Therapeutic potential of integrins in diabetic retinopathy

Abstract

Diabetic retinopathy (DR), a leading cause of visual loss, is the result of microvascular damage induced by prolonged hyperglycemia. Numerous studies have revealed the pivotal role of integrins in the pathogenesis of DR, particularly in key processes such as inflammation, vascular leakage, microthrombus formation, and angiogenesis. Consequently, targeting integrins is considered a promising strategy for the treatment of DR. This review focuses on the function of integrins in DR and their potential as therapeutic targets. It describes the molecular mechanisms through which integrins influence DR progression and summarizes the latest outcomes of integrin antagonist-based therapeutic strategies in clinical studies, evaluating their efficacy and potential challenges, which offer promise as novel treatment options for DR.

Key Words: Diabetic retinopathy; Integrin; Inflammation; Microvascular permeability; Microthrombus formation; Angiogenesis; Integrin inhibitor

Core Tip: Diabetic retinopathy (DR) is a serious and common complication of diabetes mellitus. Prolonged high glucose levels damage microvasculature in the retina and can lead to blindness. Current treatment options are limited, warranting novel therapeutic strategies. Therapies targeting integrins have shown promise. This review outlines the current understanding of the role of integrins in DR and the findings of preclinical studies and clinical trials investigating the potential of various integrin-targeted therapies. Thus, this review paper captures the current state of the field and identifies possible avenues for further study and treatment approaches.

INTRODUCTION

Diabetes mellitus (DM) is a chronic disease that leads to multi-organ damage through a cascade of homeostatic dysfunctions, resulting in macrovascular and microvascular complications. In 2022, approximately 828 million adults worldwide were estimated to have DM, representing a stark increase of 630 million compared to that in 1990[1]. Among this population, an estimated 35% have coexisting diabetic retinopathy (DR)[2]. From 1990 to 2020, the number of patients with vision-threatening DR has soared from 1.4 million to approximately 3.2 million[3]. Projections indicate that the global prevalence and disease burden of DR will continue to increase in the coming decades, with the patient population anticipated to rise from approximately 103 million in 2020 to 130 million in 2030 and potentially 161 million by 2045[4].

In its early stages, DR is typically asymptomatic, causing most patients to present with advanced disease and severe retinal damage, complicating treatment and worsening prognosis. Current DR therapies, including laser photocoagulation, intravitreal corticosteroid injection, and anti-vascular endothelial growth factor (VEGF) therapy, are effective but have notable limitations. Anti-VEGF therapy demonstrates therapeutic effects predominantly in the advanced stages of DR and necessitates frequent intraocular injections, posing infection risks and other potential side effects. Moreover, up to 50% of patients exhibit limited response to anti-VEGF monotherapy[5,6]. Prolonged corticosteroid use can significantly impact the eye, inducing complications such as elevated intraocular pressure and glaucoma[5]. Laser treatment can damage healthy retinal tissue, restrict visual fields, and impair night vision[7].

Elucidating the pathological mechanisms underlying DR has facilitated the development of innovative therapeutic strategies. Among the diverse biomolecules and cellular pathways involved in DR pathogenesis, therapies targeting integrins have shown promise. This class of transmembrane glycoprotein receptors, mediate interactions between cells and the extracellular matrix (ECM) and regulate cell proliferation, differentiation, and migration[8]. DR pathological processes are intricately linked to the aberrant proliferation and migration of vascular endothelial cells, as well as dysregulated neovascularization[9]. Inhibiting integrin activity may slow DR progression and address certain limitations of current treatments, such as altering the route of administration and reducing the need for frequent intraocular injections. This will alleviate patients^’ pain while improving treatment convenience and compliance. Nonetheless, research on this strategy remains in its early stages, and further clinical studies are required to confirm its safety and efficacy. Elucidating the relationship between retinal integrin expression and the pathological alterations that occur in DR, including inflammatory responses, vascular permeability, microthrombus formation, and neovascularization, as well as potential interventional strategies, could provide novel insights for DR treatment.

OVERVIEW OF INTEGRINS

Composition and classification of integrins

Integrins are composed of two distinct subunits, α and β, which form heterodimers through non-covalent interactions. Each subunit consists of extracellular, transmembrane, and intracellular domains. The extracellular region of the α subunit comprises β-propeller, Thigh, Calf-1, and Calf-2 domains. Notably, the α1, α2, α10, α11, αD, αX, αM, and αL subunits contain a I domain inserted between blades two and three of the seven-bladed β-propeller. The extracellular domain of the β subunit is more complex, comprising βI, Hybrid, plexin-semaphorin-integrin, four epidermal growth factor, and β-tail domains (Figure 1). In vertebrates, 18 α subunits and 8 β subunits have been identified, which combine to form 24 different integrins[8,10]. Based on structural similarities and ligand specificity, the integrin receptor family is categorized into the following four classes: (1) Receptors recognizing the Arg-Gly-Asp (RGD) sequence; (2) Laminin receptors; (3) Collagen receptors; and (4) Leukocyte-specific receptors[8].

Figure 1 Schematic illustration of integrin conformations. A: Bent-closed, inactive; B: Extended-closed, transition between inactive and active; integrins are extended but the ligand-binding site is not exposed; C: Extended-open, active; integrins are fully extended and the ligand-binding site is exposed. EGF: Epidermal growth factor; PSI: Plexin-semaphorin-integrin. Created by figdraw.com (Supplementary material).

Integrin signaling

Integrins exist in three conformational states: Bent-closed, where both subunits are folded and maintained in an inactive state by endogenous inhibitory proteins; extended-closed, following inside-out (by the binding of activators to the intracellular domain) or outside-in (by the binding of extracellular ligands) activation to an intermediate state, with extension of the integrin but no exposure of the ligand-binding site; and extended-open, the active state achieved following simultaneous binding of the actin cytoskeleton and extracellular ligands, with full extension and exposure of the ligand-binding site[11,12] (Figure 1). Integrins are crucial for stable cell–ECM adhesion and signal transduction, binding specific ECM ligands and transmitting signals bidirectionally across the membrane[12]. Integrins’ intracellular domains interact with cytoskeletal proteins such as talin, facilitating inside-out signaling and conformational changes. Although integrins lack intrinsic enzymatic activity, they mediate outside-in signaling by activating downstream pathways, including phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/AKT), extracellular signal-regulated kinase (ERK), and mitogen-activated protein kinase. Integrins can therefore function as adhesion molecules and signaling receptors, recruiting intracellular adaptors, cytoskeletal proteins, and signaling molecules to their cytoplasmic domains to achieve signal transduction[12,13].

COMPOSITION AND FUNCTION OF INTEGRINS EXPRESSED IN THE RETINA

The retina is transparent, thin, and composed of ten distinct layers. The integrin subunits α2, α3, α4, α5, and β2 are expressed in most regions of the human retina[8]. The retinal pigment epithelium, which is crucial for maintaining retinal health and visual function, ensures precise alignment of photoreceptor outer segments and the efficient phagocytosis of shed outer segment fragments, processes that are dependent on the specific distribution of integrin αVβ5 on its apical surface[14]. Additionally, integrin β8 is highly expressed in mouse Müller glial cells and retinal ganglion cells; loss of this integrin significantly impairs the normal development of the mouse retinal system[15].

ROLE OF INTEGRINS IN DR

Inflammation

Integrin involvement in inflammatory cell activation: DR is a chronic inflammatory condition, in which integrins are involved in activating inflammatory cells, inducing leukocyte adhesion and aggregation within the bloodstream and monocyte-macrophage infiltration. Leukocytes are rapidly recruited to the inflammation site through interactions with vascular endothelial cells. Integrin antagonists reduce leukocyte recruitment by decreasing the expression of integrins in their active form, disrupting leukocyte–endothelial cell adhesion, and transendothelial migration[16]. In DR, chronic inflammatory responses exacerbate retinal microvascular damage. Damaged tissues release signaling molecules, such as cytokines and chemokines, prompting endothelial cell activation. Upon receiving chemotactic signals, leukocytes adhere loosely and roll along the vessel wall via selectins. Chemokines on the endothelial surface activate leukocytes, leading to integrin activation and firm adhesion between leukocytes and endothelial cells. Subsequently, leukocytes change shape and migrate through the endothelial layer into the damaged tissue, a process mediated by complex interactions between leukocytes and endothelial cells[17]. Endothelial cells express various adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1 or CD106) and intercellular adhesion molecule-1 (ICAM-1 or CD54), to facilitate interactions with leukocytes. Activated leukocyte surface integrins strongly adhere to these ligands, ultimately allowing transendothelial migration into inflammatory tissues. For example, the binding of integrin αLβ2 to ICAM-1 enhances the adhesion of neutrophils to the vascular wall, whereas the interactions between α4β1 and the RGD-binding integrin αVβ3 with VCAM-1 enable lymphocytes to rapidly migrate across the endothelium into sites of inflammation[17,18]. Cysteine-rich 61, a pro-angiogenic factor elevated in DR[19], induces monocyte chemoattractant protein-1 (MCP-1) expression through the combined action of integrin αVβ3, focal adhesion kinase (FAK), and the PI3K/AKT and IκB kinase/nuclear factor (NF)-κB signaling pathways, promoting macrophage infiltration[20].

Interactions between integrins and inflammatory factors: The levels of various inflammatory factors, including but not limited to IL-1β, tumor necrosis factor (TNF)-α, MCP-1, and transforming growth factor (TGF)-β1, are elevated in the ocular fluid of patients with DR. These factors interact with integrins to modulate a range of inflammatory processes[21].

Integrin αVβ3 influences macrophage functions by activating signaling pathways such as PI3K/AKT, protein kinase C, and ERK. Activation of integrin αVβ3 enhances NF-κB activity, promoting the expression of pro-inflammatory genes and the production of inflammatory mediators like TNF-α. Signaling pathway regulation can therefore alter macrophage responses, providing potential strategies for the treatment of inflammatory diseases[22]. MCP-1, also known as CCL2, is found at higher levels in the vitreous humor than in the serum of patients with DR, indicating local ocular expression[23]. MCP-1 activates β1 integrin, thereby promoting the adhesion of THP-1 monocyte-like cells, primarily through the ERK signaling pathway. Inhibition of the upstream MEK pathway can suppress this effect[24].

TGF-β is a multifaceted growth factor that is pivotal in development and immunity under physiological conditions. The gene products of TGF-β encompass TGF-β1, -β2, and -β3 and exist in a latent form known as latency-associated peptide (LAP)-TGF-β. TGF-β is expressed in various cells, including macrophages, dendritic cells, and lymphocytes. Notably, the LAP of TGF-β1 and TGF-β3 contains integrin-binding motifs RGDLXXL/I, enabling them to bind to integrins αVβ6 and αVβ8. Through autocrine or paracrine signaling, these bound TGF-β isoforms regulate cell proliferation, differentiation, and activation. They also modulate the expression of adhesion molecules, facilitating the chemotaxis of associated inflammatory cells[25,26]. Gerhardinger et al[27] demonstrated the significance of the TGF-β signaling pathway in a rat model of DR, revealing significant activation of the TGF-β pathway and the differential expression of 20 TGF-β-related genes. This was associated with oxidative stress, inflammation, vascular remodeling, and apoptosis in retinal vessels. Moreover, aldose reductase inhibitors such as sorbitol and aspirin effectively inhibit TGF-β pathway upregulation, indicating their potential value in DR prevention and treatment.

Microvascular permeability

VEGF plays a key role in regulating angiogenesis, exhibiting potent vasodilatory effects, and enhancing vascular permeability after binding to two tyrosine kinase receptors: VEGF receptor (VEGFR)1 and VEGFR2[28]. AXT-107 is a collagen IV-derived peptide capable of binding αVβ3 and α5β1 integrins. In human retinal endothelial cells, AXT-107 inhibits integrin β3 by interfering with the co-clustering of VEGFR-2 and β3 integrin while simultaneously reducing the overall level of VEGFR2 through increased internalization, ubiquitination, and degradation. VEGF-induced vascular leakage was reduced by 86%, one month after injection of AXT-107 into rabbit eyes[29] (Table 1). Consequently, decreasing the activity of integrin β3 may reduce pathological vascular leakage.

Table 1 Summary of integrin antagonists presented in the text.

Drug name	Target integrin receptor(s)	Stage of research	Route of administration	Effect	Ref.
AXT-107	αVβ3, α5β1	Clinical research	Intravitreal injection	Reduces leakage, neovascularization and inflammation	[29,73]
JNJ-26076713	αVβ3, αVβ5	Preclinical research	/	Reduces leakage, neovascularization and inflammation	[32]
ATN-161	α5β1	Preclinical research	/	Reduces leakage, neovascularization and inflammation	[41]
Risuteganib	αVβ3, αVβ5, α5β1, αMβ2	Clinical research	Intravitreal injection	Reduces leakage, inflammation and angiogenesis, improves mitochondrial function	[5,56,57]
THR-687	αVβ3, αVβ5, α5β1	Clinical research	Intravitreal injection	Reduces leakage and fibrosis	[58-60]
SF-0166	αVβ3, αVβ6, αVβ8	Clinical research	Topical drop	Inhibits neovascularization, decreases lesion area and reduces leakage	[61,62,74]
OTT166	αVβ3, αVβ6, αVβ8	Clinical research	Topical drop	Reduces inflammation, fibrosis, leakage, and neovascularization	[63,75]
RUC-4	αIIbβ3	Clinical research	Subcutaneous injection	Inhibits thrombus formation	[71,72,76]

Angiopoietin-like proteins (ANGPTLs) regulate angiogenesis and share similarities with angiopoietins. Among them, angiopoietin-like protein 4 (ANGPTL4) reduces hypoxia-induced vascular permeability, suggesting its potential therapeutic value in preventing or treating hypoxia-related diseases such as DR. Co-administration of ANGPTL4 with a blocking antibody against αVβ3 integrin abolishes this effect, indicating that ANGPTL4 exerts its protective actions by interacting with αVβ3 integrin. Mechanistically, its binding to integrin αVβ3 enhances Src kinase recruitment, inhibiting downstream VEGFR2 signaling; this stabilizes blood vessels, increases tight junction integrity, and resists hypoxia-induced increases in vascular permeability[30]. Therefore, novel drugs targeting VEGFR2 signaling can reduce vascular permeability by increasing ANGPTL4 Levels or modulating its interaction with integrin αVβ3, improving therapeutic outcomes.

In studies on sepsis and acute lung injury, integrin αVβ3 inhibition or knockout increases vascular leakage[31]. However, administering the integrin αV antagonist JNJ-26076713 to rats with DM significantly inhibits retinal vascular permeability[32] (Table 1). These contradictory findings may be due to differences in models or mechanisms, requiring further research on integrin targeting therapies.

Pericyte loss is a hallmark of early-stage DR[33]. Pericytes provide structural support to capillaries, and their loss leads to localized capillary wall leakage. Both in vitro and in vivo studies have shown that high glucose levels induce pericyte apoptosis[34,35]. ANGPT2 expression level is upregulated in patients with DR[36]. Park et al[37] confirmed that, in mice with STZ-induced DM, ANGPT2 induces pericyte apoptosis via the p53 pathway under high-glucose conditions, mediated by binding to integrin α3β1. This involves phosphorylation of p53 at Ser-15 through the ERK1/2 pathway, which does not induce apoptosis under normoglycemic conditions. Therefore, controlling blood glucose levels or blocking ANGPT2/integrin signaling may prevent early DR pericyte loss. Elevated ANGPT levels can also induce retinal leakage and astrocyte loss in diabetic mice. In a hyperglycemic environment, ANGPT2 triggers astrocyte apoptosis via the integrin αVβ5/GSK-3β/β-catenin signaling cascade. Notably, inhibition of integrin αVβ5 substantially mitigates apoptosis and vascular leakage[38]. Furthermore, ANGPT2 mediates endothelial cell layer destabilization by activating integrin α5β1, leading to increased vascular leakage[39]. Administering an integrin β1 antibody under inflammatory conditions can improve endothelial cell junction integrity, thereby reducing vascular permeability[40]. Additionally, the integrin α5β1 inhibitor ATN-161 can inhibit NLRP3 inflammasome signaling in the mouse retina, reducing VEGF-induced vascular leakage[41] (Table 1). These findings suggest potential therapeutic strategies and targets for DR.

Prothrombotic state and microthrombosis

In patients with DM, metabolic disorders disrupt their physiological balance, resulting in a prothrombotic state characterized by platelet hypersensitivity[42]. Integrin αIIbβ3, the principal surface receptor for platelet adhesion to the ECM, mediates platelet aggregation by binding plasma fibrinogen. Under normal conditions, a complex positive feedback loop is maintained, with nitric oxide and prostaglandin I2 counteracting platelet activation and aggregation mediated by plasma thrombin, platelet-derived growth factor, and adenosine diphosphate. However, type 2 DM disrupts this balance; in vivo, platelet aggregation increases under insulin resistance, suggesting that platelets are less responsive to nitric oxide and prostaglandin I2[43]. Consequently, patients with type 2 DM may be at increased risk of thrombosis[42,44].

Platelets from patients with DR exhibit heightened sensitivity to low concentrations of adenosine diphosphate and an increased propensity to aggregate in vitro[45]. If this is reflected in vivo, microthrombosis and vascular obstruction may occur. DR pathological changes include retinal microvascular occlusion, which may result from luminal narrowing caused by endothelial cell proliferation or basement membrane thickening, or from emboli formed by aggregates of platelets, fibrin, and cholesterol[46]. Ju et al[47] established a mouse model of thrombi formation and showed that, compared to the non-diabetic control group mice, diabetic mice exhibited a significant increase in the platelet aggregation rate, aggregation extent, and thrombus area. Pretreatment with an integrin αIIbβ3 antagonist or a PI3K inhibitor suppressed platelet aggregation, whereas pretreatment with the conventional antiplatelet drugs aspirin and clopidogrel did not. This demonstrates the complexity of managing the clinical risk of thrombus formation in patients with DM.

The activation of integrins αVβ3 and αIIbβ3 can be mediated through the allosteric binding of inflammatory chemokines such as CCL5, CX3CL1, and CXCL12, through a mechanism independent of the classical inside-out signaling pathway. The binding of these chemokines enhances the affinity of integrins for the ECM, thereby triggering platelet aggregation and potentially thrombosis[48]. Niu et al[49] demonstrated that the Src family kinase inhibitor PP2 and the PI3K inhibitor wortmannin inhibit integrin αIIbβ3 outside-in signaling-induced shape changes and platelet aggregation. A study by Qin et al[50] using a mouse model of DM emphasized the importance of integrin αIIbβ3 in the early stages of thrombosis. Notably, under diabetic conditions, injured endothelial cells release endothelial microparticles containing protein disulfide isomerase, which accelerates platelet activation by binding to integrin αIIbβ3. Inhibiting protein disulfide isomerase mitigates this process, suggesting a potential therapeutic strategy for DM-related thrombotic diseases. Therefore, a deeper understanding of platelet function and the role of integrin αIIbβ3 may improve management of DM.

Angiogenesis

The high metabolic demands of the retina make it particularly susceptible to oxidative stress and metabolic dysregulation, which can initiate pathological neovascularization and tissue damage.

The complexity of angiogenesis is demonstrated by the regulatory role of integrins in the Ras-ERK pathway, with αVβ3 antibody inhibiting basic fibroblast growth factor-mediated Ras activity and c-Raf activation, whereas αVβ5 antibody affected VEGF-mediated Ras activity[51]. Upon VEGF activation, integrin αVβ5 on the cell surface is mobilized, promoting cell proliferation, migration, and invasion of tissues. FAK serves as the first signaling molecule in the integrin-mediated signal transduction system, forming a FAK/Src/αVβ5 complex, which subsequently activates Ras–Raf–ERK step-wise, ultimately promoting cell proliferation through the ERK1/2 pathway[51,52]. In contrast, bFGF activates c-Raf through αVβ3, FAK, and PAK downstream of Ras[51]. Alternatively, research indicates that VEGF activates VEGFR-2, which in turn induces the activation of c-Src and results in the phosphorylation of β3 integrin. Concurrently, the tyrosine phosphorylation of β3 integrin provides feedback to further enhance VEGFR-2 activation. This cross-activation mechanism has opened up novel avenues for anti-angiogenic strategies[53]. The distinct modes of integrin action result in varied cellular responses and angiogenic pathways. In early quail embryo vascular development, treatment with anti-αVβ3 antibodies can block vascular formation[54], and in mice, pharmacological or genetic disruption of β3 integrin inhibits the coverage of retinal vascular smooth muscle cells and arterial maturation[55]. These results underscore the critical role of β3 integrin in vascular maturation and stability, the complexity of the cellular mechanisms behind angiogenesis, and the importance of precise interventions. Understanding the specific roles of integrins and their associated signaling cascades provides avenues for the development of targeted therapies that can more effectively address DR-associated vascular abnormalities.

ANTI-INTEGRIN THERAPIES

Risuteganib is an innovative, vitreous-injected synthetic RGD oligopeptide that primarily inhibits four integrins: αVβ3, αVβ5, α5β1, and αMβ2[5]. The DEL MAR 2b trial (NCT02348918) explored the use of risuteganib as a follow-up therapy after a single anti-VEGF injection in patients with diabetic macular edema (DME)[5]. Compared to anti-VEGF monotherapy, sequential therapy demonstrated comparable efficacy to bevacizumab monotherapy in terms of the primary endpoint and required fewer total injections, with sustained efficacy observed for 12 weeks after the last risuteganib dose. Furthermore, risuteganib exhibited promising efficacy in patients with an inadequate response to anti-VEGF therapy[5,56,57] (Table 1).

THR-687, an innovative integrin receptor antagonist, has the ability to tightly bind to integrins αVβ3, αVβ5, and α5β1 at extremely low nanomolar concentrations, thereby exerting a significant impact on crucial pathological processes such as cell migration and proliferation[58]. In a Phase I clinical trial (NCT03666923) conducted on patients with DME, THR-687 exhibited favorable safety and tolerability profiles across all tested dose levels[58,59]. Following administration, the mean best-corrected visual acuity (BCVA) increased by 7.2 Letters on day 7 after injection, peaking at a mean improvement of 9.2 Letters one month later and sustaining an overall mean BCVA improvement of 8.3 Letters up to three months[58]. Furthermore, data from Part A of a Phase II trial (NCT05063734) for THR-687 in DME underscored the drug’s safety and tolerability. However, despite the encouraging safety profile, evidence of efficacy at key endpoints, namely BCVA and central subfield thickness, remains insufficient[60]. Hence, THR-687, as a novel integrin receptor antagonist, has demonstrated promising safety and potential therapeutic efficacy in treating DME (Table 1).

SF-0166 is a small molecule inhibitor of integrin αVβ3 that also inhibits αVβ6 and αVβ8 in mice. Topical application of SF-0166 can suppress neovascularization, with a reduction in lesion area comparable to that achieved by intravitreal bevacizumab injection; the drug concentration can be maintained for over 12 hours[61]. Given its ability to inhibit neovascularization induced by VEGF and other growth factors, SF-0166 offers advantages over VEGF-only antagonists. A Phase I/II, randomized, double-blind, multicenter clinical trial (NCT02914613) enrolled 40 patients with DME and randomly assigned them to two dose groups (2.5% or 5%). Patients self-administered SF-0166 ophthalmic solution topically twice daily for twenty-eight days. SF-0166 exhibited biological activity in both dose groups, with 53% of patients experiencing reduced retinal thickness and improved visual acuity. In terms of safety, the trial achieved its primary endpoint, with mild ocular adverse events occurring in six patients, one of which may have been related to the drug[62] (Table 1). In summary, SF-0166 has shown promising efficacy in inhibiting neovascularization and reducing retinal lesions in both preclinical and clinical studies. Its safety in patients with DME has also been verified, demonstrating significant biological activity and sustained therapeutic effects, which support further clinical research.

OTT166 is a highly potent and selective small molecule RGD-binding integrin inhibitor targeting integrins αVβ3, αVβ6, and αVβ8[8]. In a multicenter, randomized, double-blind Phase II study of DR: Early Active Management (NCT05409235), enrolled 225 adult patients with moderate to severe non-proliferative DR or mild proliferative DR and mild visual impairment. Patients were randomly assigned to four groups: 5% OTT166 topical eyedrops twice or four times daily via self-administration, placebo eyedrops twice or four times daily via self-administration for 24 weeks. Although OTT166 (5%) demonstrated good safety performance, it failed to show statistically significant improvement in the primary or key secondary efficacy endpoints. Nevertheless, safety remains a notable advantage, providing a foundation for further clinical trials[63] (Table 1).

Platelet integrin αIIbβ3 inhibitors block the final pathway of platelet activation, preventing platelet aggregation[64]. Intracoronary injection of the integrin αIIbβ3 antagonist abciximab, approved for clinical use in 1994[65,66], can significantly reduce the incidence of major cardiovascular events within one year in patients with DM and ST-segment elevation myocardial infarction[67,68]. However, oral integrin αIIbβ3 inhibitors have not been approved due to the increased risk of bleeding and mortality[69,70]. The new integrin αIIbβ3 antagonist, RUC-4, is administered subcutaneously and binds to the metal ion-binding site of integrin β3, blocking its interaction with fibrinogen and preventing conformational changes. RUC-4 has advanced to clinical trials, demonstrating its safety and tolerability in the studied populations. However, the efficacy and safety of RUC-4 in patients with DR remain unexplored, necessitating further clinical studies to ascertain its potential therapeutic benefits within this patient cohort[71,72] (Table 1).

CONCLUSION

DR, a common and complex complication of DM, involves a myriad of interdependent biological processes, exemplified by the multifaceted roles of integrins in DR. This review summarizes the contributions of integrins to the pathogenesis of DR, particularly their roles in inflammation, microvascular permeability, thrombosis, microthrombus formation, and neovascularization. Although we have recognized the role of integrins in promoting DR, their molecular mechanisms require further characterization, especially regarding the crucial role of integrins in diabetic vascular dysfunction. The ability of integrins to act upstream and downstream of the VEGF pathway accounts for why some patients with poor responses to anti-VEGF therapy experience good efficacy with risuteganib[5]. Therefore, risuteganib holds promise as a new option in the treatment of DME, particularly in reducing the number of required injections and improving efficacy in refractory patients. Furthermore, although OTT166 failed to significantly improve the primary endpoint in the overall patient population in a Phase II clinical trial[63], the effect observed in patients with more severe baseline lesions warrants further investigation. Additionally, more precise patient selection must be implemented to assess OTT166 efficacy in these specific patient groups. Optimizing the therapeutic effect of OTT166 can be further achieved by increasing the dosage, extending the treatment duration, or combining it with other treatment methods. Non-invasive treatment options can provide convenient therapy for patients, delaying or reversing DR progression and changing the management approach to DR. Although anti-integrin therapy holds potential for treating DME and DR, its efficacy is variable. For instance, patients who exhibit poor responses to VEGF inhibitors demonstrate better reactions to anti-integrin therapy[5], suggesting that anti-integrin treatment may be more suitable for specific patient populations rather than all patients with DME. Therefore, further research is required to identify which patients are most likely to benefit. Current clinical trials primarily focus on short-term efficacy, whereas the long-term effects and safety of anti-integrin therapy have not been fully evaluated. Considering that integrins participate in various physiological and pathological processes, their inhibitors may affect multiple pathways. Consequently, long-term exposure to integrin inhibitors may produce unknown side effects on the eyes and other organs, necessitating long-term follow-up studies. Moreover, even with fewer injections, intravitreal injection remains a relatively invasive treatment, which may affect patient adherence. Therefore, the development of more convenient and patient-friendly drug administration methods represents an important research direction. Future research should concentrate on elucidating the specific functionalities and underlying mechanisms of integrins at various stages of DR, examining how different integrin subtypes interact and synergize. This will help resolve the associated intricate cellular signaling networks and determine whether improving the hypercoagulable state can be achieved in patients with diabetes when blood glucose levels are adequately managed and controlled. DR treatment remains challenging, yet integrins and their associated signaling pathways offer numerous potential therapeutic targets. Further research on the molecular mechanisms involved should facilitate the development of more precise and effective treatments.