy, despite their impact on normal physiological functions.

AMD

Macula, as a highly metabolically demanding tissue, requires a high quantity of cholesterol for optimal function. However, derangement of cholesterol metabolism can potentially lead to adverse effects, such as abnormal lipid deposition and oxidative stress, which play a role in the pathogenesis of several degenerative diseases, including AMD [53]. Various mechanisms have been proposed for the involvement of cholesterol in AMD. Firstly, surplus cholesterol has been implicated in drusen formation, which are extracellular deposits located between Bruch’s membrane and the RPE [54]. Drusen cause disruption of normal cell function and nutrient transport and consequently induce inflammation and oxidative stress in the macula [55]. Secondly, cholesterol impacts the RPE directly, causing it to fail and triggering the formation of cytotoxic metabolites that damage retinal cells. Finally, cholesterol is involved in angiogenesis, the development of pathological new vessels, and its deregulation has been implicated in neovascular AMD, an aggressive variant of the disease [56].

There is growing evidence to support the association between cholesterol and AMD. Epidemiological studies have consistently reported that individuals with high levels of cholesterol, especially LDL cholesterol (“bad” cholesterol), are at greater risk of developing AMD [57]. Furthermore, longitudinal studies have produced evidence of a dose-response gradient for cholesterol and AMD progression and suggest that high levels of cholesterol can worsen the outlook for this disease.

Understanding the role of cholesterol in the pathogenesis of AMD also has important therapeutic implications. Cholesterol-lowering drugs, such as statins, have been used widely in the treatment of cardiovascular disease and may confer additional benefit in reducing the risk of development or progression of AMD. Use of statins has been recently found to have a possible protective effect against AMD, and the drugs may represent a potential future target [58]. However, further research is needed to determine the proper dose and treatment duration. In addition, dietary changes to reduce cholesterol levels, such as following a Mediterranean-type diet rich in fruits, vegetables, whole grains, and healthy fats, have been associated with a decreased risk of AMD.

Retinal vascular diseases

Cholesterol metabolism also plays a role in retinal vascular disorders, including diabetic retinopathy (DR) and retinal vein occlusion (RVO). The aim of this section is to review the relationship between cholesterol and retinal vascular diseases, clarifying the mechanisms, impact, and potential preventive and therapeutic approaches [59].

DR is among the leading causes of blindness worldwide and is associated with high morbidity and mortality in diabetics [60]. Several risk factors that play a fundamental role in the development and progression of DR, including dyslipidemia, particularly elevated cholesterol levels [61]. Chronic hyperglycemia, a feature of diabetes, triggers a cascade of pathophysiological processes, resulting in deranged retinal circulation, oxidative stress, and inflammation [62]. Changes in cholesterol metabolism have been suggested in the pathogenesis of DR [63]. Dyslipidemia, as represented by elevated total cholesterol, LDL cholesterol, and triglyceride levels, has been associated with a high risk of DR progression [64]. The presence of dyslipidemia, particularly hypercholesterolemia, affects the retinal microvasculature.

High cholesterol disrupts endothelial function, vascular permeability, and integrity of the blood-retinal barrier, leading to the development of retinal microaneurysms, hemorrhages, and exudates [65]. Cholesterol can also enhance the generation of oxidative stress with the production of reactive oxygen species (ROS) and subsequent injury to the retinal tissue [66]. Oxidative stress, in turn, triggers inflammatory responses with cytokines and chemokines, which contribute to the development of DR [67]. Pro-inflammatory action mediated via cholesterol can trigger various signaling pathways recruiting and activating immune cells. Inflammatory processes have a central role in the pathogenesis and progression of DR, and cholesterol-mediated inflammation enhances retinal damage and neovascularization [68]. Additionally, dyslipidemia, as caused by hypercholesterolemia, affects retinal endothelial cells, pericytes, and macrophages, leading to retinal neovascularization [69]. Angiogenesis, or new blood vessel formation, is one of the hallmark characteristics of DR. Cholesterol-rich microenvironments promote angiogenesis through multiple molecular mechanisms involving vascular endothelial growth factor (VEGF) and other angiogenic factors. Inhibition of the cholesterol synthesis pathway and regulation of lipid-mediated signaling are promising therapeutic targets for DR [70].

Therapies aiming at cholesterol regulation have also been effective in preclinical and clinical studies. Statins, which are widely used drugs for lowering cholesterol, have also been found to be effective in reducing the risk and development of DR. Novel therapeutic strategies targeting lipid-mediated pathways are also being developed to counteract the harmful effects of cholesterol on the retina [71].

Accumulating evidence shows that the relationship of cholesterol with DR is altered in the presence of other risk factors, such as hypertension, hyperglycemia, and obesity. These risk factors coexist with dyslipidemia and facilitate the development of DR. Clarification of the intricate interaction between cholesterol and these risk factors will culminate in an understanding of the multifactorial etiology of DR and the development of personalized treatment strategies. The relationship between dyslipidemia, especially high cholesterol, and DR is complex and multifactorial. Accumulating evidence suggests that high cholesterol plays a critical role in the pathogenesis and progression of DR, causing microvascular damage, and increasing oxidative stress and inflammation [72]. However, active interventions, including therapeutic interventions of statin therapy and metformin, and lifestyle intervention against dyslipidemia, have been shown to be effective in reducing the risk and severity of DR [73].

RVO is a common vascular retinal disease associated with severe visual loss and blindness [74]. Although hypertension and diabetes are well-proven risk factors, greater importance has been attached to the role of cholesterol in RVO development and progression. Several studies have shown that elevated levels of total cholesterol, LDL cholesterol, and TG are associated with an increased risk of RVO [75]. Cholesterol, particularly LDL, is a cause of atherosclerosis, involving both the large and small vessels. Atherosclerotic changes in the retina cause narrowing of retinal veins, endothelial dysfunction, and thrombosis, especially at the junctions between arteries and veins [76]. These changes are accountable for retinal blood flow impairment and can cause ischemia.

Of the RVO subtypes, branch RVO (BRVO) is the most common and is most frequently associated with systemic vascular risk factors, including high cholesterol levels. BRVO may result from local inflammation, oxidative stress, and thrombogenesis at sites of vascular compression. Central RVO (CRVO), while less common, typically presents with more severe visual impairment and also has been linked to high cholesterol levels [77].

Statins, which are widely used for cholesterol control, have been demonstrated to exert other-than-lipid-lowering effects. Statins improve endothelial function, stabilize atherosclerotic plaques, and reduce inflammation. All these mechanisms might be linked to reduced RVO risk in patients on statins. Clinical trials have shown that the use of statins can improve visual acuity and reduce the risk of recurrence in RVO patients, and therefore it has a possible role in prevention as well as treatment.

Genetic factors are also responsible for susceptibility to RVO in terms of cholesterol metabolism. APOE and LPL gene variants have been found with dyslipidemia and are speculated to have the potential to increase the risk of RVO. Such findings support the idea of individualized RVO management based on genetic profiling and evaluation of risk in individuals. New research is exploring new mechanisms by which cholesterol pathways in the eye are targeted. It has been suggested that the identification of individuals with genetic mutations related to lipid metabolism would provide a rationale for early intervention [78]. This approach might prove beneficial in the prevention of RVO in high-risk individuals.

Cataracts

Cholesterol plays an important role in maintaining the structural stability and transparency of the lens because the lens membrane has the highest cholesterol-to-phospholipid ratio in the human body. This unique lipid structure offers maximal fluidity of the membrane, protein stability, and lens transparency [79]. It is, however, disruptions to cholesterol homeostasis via genetic mutation, systemic hypercholesterolemia, or oxidative damage that make the lens opaque and cause cataract formation [80]. Oxidative stress, in particular, triggers lipid peroxidation, protein aggregation, and crystallin degradation to cause opacification [1]. Defective cholesterol transport mechanisms, including impaired function of ATP-binding cassette (ABC) transporters such as ABCA1, play a crucial role in cataract pathogenesis by dysregulating cholesterol efflux and triggering cell damage to the lens [81].

Hypercholesterolemia and dyslipidemia are increasingly being recognized as systemic risk factors for cataractogenesis. Raised serum cholesterol is associated with increased oxidative damage to the lens, encompassing the production of ROS and alterations in lipid metabolism [82]. This redox environment affects membrane-bound proteins and incapacitates lens epithelial cell function, favoring cortical and nuclear cataractogenesis. In addition, metabolic disorders such as diabetes and metabolic syndrome, which are often associated with dyslipidemia, promote lens damage through advanced glycation end-products (AGEs) and oxidative mechanisms. Clinical research and animal models have shown that lipid-lowering drugs, including statins, in addition to their ability to reduce systemic cholesterol levels, may also be protective against cataract formation, but the long-term effect of these interventions on lens health remains an area of current investigation [83, 84].

Excess cholesterol contributes to cataractogenesis by disrupting lens membrane architecture and protein homeostasis, both of which are essential for maintaining lens transparency. The lens fiber cell membrane is uniquely enriched in cholesterol, and pathological increases further enhance membrane rigidity, reducing fluidity and impairing the function of critical membrane proteins such as aquaporin-0 and connexins that regulate water transport and intercellular communication [1, 2]. These alterations compromise ionic and osmotic balance within the lens, leading to fiber cell swelling and increased light scattering. In addition, cholesterol-rich membrane domains promote the formation of cholesterol crystalline phases, which destabilize membrane organization and interfere with lens fiber cell packing [3]. Oxidative stress further exacerbates this process through the generation of cholesterol oxidation products (oxysterols), which induce ER stress, mitochondrial dysfunction, and apoptotic signaling in lens epithelial cells [4, 5]. Cholesterol-driven changes in lipid raft composition also disrupt protective signaling pathways and accelerate crystallin protein misfolding, aggregation, and insolubilization – hallmark molecular events in age-related nuclear cataract formation [6]. Moreover, excessive cholesterol accumulation increases susceptibility of lens membranes to ultraviolet-induced lipid peroxidation, amplifying oxidative damage and accelerating cataract progression with aging [5, 7].

Recent studies have highlighted the critical role of cholesterol homeostasis in maintaining lens transparency and preventing cataract formation. SREBP2-mediated cholesterol biosynthesis has been identified as a key pathway regulating lens membrane composition and protein stability, with disruption leading to protein aggregation and opacification of the lens [85]. In human cataractous lenses, altered expression of enzymes involved in cholesterol metabolism, such as lanosterol synthase and 7-dehydrocholesterol reductase, has been observed, indicating that impaired local sterol synthesis contributes to age-related lens degeneration [86]. Genetic studies further support this link; variants in HMGCR and other cholesterol-lowering genes are associated with an increased risk of cataract formation, suggesting that lifelong alterations in systemic cholesterol metabolism may influence lens homeostasis and susceptibility to opacification. At the molecular level, cholesterol depletion or imbalance in the lens membrane disrupts lipid rafts and α-crystallin interactions, destabilizing protein conformation and promoting aggregation. Oxidative modifications of cholesterol and other membrane lipids exacerbate these effects by increasing ROS-mediated damage, impairing lens protein repair mechanisms, and ultimately triggering cataractogenesis [87]. Experimental models corroborate these findings, showing that pharmacologic or genetic inhibition of cholesterol biosynthesis in the lens induces cataract formation, emphasizing the necessity of maintaining local cholesterol levels for lens clarity [88].

Additionally, hormonal imbalances – particularly changes in corticosteroids, estrogen, and thyroid hormones – can alter systemic and local cholesterol metabolism, indirectly affecting lens membrane composition and susceptibility to oxidative stress. These hormonal influences may modify the expression of key cholesterol biosynthetic enzymes and antioxidant defense pathways, further contributing to cataract formation in both age-related and secondary cataracts. Collectively, these findings underscore a multifactorial pathophysiological mechanism, where genetic predisposition, disturbed cholesterol metabolism, oxidative damage, and hormonal regulation converge to compromise lens transparency and promote cataractogenesis.

Glaucoma

Cholesterol metabolism has emerged as a critical factor in the pathophysiology of glaucoma, a progressive optic neuropathy characterized by retinal ganglion cell (RGC) loss and optic nerve damage [89]. Cholesterol homeostasis in the retina and optic nerve is tightly regulated to ensure proper neuronal function and membrane integrity. Dysregulation of cholesterol transport and metabolism, mediated by aberrant activity of LDL, HDL, and ATP-binding cassette (ABC) transporters such as ABCA1 and ABCG1, has been implicated in glaucomatous damage [90]. Excess cholesterol accumulation in RGCs and surrounding glial cells promotes oxidative stress, inflammation, and mitochondrial dysfunction, ultimately exacerbating neuronal apoptosis. These findings suggest a complex interplay between lipid metabolism and glaucomatous neurodegeneration.

Epidemiological studies have highlighted an association between systemic dyslipidemia and an increased risk of glaucoma, particularly primary open-angle glaucoma (POAG) [91]. Elevated serum cholesterol levels, alongside altered LDL-to-HDL ratios, have been linked to impaired aqueous humor outflow and elevated intraocular pressure (IOP), a key modifiable risk factor for glaucoma [92]. Cholesterol accumulation in the trabecular meshwork disrupts cellular function and extracellular matrix remodeling, leading to reduced drainage and elevated IOP [93]. Moreover, systemic lipid abnormalities may influence optic nerve head perfusion and vascular health, further contributing to glaucomatous damage. Statins, widely prescribed for hypercholesterolemia, have shown potential neuroprotective effects in glaucoma patients by improving endothelial function, reducing oxidative stress, and modulating lipid metabolism, although their precise role in glaucoma management remains under investigation.

Mevalonate pathway and SREBP-2 regulation

Cholesterol biosynthesis begins with acetyl-CoA, which is converted to mevalonate by the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). The mevalonate route involves multiple intermediates, including squalene and lanosterol, before producing cholesterol and necessary isoprenoids for cellular activity [94]. The transcriptional regulator of this pathway is sterol regulatory element-binding protein 2 (SREBP2). SREBP2 increases the expression of genes such as HMGCR and LDL receptor genes, promoting cholesterol synthesis and absorption. It is first produced as an inactive precursor embedded in the ER membrane. When intracellular cholesterol levels are low, SREBP2 is transferred to the Golgi apparatus and cleaved to release the active domain. This domain then penetrates the nucleus and activates target gene expression [21].

However, under high cholesterol conditions, SREBP2 activation is suppressed through a feedback mechanism involving SCAP and insulin-induced gene (INSIG) proteins. SCAP binds to SREBP2 and, in the presence of sufficient cholesterol, interacts with INSIGs in the ER, anchoring the complex and preventing its transport to the Golgi [95, 96]. This regulatory system maintains cholesterol homeostasis and prevents overproduction. Disruption of the cholesterol manufacturing pathway can cause aberrant cholesterol accumulation in tissues, which contributes to illnesses including AMD. Dysregulation of the mevalonate system, in particular, causes cholesterol deposits in ocular tissues, particularly the RPE and Bruch’s membrane, which promotes the production of drusen, a hallmark of early AMD [57]. Drusen are yellowish-white extracellular deposits seen beneath the RPE. They are made up of lipids, amyloid, complement proteins, crystallins, and other cell detritus. The presence of drusen is one of the first and most distinguishing pathogenic characteristics of AMD. Their size and number are strongly associated with the probability of development of early to severe stages of the disease. Larger and more frequent drusen increases the likelihood of retinal degeneration [97].

Given the importance of cholesterol in drusen formation, the mevalonate pathway, which regulates cholesterol production, is regarded as a key therapeutic target (Figure 2). Statins, which inhibit HMG-CoA reductase (HMGCR) in this pathway, are routinely used to reduce cholesterol levels in cardiovascular and metabolic disorders and have also been investigated as potential AMD therapies. Statins, which reduce intracellular cholesterol synthesis, may help restrict drusen growth and decrease AMD progression, while clinical effects are still being investigated.

Figure 2

Proposed mechanism of cholesterol dysregulation in RPE and drusen formation. The diagram illustrates the biosynthetic and regulatory pathways involving HMGCR and SREBP-2 in the context of AMD pathology

ABCA1/ABCG1-mediated reverse cholesterol transport

Cholesterol efflux from retinal pigment epithelial (RPE) and glial cells is essential for maintaining lipid homeostasis in the retina. This efflux is mediated by ATP-binding cassette (ABC) transporters, including ABCA1 and ABCG1, which promote the transfer of cholesterol to apolipoprotein acceptors such as ApoA1 and HDL [98]. Dysfunction of these transporters, particularly ABCA1, has been associated with pathological cholesterol buildup, oxidative stress, and retinal damage [99]. ABCA1 is widely expressed in organs including the liver, intestines, adipose tissue, and macrophages, where it controls cholesterol and phospholipid efflux as well as cellular signaling [100].

The liver X receptor (LXR), a ligand-activated nuclear receptor that responds to intracellular oxysterols, which accumulate when cholesterol levels are high, regulates transcription of both ABCA1 and ABCG1 [101]. LXR is a critical regulator of the RCT pathway. When activated, LXR forms a heterodimer with the retinoid X receptor (RXR), which binds to certain DNA response regions and promotes transcription of target genes such as ABCA1, ABCG1, SREBP-1c, and ApoE [102]. ABCG1, albeit less explored than ABCA1, is critical in intracellular sterol distribution and export to mature HDL particles [100]. Unlike ABCA1, which enables cholesterol transfer to lipid-poor ApoA1, ABCG1 promotes cholesterol efflux to lipid-rich HDL, which helps to maintain cholesterol balance. ABCG1 is mostly present in intracellular compartments, and its function appears to be cell type specific [103]. ABCG1 dysregulation has been linked to a number of diseases, including atherosclerosis, Alzheimer’s disease, and metabolic disorders [104].

LXR agonists have shown therapeutic promise in preclinical models of retinal degeneration by increasing cholesterol efflux and decreasing inflammation. These medicines increase the expression of ABCA1 and ABCG1, which reduce cholesterol accumulation in RPE cells and modulate inflammatory pathways, including inhibiting NF-κB signaling [105]. LXRα and LXRβ, the two isoforms of LXR, are distributed differently throughout tissues, with LXRβ being more widely expressed. Overall, the LXR-ABCG1 axis is critical in regulating cholesterol levels in the retina and other tissues. Its activation could be a therapeutic target for disorders characterized by lipid imbalance and persistent inflammation [101] (Figure 3).

Figure 3

Regulation of retinal cholesterol homeostasis via liver X receptor (LXR)-ABCA1/ABCG1 signaling. In RPE cells and glial cells, cholesterol efflux is mediated by the ATP-binding cassette transporters ABCA1 and ABCG1. Activation of LXR upregulates ABCA1 expression, thereby enhancing cellular cholesterol efflux to extracellular apolipoprotein acceptors. This process facilitates reverse cholesterol transport and prevents intracellular cholesterol accumulation. Therapeutic LXR agonists may augment this pathway, promoting cholesterol clearance and contributing to the maintenance of retinal lipid homeostasis

VEGF and angiogenic pathways

VEGF is a crucial regulator of angiogenesis, or the development of new blood vessels, and is involved in both normal physiological processes and pathological disorders such cancer, preeclampsia, and ophthalmic disorders. The VEGF family consists of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, placental growth factor (PlGF), and endocrine gland-derived VEGF (EG-VEGF), all of which have a cystine knot structural motif. VEGF proteins form dimers and bind to certain tyrosine kinase receptors (VEGFR-1, VEGFR-2, and VEGFR-3), triggering intracellular signaling cascades that control vascular permeability, endothelial cell migration, and lymphangiogenesis [106].

VEGF’s critical function in pathological angiogenesis is well recognized in AMD and DR, the two primary causes of visual loss. Chronic metabolic stress, such as dysregulated lipid metabolism, oxidative stress, and hypoxia, promotes the overexpression of VEGF, particularly VEGF-A. This causes aberrant neovascularisation, increased vascular permeability, and the collapse of the blood-retinal barrier [107]. In wet AMD, high VEGF causes the development of fragile, leaky blood vessels beneath the retina, resulting in fluid accumulation and vision impairment [108]. Elevated VEGF causes capillary leakage in diabetic macular edema (DME), a consequence of DR, which is exacerbated by the failure of Müller glial cells that usually regulate fluid balance in the retina [109].

The VEGF/VEGFR2 signaling pathway stimulates downstream mediators such as PI3K/Akt and MAPK/ERK, which promote endothelial cell survival, proliferation, and migration [110]. Anti-VEGF treatments, such as ranibizumab and aflibercept, target this system to minimize pathological angiogenesis and vascular leakage in ocular disorders [111]. In contrast, VEGF does not have a direct role in dry AMD, which is characterized by drusen buildup and RPE dysfunction [108]. However, the chronic hypoxic and inflammatory milieu in dry AMD may indirectly upregulate VEGF as a compensatory response to reduced choroidal perfusion [112].

Aside from the eye, VEGF plays an important function in diabetic nephropathy, where chronic hyperglycemia and metabolic stress cause hypoxic conditions in the renal milieu [113]. Hypoxia in the kidney increases VEGF expression in renal cells, particularly mesangial cells and podocytes, as a compensatory reaction to improve oxygen delivery through angiogenesis. However, chronic hypoxia-induced VEGF overexpression breaks the glomerular filtration barrier by increasing vascular permeability, resulting in proteinuria and glomerular injury. The presence of VEGF receptors (VEGFRs) on kidney cells mediates the detrimental effects [114]. This mechanism is similar to the retinal vascular alterations observed in diabetic retinopathy, where hypoxia-induced VEGF overexpression causes aberrant neovascularisation and vascular leakage. Thus, hypoxia is a critical upstream driver for VEGF dysregulation in both diabetic nephropathy and retinopathy, connecting poor oxygen delivery to pathological angiogenesis and vascular dysfunction in diabetes [115] (Figure 4).

Figure 4

Proposed mechanistic pathway linking dysregulated cholesterol metabolism to retinal neovascularization and barrier breakdown via VEGF signaling. Dysregulated cholesterol metabolism induces tissue hypoxia and oxidative stress, leading to activation of vascular endothelial growth factor receptor-2 (VEGFR2). Subsequent stimulation of downstream PI3K/Akt and MAPK/ERK signaling cascades promotes endothelial cell proliferation and migration, contributing to pathological neovascularization and degradation of the blood–retinal barrier. Anti-VEGF therapies, including ranibizumab and aflibercept, act by inhibiting VEGFR2-mediated signaling, thereby attenuating angiogenic responses and vascular permeability

Other pathways

PPAR-α pathway in lipid and vascular homeostasis

Peroxisome proliferator-activated receptor α (PPAR-α) is a nuclear receptor that regulates lipid metabolism and fatty acid oxidation. It is a member of the nuclear hormone receptor superfamily, which includes both classical hormone receptors (e.g., glucocorticoid and thyroid hormone receptors) and metabolic sensors such as PPARs and liver X receptors. PPAR-α is highly expressed in metabolically active tissues with enhanced fatty acid β-oxidation, such as liver, heart, kidney, skeletal muscle, brown adipose tissue, and retina. PPAR-α is found in retinal vascular cells responsible for choroidal neovascularization (CNV) [128]. Clinically, PPAR-α is the primary target of fibrate drugs (including fenofibrate, gemfibrozil, and clofibrate), which are used to lower serum TG and cholesterol [129]. Apart from lipid regulation, PPAR-α activation has been shown to have anti-inflammatory and anti-angiogenic effects, particularly in retinal diseases. Fenofibrate, a PPAR-α agonist, has demonstrated efficacy in reducing retinal inflammation and neovascularization, key features of DR [130]. Clinical trials have shown that fenofibrate can reverse retinal endothelial dysfunction and inhibit VEGFR2 expression, a key mediator in pathological angiogenesis [131, 132]. Varet et al. further confirmed the anti-angiogenic effect of fenofibrate both in vitro and in vivo, highlighting the therapeutic potential of PPAR-α activation in retinal vascular diseases [133].