Интегрин α4β7:: патогенные роли в заболеваниях метаболики и воспаления и в терапии перевода.

Introduction

Integrins are a family of cell surface glycoprotein receptors that play a critical role in cell-matrix and cell-cell adhesion. 1 They are heterodimeric, consisting two non-covalently associated subunits: α (alpha) and β (beta). 2 To date, there are 18 known α subunits and 8 β subunits in humans that can combine to form 24 distinct integrin receptors. 3 Integrin signaling is involved in numerous physiological processes, and its functions are exquisitely regulated both biochemically and mechanically. 4 The regulatory functions of integrins in innate and adaptive immunity, together with their prominent roles in inflammatory responses, are fundamental and central to driving pathological processes and disease progression. The selective recruitment of circulating leukocytes to inflamed tissues represents the initiation and key step of tissue inflammatory responses. Several integrins, including αLβ2, αMβ2, α4β1, and α4β7, are abundantly expressed on leukocytes and govern immune cell trafficking. 5 Activated integrins mediate leukocyte arrest and crawling on the endothelium by binding to intercellular adhesion molecule 1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1). 6 They also disrupt endothelial junctions and act in concert with JAMs and PECAM-1 to promote transendothelial migration—the final step in leukocyte homing. 7–9

The pathogenesis of various inflammatory and metabolic diseases has been linked to dysregulated integrin functions. For instance, integrins αvβ3 and α5β1 bind to extracellular matrix (ECM) ligands, promoting synovial fibroblast and chondrocyte proliferation, driving synovial hyperplasia and bone/cartilage destruction via inflammatory cytokine production in rheumatoid arthritis. 10 In arterial bifurcations and curved regions, endothelial integrin α5 activated by disturbed flow triggers endothelial activation, inflammation, and subsequent atherosclerotic plaque formation. 11 On the vascular basement membrane, integrin α5β1 amplifies endothelial inflammation through fibronectin (FN) interactions, contributing to vascular complications in type 1 diabetes. 12 Integrin α4β1 mediates leukocyte adhesion and migration into inflamed tissues by binding VCAM-1, thereby promoting airway inflammation and endothelial adhesion in asthma. 13 It also contributes to tumor inflammation and growth by recruiting myeloid cells. 14 Integrin αEβ7 promotes T cell retention at intestinal inflammatory sites by mediating adhesion to intestinal epithelial cells via E-cadherin, a mechanism implicated in inflammatory bowel disease (IBD). 15 , 16

Integrin α4β7, composed of α4 and β7 subunits, is expressed on most leukocytes, particularly on homing T and B cells, and also on NK cells, stimulated monocytes, macrophages, and eosinophils. 17 It binds primarily to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), VCAM-1, and FN. 6 , 18 Currently, it is believed that the key biological function of integrin α4β7 is to mediate lymphocyte homing to the gut-associated lymphoid tissue (GALT) and intestinal lamina propria by binding to its main ligand, MAdCAM-1, on gut endothelial cells, facilitating lymphocyte tethering, rolling, and firm adhesion, which is essential for normal intestinal immune surveillance and mucosal immunity. 17 Dysregulated α4β7 function is critically implicated in multiple diseases. For instance, it drives pathological lymphocyte recruitment into the gut, sustains chronic inflammation, and promotes the progression of IBD, including ulcerative colitis (UC) and Crohn’s disease (CD). 19 In HIV pathogenesis, α4β7 acts as a co-receptor that facilitates viral entry into gut-tropic T cells, contributing to early viral dissemination and severe depletion of intestinal CD4⁺ T cells. 20 α4β7 may also promote colorectal cancer metastasis 21 and participate in the pathogenesis of autoimmune diseases including multiple sclerosis 22 and lupus nephritis. 23 Current research on integrin α4β7 primarily focuses on its association with IBD. It is considered a validated therapeutic target for IBD treatment, with numerous reports on the use of α4β7 antagonists, such as vedolizumab. 24 However, there is currently a lack of systematic summaries of its role in other inflammatory and metabolic diseases, as well as elucidations of the mechanisms by which α4β7 contributes to these diseases, including IBD.

This review systematically and comprehensively summarizes the roles and mechanisms of integrin α4β7 in various inflammatory and metabolic diseases, including IBD, cardiovascular diseases, diabetes mellitus, liver diseases, autoimmune diseases, gastrointestinal malignancies, HIV infection, asthma, and graft-versus-host disease. It also reviews the applications or potential values of various α4β7-targeting antibodies in the aforementioned diseases. It is anticipated that this will provide valuable insights for the further exploration of its biological functions and the development of targeted therapies.

Methods

A structured literature search was conducted in PubMed/MEDLINE, Embase, and Web of Science from database inception to December 2025. The search strategy was iteratively refined as the review progressed, with additional keywords incorporated upon identification of relevant associations. Representative search terms are provided below; the list is illustrative rather than exhaustive.

The initial search strategy focused on the integrin receptor and its primary ligands using a combination of Medical Subject Headings (MeSH) and free-text keywords: “integrin alpha4beta7”, “α4β7 integrin”, “LPAM-1”, “MAdCAM-1”, “mucosal addressin cell adhesion molecule 1”, “VCAM-1”, “vascular cell adhesion molecule 1”, and “fibronectin”, combined with broad terms for immunity and inflammation, including but not limited to “inflammation”, “lymphocyte trafficking”, “mucosal immunity”, and “immune homing”.

As initial results revealed associations with a wide spectrum of diseases, we extended the search using disease-specific terms, including “inflammatory bowel disease”, “Crohn’s disease”, “ulcerative colitis”, “cardiovascular diseases”, “diabetes”, “liver diseases”, “autoimmune diseases”, “HIV infections”, “asthma”, “graft-versus-host disease”, “colorectal cancer”, and “gastric cancer”. In parallel, targeted searches were performed for therapeutic agents using terms such as “vedolizumab”, “etrolizumab”, “ontamalimab”, “abrilumab”, “natalizumab”, “carotegrast methyl”, “AJM300”, “PTG-100”, “CDP323” (Zaurategrast), and “integrin antagonist”. Boolean operators (AND, OR) were applied to combine terms within and across domains. To supplement the database searches, we hand-searched the reference lists of retrieved articles and key reviews, and performed forward citation tracking of seminal papers using Web of Science.

Articles were selected for inclusion if they met the following criteria: (1) reported original research, provided mechanistic insights, or described clinical trial outcomes relevant to the structure, function, or pathogenic roles of integrin α4β7; (2) addressed the role of this integrin in the diseases or therapeutic contexts covered in this review; and (3) were published in English. Editorials, conference abstracts, and non-English articles were excluded. Priority was given to high-impact original studies, authoritative reviews, and peer-reviewed clinical trial reports. The final reference list was curated through an iterative, expert-informed synthesis.

Overview of α4β7 Integrin

Structure

α4β7 (also known as LPAM-1) is a transmembrane heterodimeric glycoprotein formed by noncovalent binding of the α4 (CD49d) and β7 (CD107) subunits. 25 Its structure includes a transmembrane segment, an extracellular domain and an intracellular domain. 26 Integrins require ligand binding to manifest their biological activities. They bind to ligands by recognizing specific peptide sequences. The metal ion-dependent adhesion site (MIDAS) site on the β chain plays a pivotal role in the interaction between integrin α4β7 and its ligands, while G190A and Y187A on the α4 chain also significantly influence ligand recognition. 27 Integrin α4β7 contains a long, straight ligand-binding groove (~40 Å long, ~10 Å wide, and ~10 Å deep) at the α4–β7 subunit interface. This unique pocket structure enables it to bind to the immunoglobulin superfamily (IgSF) domain, thereby achieving specific recognition and interaction with the ligand. 28 The α4β7 integrin can present different conformations under different conditions. In the absence of ligands, it is mainly in a closed conformation. When Mn2 + exists, it can be partially open. In addition, it can be differentially activated under different physiological stimuli and stabilized in different intermediate state activation conformations. 29

Ligands

The integrin α4β7 interacts with three ligands: MAdCAM-1, VCAM-1, and FN. These interactions are crucial for leukocyte rolling and firm adhesion. 30

MAdCAM-1

MAdCAM-1 serves as a specific ligand for α4β7 and is predominantly expressed on high endothelial venules of GALT and mucosal lamina propria venules, as well as on venules at sites of chronic inflammation. 31 MAdCAM-1 consists of two immunoglobulin-like domains (D1 and D2), a mucin-like region, and a membrane-proximal region similar to leukocyte function-associated antigen-1 (LFA-1). The CC′ loop in D1 and DE loop in D2 of MAdCAM-1 are critical for binding to integrin α4β7. Asp42 within the CC′ loop coordinates the MIDAS motif in the β7 subunit, which is indispensable for MAdCAM-1 association with both low- and high-affinity forms of α4β7. Functional studies further identified three linear residues of LDT (Leu40-Asp41-Thr42) as the binding motif. Mutation of any one of these residues completely abolished α4β7 binding. 32 Other residues in the CC′ loop primarily contribute to low-affinity binding, whereas the DE loop plays a critical role in stabilizing low-affinity interactions. 33

The affinity states of integrins are dynamically modulated by intracellular signaling and extracellular cues such as divalent cations. 33 Physiological plasma concentrations of Mg 2 ⁺ and Ca 2 ⁺ maintain α4β7 in a low-affinity state, mediating weak interactions with MAdCAM-1 to support lymphocyte rolling on vascular endothelium. 33 , 34 Chemokines including CCL25, CXCL10, and CXCL12 trigger inside-out signaling via distinct kinase pathways to activate α4β7. This drives a conformational shift from a folded to an extended, high-affinity state (experimentally induced by Mn 2 ⁺), enabling stable binding to MAdCAM-1 and firm lymphocyte adhesion. 24 , 29 , 34 The cytoskeletal protein talin directly binds the β subunit to promote ligand binding, while kindlin acts synergistically with talin to stabilize the high-affinity conformation of α4β7. 33 , 35 , 36

MAdCAM-1 also serves as an important ligand for L-selectin, a key molecule mediating lymphocyte entry into the high endothelial venules (HEVs) of peripheral lymph nodes. 36 , 37 The dual ligand activity of MAdCAM-1 toward both α4β7 and L-selectin enables it to act synergistically at distinct stages of the adhesion cascade, establishing a highly efficient platform for lymphocyte recruitment. 6 , 38 , 39

VCAM-1

VCAM-1, one of the key members of the IgSF, is widely expressed on stimulated endothelial cells of blood vessels, peripheral lymph nodes, and bone marrow. 40 The extracellular region of VCAM-1 comprises seven tandem Ig-like domains that form its functional core, with domains 1 and 4, 2 and 5, and 3 and 6 exhibiting high sequence homology. 41 , 42 In addition to the predominant full-length isoform with seven Ig-like domains, a six-domain splice variant lacking domain 4 has also been identified. 42 The most distal domain 1 at the N-terminus is regarded as the primary site for binding to integrin ligands. 41 Extensive studies have confirmed that domain 1 and the subsequent domain 2 are essential for the interaction with α4 integrins, including α4β1 and α4β7. 41 The primary function of VCAM-1 is to regulate the migration of white blood cells from the bloodstream to the inflammatory tissues. Under normal physiological conditions, vascular endothelial cells hardly express VCAM-1. When tissues are infected or damaged, locally released pro-inflammatory cytokines, such as TNF-α, IL-1β, and IFN-γ, act on the endothelial cells, activating downstream signaling pathways such as the NF-κB pathway, and thereby inducing the transcription and expression of the VCAM-1 gene. 42–45

Fibronectin (FN)

FN is a high-molecular-weight glycoprotein synthesized and secreted by fibroblasts, vascular endothelial cells, and hepatocytes. It exists either as a soluble form in the bloodstream (plasma FN) or as an insoluble mesh in tissues (cellular FN). Structurally, each subunit is primarily composed of different types of repeating units: 12 type I repeats, two type II repeats, 15–17 type III repeats, and a variable region (V or IIICS) located between FNIII14 and FNIII15. 46 α4β7 binds to FN primarily by recognizing the LDV (Leucine-Aspartic acid-Valine) sequence located in the alternatively spliced CS-1 region. 47 Additionally, it can interact with a second site containing the KLDAPT sequence within the FN-III5 repeat. 48 Interestingly, studies also show that α4β7 can recognize the common RGD (Arginine-Glycine-Aspartic acid) tripeptide, suggesting the binding sites for these different ligands may be overlapping. 49

FN contains binding domains for integrins (including α9β1, α4β1, α4β7, β3, and β5), fibrin, heparin, heparan sulfate, gelatin, and collagen, which dictate various cellular behaviors. 50 The protein structure of FN includes two alternatively spliced extra domains: extra domain A (EDA) and extra domain B (EDB). In normal adult biological tissues, the expression level of EDA-FN containing EDA is extremely low or undetectable During processes such as embryonic development, tissue injury repair, inflammatory response, and tumor progression, which involve cell remodeling and proliferation, the expression of EDA-FN will significantly increase. 51–53 Through its interaction with the leukocyte integrin α4β7 and MAPK/Erk1/2-dependent signaling, EDA-FN can enhance focal adhesion kinase (FAK) activation, induce fibroblast differentiation, increase alpha-smooth muscle actin (α-SMA) expression, which in turn upregulates cell contractility and ultimately enhances ECM deposition. 54–57 Mouse embryos with knockout of either the EDA or EDB gene alone can survive, whereas those with both genes knocked out die early, demonstrating that EDB has a compensatory effect on EDA’s role in embryonic development. 58 Currently, no direct evidence links EDB to α4β7 integrin structurally or functionally; however, EDB insertion may modulate the local or global conformation of FN, thereby enhancing the accessibility of adjacent integrin-binding motifs for cellular recognition and binding. 58

Key Biological Function and Regulation

Integrin α4β7 is critically involved in mediating the selective homing of lymphocytes to GALT. 24 This process is essential for intestinal immune surveillance, the initiation of mucosal immune responses, and the maintenance of lymphocyte pools within the intestinal microenvironment. In addition to directing lymphocyte trafficking, α4β7 delivers co-stimulatory signals and supports lymphocyte retention and survival in the intestinal mucosa, thereby acting as a central regulator of the gut-immune axis.

Lymphocyte homing depends on the interaction between α4β7 and its ligands, which is facilitated by ion- and cytokine-dependent flow-enhanced adhesion processes and is regulated by a catch-bond mechanism. 34 During inflammation, activated endothelial cells express adhesion molecules and synthesize chemokines that are presented on their luminal surface. 30 Under hemodynamic shear conditions, chemokines are thought to trigger α4β7-mediated adhesion to both VCAM-1 and MAdCAM-1 on mucosal vessels. 59 Notably, this adhesive response is ligand-selective. CC-chemokines (CCL12, CCL25, CCL28) and CXCL12 induce α4β7-dependent lymphocyte arrest on MAdCAM-1 but not on VCAM-1. By contrast, CXCL10, CCL5, and CCL20 enhance adhesion to VCAM-1 while reducing binding to MAdCAM-1. 59 , 60 The cytokine IL‑7 also modulates the α4β7–MAdCAM‑1 interaction; in lymphopenic hosts, elevated IL‑7 signaling activates α4β7 on naive T cells and strengthens their binding to MAdCAM‑1. 61 Excessive homing and infiltration of immune cells into the intestine drive chronic intestinal inflammation by activating proinflammatory cytokines (IL‑6, TNF‑α) and tumor‑promoting transcription factors including p‑STAT3 and NF‑κB. 62

Role and Mechanism of α4β7 in Inflammatory and Metabolic Diseases

Mechanisms of α4β7 in IBD Pathogenesis

IBD, encompassing UC and CD, is characterized by chronic intestinal inflammation driven by dysregulated immune responses. α4β7 plays a pivotal role in IBD pathogenesis by mediating leukocyte trafficking to the gastrointestinal tract. This section comprehensively summarizes the molecular and cellular mechanisms underlying α4β7’s contribution to IBD development, integrating recent advances and highlighting unresolved questions.

Lymphocyte Homing to the Gut

Integrin α4β7 facilitates lymphocyte migration from the bloodstream to the intestinal mucosa by binding to its ligand, MAdCAM-1. Under normal conditions, α4β7 is widely expressed on circulating and mucosal T cells, allowing them to home to the gut by binding to MAdCAM-1 on HEVs in Peyer’s patches (PPs) and mesenteric lymph nodes (MLNs). 17 Typically, α4β7 exists in a low-affinity conformation, enabling transient tethering and rolling of lymphocytes along endothelial cells, which plays a key role in immune surveillance and maintaining GALT. 63 In IBD, pathological stimuli induce a conformational shift of α4β7 to a high-affinity state and upregulate MAdCAM-1 expression on endothelial cells in inflamed intestinal tissues, leading to increased recruitment of α4β7-expressing lymphocytes. 64 Key studies in β7-deficient mice demonstrate that disrupted α4β7-MAdCAM-1 interactions reduce T-cell infiltration into the gut, attenuating experimental colitis. 65 During intestinal inflammation, other adhesion molecules such as α4β1 (binding to VCAM-1) and LFA-1 (binding to ICAM-1) are also upregulated, creating redundancy in lymphocyte recruitment pathways. This redundancy allows lymphocytes to use alternative pathways to enter the inflamed gut, even when α4β7/MAdCAM-1 interactions are blocked. 17

The adhesion of lymphocytes mediated by α4β7 to the intestinal tract plays a central role in the pathological process of IBD and is regulated by multiple factors. The transcription factor leukemia/lymphoma-related factor (LRF) drives integrin β7 expression and intestinal homing in intraepithelial lymphocyte precursors (IELps), and is required for the expression of signature genes in mature IELps. 66 Retinoic acid produced by intestinal dendritic cells (DCs) enhances TGF-β signaling, 67 thereby upregulating α4β7 and CCR9 on T cells to promote intestinal lymphocyte homing. 68 Genetic variations also modulate α4β7 expression or function to affect lymphocyte trafficking. Human genetic studies have identified associations between ITGB7 (encoding β7) polymorphisms and IBD susceptibility, particularly in individuals with severe mucosal inflammation. 69 These variants alter β7 folding or ligand-binding affinity, modulating lymphocyte trafficking efficiency.

T Cell Activation, Differentiation, and Inflammatory Cascade

α4β7 not only mediates lymphocyte adhesion and homing but is also involved in T cell activation and the release of inflammatory cytokines. It has been demonstrated that α4β7 acts as a co-stimulatory molecule for T cell activation. Experiments show that co-stimulation with MAdCAM-1 and anti-CD3 antibodies (mimicking antigen presentation) significantly enhances the proliferation of CD4+ T cells and promotes the release of Th1-type cytokines (eg, IFN-γ, TNF-α) and Th17-type cytokines (eg, IL-17A). 70 The co-stimulatory effect of MAdCAM-1 on T cell proliferation is comparable to that of CD28 and becomes more pronounced in the presence of retinoic acid. 71 This co-stimulation can be blocked by anti-α4β7 antibodies (eg, PN-943, vedolizumab), confirming its dependence on α4β7 expression. Furthermore, the co-stimulatory effect correlates with the surface expression level of β7, which increases during cell proliferation, suggesting that α4β7 may amplify T cell activation through autocrine or paracrine signaling. 70 Additionally, the co-stimulatory effect of MAdCAM-1 exhibits a “remote” effect, functioning even when spatially separated from the site of TCR signaling. 72 The activation of α4β7-expressing T cells leads to the production of pro-inflammatory cytokines such as TNF-α, IFN-γ, and IL-17. These cytokines amplify the inflammatory response by recruiting additional immune cells, activating resident macrophages, and inducing the production of other inflammatory mediators. The resulting cytokine storm perpetuates tissue damage and contributes to the chronicity of IBD. 73 However, in vivo studies show that the proportion of α4β7-expressing T cells (CD3 + ) in the peripheral blood and intestinal lamina propria of IBD patients is lower than in non-inflammatory controls. This may be due to the nonspecific recruitment of naïve T cells during inflammation, which dilutes the α4β7-expressing cell population. 63

Thus, the costimulatory role of α4β7-MAdCAM-1 binding in T cells highlights its impact on T cell signaling and subsequent immune responses and inflammation in IBD. Accordingly, anti-α4β7 antibodies may exert therapeutic effects in IBD not only by blocking T cell adhesion and migration but also by regulating T cell proliferation, activation, and function, with effects varying by antibody type. 74 , 75

Dysregulation of Immune Cell Subsets

Different immune cell subsets (eg, Th1, Th17, Treg) have varying dependencies on α4β7-mediated homing. While α4β7 is essential for effector T-cell migration, its role in regulatory T cells (Tregs) trafficking reveals a paradoxical balance. Complete inhibition of α4β7 (eg, via high-dose anti-α4β7 antibodies) depletes intestinal Tregs, exacerbating innate immune-mediated colitis in murine models. 76 In contrast, partial inhibition preserves Treg populations, which suppress aberrant effector T-cell responses and maintain mucosal tolerance. 77 This dichotomy explains why vedolizumab—a gut-selective α4β7 antagonist—achieves therapeutic efficacy by selectively blocking effector T-cell homing while sparing a subset of α4β7+ Tregs expressing β1 integrins or PI16. 78 Therefore, dysregulation of immune cell subsets caused by α4β7 may also play a role in the pathogenesis of IBD. The balance between effector and regulatory immunity underscores the complexity of targeting α4β7 in IBD. Future therapies must balance inhibition of pathogenic homing with preservation of mucosal homeostasis, guided by deeper mechanistic insights into α4β7 activation and crosstalk with immune niches.

Gut Microbiota and Epithelial Barrier Crosstalk

The gut microbiota is now recognized as a key mediator in IBD pathogenesis. Patients with IBD exhibit markedly reduced intestinal microbial diversity and stability compared with healthy individuals. 79 The relative abundance of anti-inflammatory and immunomodulatory commensals (eg, Bifidobacterium, Lactobacillus ) is significantly decreased in IBD, 80 while proinflammatory pathogenic bacteria (eg, adherent-invasive Escherichia coli, Veillonella ) are enriched. 79 Integrin α4β7 has been reported to influence the composition and function of the gut microbiota by modulating immune responses. α4β7-expressing Tregs are essential for maintaining tolerance to commensal bacteria. Dysregulation of this process can lead to an aberrant immune response against the microbiota, contributing to inflammation. 81 , 82 Studies have found that β7 integrin deficiency had no significant effect on the structure of the fecal microbiota in mice under steady-state conditions, but this effect may be amplified under pathological conditions such as IBD. It was revealed that the absence of α4β7 (in Il10 −/− β7 −/− mice) or blockade of its ligand MAdCAM-1 led to a decrease in intestinal microbiome diversity, with an expansion of clostridiales species and a decrease in bacteroides. 83 This microbiome profile is similar to what is observed in patients with active IBD. 84

Impaired intestinal mucosal barrier function is a key trigger for the onset and recurrence of IBD. 85 In patients with delayed gastric emptying, elevated numbers of small intestine-homing T lymphocytes (specifically CD4 + α4β7 + CCR9 + T cells) are associated with proinflammatory cytokine release and intestinal barrier dysfunction. 86 Anti-α4β7 integrin therapy can alleviate colitis symptoms by reducing intestinal inflammation and improving the function of the intestinal epithelial barrier. This reparative effect is linked to modulation of the gut microbiota and bile acid metabolism. 87 Another study found that anti-α4β7-integrin therapy significantly mitigated intestinal inflammation and gut barrier disruption in remission-achieving colitis mice. 88 The gut microbiota composition can predict response to anti-α4β7 therapy. Mice achieving remission had higher baseline levels of beneficial bacteria like Lactobacillus . 87

Notably, the gut microbiota and epithelial barrier integrity have a bidirectional relationship with α4β7 signaling. Probiotic Bifidobacterium species have been shown to alleviate IBD, potentially by modulating α4β7 activity via FXR, TGR5 and their downstream targets. 87 The gut microbiota also indirectly influences the homing of α4β7+ cells by regulating MAdCAM-1 expression. Dysbiosis in IBD alters microbial metabolites such as short-chain fatty acids, thereby downregulating MAdCAM-1 and impairing α4β7-mediated lymphocyte homing. 89 By contrast, pathogenic bacteria including adherent-invasive Escherichia coli (AIEC) upregulate MAdCAM-1 through TLR signaling, thus enhancing α4β7⁺ cell recruitment. 90 Epithelial damage further exacerbates α4β7-driven inflammation. Loss of tight junction proteins (eg, occludin) increases permeability, allowing luminal antigens to activate DCs and promote α4β7⁺ T cell recruitment in GALT. 91 In CD, Paneth cell dysfunction reduces antimicrobial peptides (eg, α-defensins), exacerbating dysbiosis and perpetuating α4β7-MAdCAM-1 interactions. 92

α4β7 and Cardiovascular Diseases

Clinical and preclinical studies have linked integrin α4β7 to atherosclerosis and coronary heart disease, suggesting its pathogenic involvement in these conditions. The ability of α4β7 to mediate inflammatory cell adhesion and proinflammatory responses via ligand binding likely represents its main mechanism of action. 93 In acute coronary syndrome (ACS) patients, microarray and qRT‑PCR analyses revealed upregulated expression of the integrin β7 gene ( ITGB7 ) and other adhesion molecules, implying that β7 integrin may contribute to atherosclerosis and ACS progression. It may act synergistically with other adhesion proteins to aggravate inflammation, platelet aggregation, and coronary thrombosis. 94 In atherosclerotic apolipoprotein E‑deficient (ApoE − / − ) mice, plaque formation was accompanied by elevated α4β7 and its ligands (VCAM‑1, MAdCAM‑1) in lesions and increased α4β7 on peripheral blood lymphocytes, which positively correlated with aortic lesion size. By contrast, α4β7‑deficient ApoE − / − mice exhibited markedly reduced atherosclerotic plaques, lower plasma cholesterol, impaired macrophage lipoprotein uptake and phagocytosis, and decreased FAK and MAPK/ERK1/2 activation. These results indicate that α4β7 promotes atherogenesis by modulating macrophage function via FAK and MAPK/ERK1/2 signaling. 95 In vitro studies showed that anti‑α4 integrin antibodies blocked endothelial progenitor cell (EPC) adhesion to VCAM‑1, mobilizing EPCs into the circulation to enhance angiogenesis and tissue repair in hindlimb ischemia and myocardial infarction (MI). Anti‑α4 treatment also reduced infarct fibrosis and improved cardiac function, 96 suggesting that α4‑ligand interactions may impair tissue recovery. Notably, α4β7 can also exert cardioprotective effects after MI. IL‑2‑activated NK cells promoted endothelial proliferation and angiogenesis via α4β7‑VCAM‑1 binding in vitro, an effect abrogated by α4β7 or VCAM‑1 neutralization. In vivo, these NK cells improved cardiac repair through α4β7‑dependent angiogenesis. 97 α4β7 may play divergent roles in post‑MI vascular regeneration and cardiac repair in a cell‑type‑dependent manner.

α4β7 may be involved in cardiac interstitial fibrosis. Several integrins including β1, 98 αv, 99 and α4, have been linked to fibrotic processes. Monocytes and macrophages with hyperactivated α4 integrin exhibit increased adhesion and infiltration into cardiac tissue, contributing to inflammation and fibrosis. 100 Upregulated α4 integrin on Th1 cells facilitates adhesion to cardiac fibroblasts in an IFN‑γ‑dependent manner, inducing TGF‑β secretion and myofibroblast differentiation. 101 In vitro, the extracellular matrix component EDA‑containing fibronectin (EDA‑FN) binds α4β7 via its EDA domain, activating FAK and MAPK/Erk1/2 signaling to drive fibroblast-to-myofibroblast differentiation, a key step in fibrosis and wound healing. 55 Blocking EDA‑FN–α4β1/α4β7 interactions attenuates fibrillar collagen production and myofibroblast formation. 53 Although direct evidence linking α4β7 to myocardial fibrosis remains lacking, the key role of FN in fibrosis implies that FN–α4β7 interactions may contribute to this process. 102

Notably, α4β7 may affect the cardiovascular system indirectly through gut metabolic pathways. α4β7⁺ intestinal intraepithelial lymphocytes (IELs) capture glucagon-like peptide-1 (GLP‑1) via GLP‑1R, thereby reducing its bioavailability ealth. 103 As GLP‑1 maintains glucose/lipid homeostasis, suppresses inflammation, and reduces major adverse cardiovascular events, 104–106 this interaction impairs metabolic and cardiovascular health. Mice lacking integrin β7 ( β7 −/− ) exhibit significantly reduced IELs and loss of GLP-1R, leading to increased GLP-1 bioavailability and resistance to metabolic syndrome and atherosclerosis under high-fat/high-sugar diets. These findings indicate that α4β7 may adversely affect cardiovascular health by modulating IEL abundance and function to regulate GLP‑1 bioavailability. 103 , 106

α4β7 and Diabetes

Type 1 Diabetes

In non-obese diabetic (NOD) mice, autoimmune insulitis involves T-cell infiltration into pancreatic islets and β-cell destruction, with B cells acting as critical antigen-presenting cells that initiate this process. Studies reveal that vascular endothelial cells in inflamed islets of NOD mice highly express MAdCAM-1, while infiltrating lymphocytes express integrin α4β7. Blocking β7 integrin or MAdCAM-1 with monoclonal antibodies significantly inhibits T-cell migration to islets and reduces diabetes incidence. 107 The α4β7/MAdCAM-1 axis is also the primary pathway for B-cell migration to pancreatic lymph nodes (PLNs). Disrupting this pathway markedly decreases B-cell infiltration into the pancreas, suppressing β-cell antigen presentation and autoimmune T-cell activation. 108 Tregs similarly rely on the α4β7/MAdCAM-1 pathway to localize to islets and exert immunosuppressive functions. α4 blockade or β7-deficient Tregs fail to enter islets, impairing their protective role against diabetes. 109 Tellurium-containing compounds (eg, AS101 and SAS) simultaneously inhibit α4β7 activity in effector T cells and Tregs but exhibit stronger suppression in effector T cells. By reducing effector T-cell migration while increasing Treg proportions, these compounds prevent or reverse type 1 diabetes (T1D). 110

α4β7 also influences insulitis via the gut-pancreas axis. In NOD mice, lymphocytes with a mucosal phenotype (expressing α4/β7 integrins) display aberrant homing behavior, preferentially migrating to non-mucosal tissues like the pancreas. These cells accumulate in early insulitis, potentially driving autoimmune inflammation. 111 This suggests that some islet-infiltrating T cells may first activate in the gut mucosa before migrating to the pancreas via α4β7-MAdCAM-1. Both animal and human studies support that diabetogenic T cells are primed in mesenteric immune systems before pancreatic infiltration. 112 , 113 Butyrate, a gut microbiota metabolite derivative, induces α4β7 + Treg migration from the gut to the pancreas and PLNs, ameliorating T1D symptoms. 114

Type 2 Diabetes

Insulin resistance is a hallmark of type 2 diabetes. 115 Mice carrying an α4 (Y991A) mutation exhibit reduced monocyte trafficking to adipose tissue due to impaired α4 signaling, preventing obesity-induced insulin resistance. 116 Moreover, beta7-integrin-deficient mice are protected from obesity-associated insulin resistance and metabolic disease. 117 Post-transplant diabetes mellitus (PTDM) patients with insulin resistance show increased peripheral α4β7+ Tregs. 118 Given that Tregs improve adipose inflammation and insulin resistance in type 2 diabetes, 119 α4β7 + Tregs may exert compensatory immunosuppression in PTDM.

α4β7 and Liver Diseases

Acute Liver Injury and Liver Fibrosis

In mouse models of acute immune-mediated hepatitis, the interaction between lymphocytes and hepatic sinusoidal endothelial cells via the MAdCAM‑1/α4β7 axis exacerbates liver injury by enhancing cell adhesion and triggering local coagulation. In contrast, liver damage is markedly alleviated in both MAdCAM‑1‑deficient and β7 integrin‑deficient mice. 31 In mice with acute liver failure (ALF) and in human patients with liver failure, hepatic and serum MAdCAM‑1 levels are significantly elevated and positively correlate with liver injury severity and proinflammatory marker expression. 120 Notably, activation of the cholinergic anti‑inflammatory pathway alleviates ALF by inhibiting MAdCAM‑1/α4β7‑mediated recruitment of gut‑derived proinflammatory lymphocytes to the liver. 120 A recent study showed abundant accumulation of α4β7⁺ T cells in the liver of patients with liver cirrhosis. In animal models, antibody blockade of α4β7 or MAdCAM‑1 reduced hepatic T‑cell infiltration and inhibited liver fibrosis progression. 121

Non-Alcoholic Fatty Liver Disease (NAFLD)

NAFLD encompasses a spectrum of liver abnormalities, from non-alcoholic fatty liver to non-alcoholic steatohepatitis (NASH). 122 In NASH mouse models, α4β7+ CD4 T cells increase significantly and are recruited to the liver via MAdCAM-1 binding, exacerbating inflammation and fibrosis. Specific α4β7 blockade alleviates these effects. MAdCAM-1 colocalizes with αSMA, a marker of hepatic stellate cell (HSC) activation, suggesting HSCs as primary MAdCAM-1-expressing cells in the liver. 123 Human NASH liver biopsies show elevated MAdCAM-1, correlating positively with α4 and β7 integrin expression, 123 implicating the α4β7/MAdCAM-1 axis in NASH. In NASH-related cirrhosis, α4β7 + T-cell infiltration rises markedly within fibrotic septa, a pattern also observed in alcohol-associated steatohepatitis (ASH)-related cirrhosis. 121

Primary Sclerosing Cholangitis (PSC)

PSC is a chronic cholestatic liver disease characterized by intrahepatic or extrahepatic bile duct narrowing and bile duct fibrosis. 124 PSC is closely associated with IBD, which affects 60–80% of patients. 125 α4β7 has been found to be the key molecule of the gut-liver axis connecting PSC and IBD. Under normal conditions, α4β7-expressing lymphocytes pair with the ligand MAdCAM-1 on the endothelium of intestinal vessels and thus specifically target the gut. In patients with PSC, liver sinusoidal endothelial cells aberrantly express the gut-specific adhesion molecule MAdCAM-1 and chemokine CCL25, accompanied by an increased proportion of CCR9⁺ (the receptor for CCL25) lymphocytes infiltrating the liver, which typically co-express α4β7 and thereby migrate into the liver by binding to the ectopically expressed MAdCAM-1 on hepatic vasculature and contributing to duct inflammation and fibrosis. 126–128 Current clinical evidence indicates that pharmacologically blocking α4β7 integrin, while effective in alleviating intestinal inflammation, does not clearly improve liver injury in PSC. 129 This suggests that the pathogenesis of PSC may be more complex, and that blocking α4β7 integrin alone is insufficient to reverse the pathological process in the liver.

α4β7 and Autoimmune Diseases

Multiple Sclerosis (MS)

MS is a chronic autoimmune disease involving T-cell-mediated CNS demyelination and axonal damage. 130 In experimental autoimmune encephalomyelitis (EAE, an MS model), α4β7 blockade selectively inhibits Th17 (but not Th1) cell adhesion, suggesting α4β7 primarily mediates Th17 migration to inflamed meninges. 22 It has been reported that α4β7 may influence MS via the gut-brain axis. In EAE, α4β7/MAdCAM-1 blockade reduces colonic Th17 infiltration and symptoms, linking gut immunity to CNS disease. 131 MS patients exhibit reduced gut microbiome diversity and increased circulating α4β7 + CXCR3 + T cells, suggesting gut-immune crosstalk. 132 While some studies show β7 deficiency or antibodies alleviate EAE, 133 others report no impact on CNS inflammation, 134 , 135 possibly due to model variations. Recent studies have demonstrated that Natalizumab (an anti-α4 monoclonal antibody) effectively ameliorates relapsing-remitting multiple sclerosis (RRMS), primarily through the blockade of the α4β1/VCAM-1 interaction, while the contribution of α4β7 appears to be secondary. 136 , 137

Systemic Lupus Erythematosus (SLE)

SLE is a chronic inflammatory disease that causes kidney damage in approximately half of the patients. 138 Lupus nephritis is one of the most serious clinical complications of SLE and is closely related to the prognosis of patients. A 2013 study found that the expression of α4β7 integrin on B lymphocytes and T lymphocytes in the peripheral blood of SLE patients was significantly lower than that in the healthy control group, but the specific mechanism was not clearly identified. 139 In lupus nephritis, integrin α4β7 exerts a protective effect by retaining group 2 innate lymphoid cells (ILC2s) in renal tissue. Through binding to VCAM‑1 and E‑cadherin, α4β7 anchors ILC2s to produce amphiregulin, a tissue‑repair cytokine that inhibits local inflammation. However, during active disease, TLR7/9 signaling downregulates α4β7 expression on ILC2s, causing their detachment from the tissue and loss of this protective, repair-promoting function. 23 This discovery has overturned the traditional understanding that integrins only mediate inflammation.

Celiac Disease

Celiac disease is a chronic autoimmune enteropathy triggered by dietary gluten in genetically predisposed individuals, characterized by small intestinal mucosal damage, villous atrophy, and crypt hyperplasia. 140 A study demonstrated significantly higher MAdCAM‑1 expression in the small intestine and lower β7⁺ T‑cell proportions in peripheral blood in active CD patients compared with healthy controls, 141 indicating massive recruitment of α4β7⁺ T cells from circulation into the intestinal tissue. In vitro experiments revealed that direct stimulation of intestinal tissue from celiac disease patients with gluten digests induced MAdCAM‑1 overexpression, confirming that gluten promotes α4β7⁺ T‑cell migration. 141 Consistent with this, celiac disease patients on a gluten‑free diet exhibited normalized intestinal MAdCAM‑1 expression and restored peripheral α4β7⁺ T‑cell counts. 141 This mechanism depends on interferon‑α signaling, as neutralizing anti‑IFN‑α antibodies abolished gluten‑induced MAdCAM‑1 upregulation. 141

α4β7 and Gastrointestinal Malignancies

Colorectal Cancer (CRC)

Intestinal inflammation significantly increases CRC risk. 142 β7 integrin-deficient mice in inflammation-driven tumor models develop smaller tumors and improved survival, indicating that β7 integrins (particularly α4β7) promote intestinal tumor growth. 21 In CRC patients, low tumor MAdCAM-1 expression correlates with better survival. 21 Conversely, increased MAdCAM-1 + vessels in colitis-associated carcinogenesis enhance inflammatory cell infiltration and pro-tumor signaling, accelerating tumor progression. 62 Interestingly, the α4β7–VCAM-1 interaction may exert antitumor effects. T cells bind to MCA-38 colon adenocarcinoma cells via α4β7–VCAM-1 to mediate antitumor immunity. 143 This interaction can be suppressed by anti-α4 antibodies or adenosine in the hypoxic tumor microenvironment, thereby weakening antitumor immune responses. 143

Gastric Malignancies

Helicobacter pylori infection is associated with gastric ulcers, adenocarcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma. 144 Following H. pylori vaccination, elevated circulating α4β7⁺CD4⁺ T‑cell frequencies correlate with lower gastric bacterial loads in mice, suggesting H. pylori recruits these T cells to gastric tissue. 145 In gastric MALT lymphoma, H. pylori also upregulates α4β7 on B cells, modifying their homing behavior and promoting intestinal dissemination. 146 In gastric adenocarcinoma, the tumor microenvironment downregulates endothelial MAdCAM‑1, impairing α4β7⁺ T‑cell homing and infiltration and thus facilitating immune evasion. 147

α4β7 and HIV Infection

CD4 + T cells, the primary HIV targets, rely on α4β7 for gut homing. The gut and gut-associated lymphoid tissues are critical sites for HIV replication and CD4 + T-cell depletion. 148–150

Viral Targeting and Infection

HIV gp120 binds host CD4 and coreceptors (CCR5/CXCR4) for entry. 151 , 152 gp120 also interacts with activated α4β7 via a V2 loop tripeptide mimicking natural ligands (eg, MAdCAM-1/VCAM-1). 153 α4β7 and CD4 form complexes, with gp120’s V2 region mimicking CD4 D2-α4β7 interactions, potentially explaining HIV’s preference for α4β7 + CD4 + T cells. 154 High α4β7 expression correlates with Ki-67/CCR5 upregulation, rendering these cells metabolically active and susceptible to HIV, driving viral adaptation for α4β7 affinity. 155 Thus, while α4β7 is non-essential for HIV entry, it enhances infection efficiency.

Gut Immune Damage and Viral Reservoir Formation

HIV-1 virions incorporate functional α4β7, enabling gut homing and tissue dissemination. 150 Circulating α4β7 + virions are detected in early infection. 150 In acute SIV infection, α4β7 hi CD4 + Th17 cells—critical for mucosal barrier integrity—are preferentially depleted, disrupting Th17/Th1 balance and mucosal homeostasis. 156 The gut is a key site for α4β7-mediated viral reservoir persistence, explaining why antiretroviral therapy (ART) fails to eradicate HIV. 157 Anti-α4β7 mAbs (eg, vedolizumab) show potential in reducing gut viral loads, 158 , 159 though efficacy varies due to microbiome composition, myeloid differentiation, and macrophage phenotypes. 160

α4β7 and Asthma

Asthma is a heterogeneous disease characterized by chronic inflammation of the airways, airway hyperresponsiveness (AHR), and reversible airflow limitation. Inhibition of the α4 subunit of both the α4β1 and α4β7 integrins has shown promise in decreasing airway inflammation and AHR in various animal models, and α4β1/α4β7 dual antagonist has shown the effect of reducing eosinophil infiltration and lowering AHR in the experimental allergic asthma model. 161 , 162 Individually, α4β1 antagonists can reduce the migration of eosinophils to the lungs and improve AHR in mouse models with airway inflammation. 161 A recent study has demonstrated that α4β7 directly participates in allergic airway remodeling and AHR by regulating fibroblast activation and differentiation, independently of eosinophilic inflammation. 163 This suggests that α4β7 may play a more direct or unique role in regulating downstream pathological processes related to AHR (such as smooth muscle hyperplasia and fibrosis) compared to α4β1.

α4β7 and Graft-Versus-Host Disease (GVHD)

In GVHD, integrin α4β7 plays a critical pathogenic role by mediating the gut homing of donor-derived T cells, which bind to MAdCAM-1 aberrantly expressed on intestinal endothelial cells, thereby facilitating their migration to gut-associated lymphoid tissue and intestinal mucosa and triggering severe intestinal injury. 164 Notably, elevated α4β7 expression on peripheral blood T cells serves as a predictive biomarker for acute intestinal GVHD, and therapeutic targeting of this pathway with α4β7 antagonists such as vedolizumab has shown promising efficacy in steroid-refractory cases and is currently being evaluated in prospective clinical trials for GVHD prevention. 165 , 166

α4β7-Targeting Antibodies

Several monoclonal and small-molecule antibodies targeting α4β7 have been developed. Some have been approved for clinical use, while others are still under investigation, primarily for the treatment of IBD, as well as for other diseases such as HIV and relapsing multiple sclerosis (RMS). Below is a summary of agents that are currently approved or in clinical trials ( Table 1 ). Table 1 Summary of α4β7-Targeted Therapeutic Agents Drug Route Category Target Disease Clinical Status Vedolizumab Intravenous Monoclonal Antibody α4β7 integrin UC, CD Approved HIV Phase I GVHD Phase III Chronic Pouchitis Phase IV Abrilumab (AMG 181 or MEDI 7183) Subcutaneous Monoclonal Antibody α4β7 integrin CD Phase IIb UC Phase IIb Natalizumab Intravenous Monoclonal Antibody α4 integrin RMS Approved CD Approved UC Phase II Etrolizumab Intravenous or subcutaneous Monoclonal Antibody β7 integrin CD Phase III UC Phase III Ontamalimab (PF-00547659 or SHP647) Intravenous or subcutaneous Monoclonal Antibody MAdCAM-1 UC Phase III CD Phase II Carotegrast Methyl (AJM300) Oral Small Molecule α4 integrin UC Approved CDP323 (Zaurategrast) Oral Small Molecule α4 integrin RMS Phase I/II PTG-100 (PN-10884A) Oral Peptide α4β7 integrin UC Phase IIa Abbreviations : CD, crohn’s disease; GVHD, graft-versus-host disease; MadCAM-1, mucosal addressin cell adhesion molecule-1; RMS, relapsing multiple sclerosis; UC, ulcerative colitis.

Table 1 Summary of α4β7-Targeted Therapeutic Agents Drug Route Category Target Disease Clinical Status Vedolizumab Intravenous Monoclonal Antibody α4β7 integrin UC, CD Approved HIV Phase I GVHD Phase III Chronic Pouchitis Phase IV Abrilumab (AMG 181 or MEDI 7183) Subcutaneous Monoclonal Antibody α4β7 integrin CD Phase IIb UC Phase IIb Natalizumab Intravenous Monoclonal Antibody α4 integrin RMS Approved CD Approved UC Phase II Etrolizumab Intravenous or subcutaneous Monoclonal Antibody β7 integrin CD Phase III UC Phase III Ontamalimab (PF-00547659 or SHP647) Intravenous or subcutaneous Monoclonal Antibody MAdCAM-1 UC Phase III CD Phase II Carotegrast Methyl (AJM300) Oral Small Molecule α4 integrin UC Approved CDP323 (Zaurategrast) Oral Small Molecule α4 integrin RMS Phase I/II PTG-100 (PN-10884A) Oral Peptide α4β7 integrin UC Phase IIa Abbreviations : CD, crohn’s disease; GVHD, graft-versus-host disease; MadCAM-1, mucosal addressin cell adhesion molecule-1; RMS, relapsing multiple sclerosis; UC, ulcerative colitis.

Summary of α4β7-Targeted Therapeutic Agents

Abbreviations : CD, crohn’s disease; GVHD, graft-versus-host disease; MadCAM-1, mucosal addressin cell adhesion molecule-1; RMS, relapsing multiple sclerosis; UC, ulcerative colitis.

Vedolizumab

Vedolizumab, a humanized IgG1 monoclonal antibody, primarily functions to selectively antagonize the α4β7 integrin by specifically blocking its interaction with MAdCAM-1. 167 It was approved by the FDA in 2014 for the treatment of moderate-to-severe UC and CD in patients who are refractory or intolerant to TNF-α inhibitors, 167 , 168 it is used for both induction and maintenance therapy. 169 , 170 Long-term efficacy and safety are well-documented, with low severe infection rates (≤0.6%) and no reported cases of progressive multifocal leukoencephalopathy (PML). 171

Vedolizumab is also undergoing clinical trials at various stages for the treatment of several other diseases. In rhesus macaques, α4β7 blockade achieved sustained HIV virologic remission (SVR), 158 but Phase I trials in humans failed to replicate significant antiviral effects, suggesting limited utility for HIV remission post-ART interruption. 172 The ongoing HAVARTI trial ( NCT02788175 ) evaluates vedolizumab’s safety and potential to induce SVR after ART pause. 173 A Phase III trial demonstrated vedolizumab’s efficacy in preventing intestinal acute graft-versus-host disease (aGVHD) post-allo-HSCT when added to standard prophylaxis. 174 Additionally, a Phase IV trial has confirmed its benefits for chronic pouchitis. 175

Abrilumab

Abrilumab (also known as AMG 181 or MEDI7183) is a fully human IgG2κ monoclonal antibody that selectively blocks α4β7-MAdCAM-1 interactions to inhibit lymphocyte gut homing without binding to α4β1 or αEβ7 integrins, thereby preserving systemic immune surveillance. 176 Administered via subcutaneous injection, Abrilumab was evaluated in a pivotal Phase IIb UC trial ( NCT01694485 ) involving 354 patients using regimens including 7 mg, 21 mg, 70 mg every 4 weeks, and a single 210 mg dose followed by placebo. At Week 8, the 70 mg and 210 mg doses demonstrated significant efficacy, achieving clinical remission rates of 13.5% and 13.4%, respectively, compared to 4.4% for placebo. 177 A separate Japanese Phase II study similarly showed numerically higher remission rates with these doses and confirmed a favorable safety profile with no PML cases. 178 However, in CD, a Phase II study ( NCT01696396 ) missed its primary endpoint of clinical remission at Week 8, with the 21 mg and 210 mg doses failing to show statistical superiority over placebo, and inconsistent results ultimately limited its further development. 179 Although abrilumab demonstrated a favorable safety, immunogenicity, pharmacokinetic, and efficacy profile suitable for further UC testing, its development was discontinued in 2016.

Natalizumab

Natalizumab is a recombinant humanized IgG4κ monoclonal antibody that targets the α4 subunit of integrins, thereby blocking both the α4β1-VCAM-1 and α4β7-MAdCAM-1 pathways. 180 It was first approved by the FDA in 2004 for relapsing forms of MS (RMS) but was temporarily withdrawn after reports of PML; following safety reviews and the implementation of a rigorous risk minimization program (the TOUCH Prescribing Program), it was reintroduced in 2006. 175 While effective for moderately to severely active CD, earning FDA approval in 2008, concerns about PML restrict its use to second- or third-line therapy in patients with inadequate response to conventional or anti-TNF agents, and it should not be combined with other immunosuppressants. 180 A Phase II trial in active UC demonstrated modest efficacy, including significant improvements in response and remission rates at Week 6, but safety concerns and competition from gut-selective agents like vedolizumab halted further UC-specific development. 181

Etrolizumab

Etrolizumab is a humanized IgG1 monoclonal antibody that specifically targets the β7 subunit of the integrin α4β7 and αEβ7. 182–184 By binding to β7, it exerts a dual mechanism of action: it inhibits the trafficking of leukocytes to the gut mucosa by blocking the α4β7/MAdCAM-1 interaction, and it reduces the retention of lymphocytes, particularly CD8+ T cells, within the intraepithelial compartment by blocking the αEβ7/E-cadherin interaction. 182 , 185 While a Phase II trial (EUCALYPTUS) demonstrated its potential to induce clinical remission in patients with UC, 186 subsequent Phase III programs yielded mixed results and failed to meet their primary endpoints. In UC, the GARDENIA trial showed that etrolizumab was not superior to infliximab in achieving the combined primary endpoint of clinical response at week 10 and clinical remission at week 54 (18.6% vs 19.7%, p=0.81). 187 The HIBISCUS I and II trials reported that etrolizumab did not demonstrate superiority over adalimumab or placebo for induction of remission at week 10. 188 The HICKORY trial achieved its induction-phase remission endpoint (18.5% vs 6.3%, p = 0.0033) in anti-TNF-experienced patients but failed to show a significant benefit for maintaining remission at week 66 (24.1% vs 20.2%, p=0.5). 189 Similarly, the LAUREL trial did not meet its primary maintenance endpoint. 190 In contrast, the Phase III BERGAMOT trial in CD reported that etrolizumab did not meet the co-primary induction endpoints at week 14, but it did demonstrate significant benefits over placebo for clinical remission (35% vs 24%, p=0.0088) and endoscopic improvement (24% vs 12%, p=0.0026) during the maintenance phase. 191 While the safety profile of etrolizumab appears generally favorable, long-term data remain limited.

Ontamalimab

Ontamalimab (also known by its research codes PF-00547659 or SHP647) is a fully human IgG2 monoclonal antibody that uniquely targets MAdCAM-1, the endothelial ligand for α4β7 integrin. In UC, the Phase II TURANDOT I trial demonstrated significant efficacy at Week 12 with a sustained safety profile over 144 weeks in the TURANDOT II extension, and this was confirmed in Phase III studies ( NCT03259334 ) where the 75 mg subcutaneous dose showed clear superiority over placebo for both induction and maintenance of remission. 192–194 However, results in CD from the OPERA I/II trials were more complex; while the drug consistently reduced inflammatory biomarkers such as fecal calprotectin and C-reactive protein, clinical remission rates were inconsistent and, in the long-term OPERA II extension, declined gradually from 48.1% to 37.3% at week 72 despite sustained biological activity. 195 , 196 Collectively, ontamalimab represents a well-tolerated and effective therapy for UC with a distinctive anti-MAdCAM-1 mechanism and was granted FDA orphan drug designation for UC in 2017, but its development in CD has been challenged by the disconnect between biomarker improvement and durable clinical efficacy. Development of the drug was officially terminated in May 2024 for commercial reasons.

Carotegrast Methyl

Carotegrast Methyl (also known by its developmental code AJM300) is an oral, small-molecule α4 integrin antagonist approved in Japan (March 2022) for moderately active UC in patients with an inadequate response to 5-aminosalicylic acid. 197 As a prodrug, it is rapidly converted in vivo to its active metabolite, HCA2969, which exerts a dual anti-inflammatory effect by selectively blocking both α4β1 and α4β7 integrins, thereby inhibiting the adhesion and extravasation of inflammatory cells like lymphocytes into the colonic mucosa. 197 , 198 A Phase 3 trial ( NCT03531892 ) demonstrated its efficacy as induction therapy: at week 8, 45% of patients receiving Carotegrast Methyl achieved clinical response compared to 21% with placebo (p=0.00028). 199 The therapy was well-tolerated, with a safety profile comparable to placebo and no new safety signals identified. 199 Notably, its oral formulation offers a potential advantage over biologic α4 integrin inhibitors, providing a non-immunogenic option suitable for intermittent or cyclic use. 199 However, data on its application in CD remain limited.

CDP323

CDP323 (also known by its developmental code Zaurategrast) is an oral, small-molecule α4 integrin inhibitor that was investigated for the treatment of RMS. 200 , 201 It is an ethyl ester prodrug of the active carboxylic acid moiety CT7758 designed to improve oral bioavailability. Its active metabolite exerts its effect by antagonizing both α4β1 and, to a lesser extent, α4β7 integrins. In a randomized, double-blind, placebo-controlled Phase 1/2 study ( NCT00726648 ) involving 71 RMS subjects over 28 days, CDP323 demonstrated clear pharmacodynamic activity. 200 At daily doses of 1000 mg or 2000 mg, it significantly increased lymphocyte counts in peripheral blood and suppressed the capacity of lymphocytes to bind VCAM-1. 200 However, despite this evidence of target engagement, its clinical development was discontinued in 2009. This decision was based on inadequate interim efficacy data from a larger Phase II trial ( NCT00484536 ), which failed to demonstrate sufficient clinical benefit in the central nervous system to warrant further development. Currently, no active studies are investigating CDP323, particularly those targeting the α4β7 integrin for indications like IBD.

PTG-100

PTG-100 (also known by its research code PN-10884A) is an oral, synthetic peptide antagonist selectively blocking the α4β7 integrin, thereby inhibiting its interaction with MAdCAM-1. 202 A Phase 2a trial ( NCT02895100 ) enrolled patients with moderate to severe active UC who were randomized to receive PTG-100 (150, 300, or 900 mg) or placebo once daily for 12 weeks. 202 Although the study initially did not meet its primary endpoint based on the original read, a subsequent blinded central reread of endoscopy videos revealed significant efficacy. 202 , 203 In this revised analysis, the 900 mg dose achieved a clinical remission rate of 15.8% compared to 4.8% with placebo, along with histological remission, demonstrating a clear dose-response relationship. 202 A key pharmacodynamic insight from this study is that efficacy correlated with less than 100% receptor occupancy on peripheral blood T cells. 202 , 204 This supports the hypothesis that PTG-100’s local activity in GALT, rather than complete saturation in the bloodstream, is sufficient and potentially important for therapeutic effect. The drug was safe and well-tolerated across both Phase 1 and Phase 2 studies. 202 Despite these positive signals, a subsequent Phase 2b study of PTG-100 was terminated.

Conclusion and Prospects

Integrin α4β7 is a critical regulator of immune cell trafficking, particularly to the intestinal mucosa, and has emerged as a key player in the pathogenesis of a broad spectrum of inflammatory and metabolic diseases. A schematic overview of these α4β7-mediated pathways and their associated therapeutic interventions across inflammatory and metabolic diseases is presented in Figure 1 . Beyond its well-established role in mediating lymphocyte homing via MAdCAM-1, recent studies have uncovered additional functions of α4β7, including T cell co-stimulation, modulation of regulatory and effector T cell balance, and involvement in tissue fibrosis, angiogenesis, and metabolic regulation. Dysregulation of α4β7-dependent pathways contributes to disease progression not only in inflammatory bowel disease but also in conditions such as atherosclerosis, T1D, NASH, PSC, MS, lupus nephritis, and GVHD, underscoring its broad pathological relevance. Notably, α4β7 also participates in gut-liver, gut-pancreas, and gut-brain axes, highlighting its role as a molecular link between mucosal immunity and systemic disease. Figure 1 Schematic overview of α4β7 integrin-mediated pathways and targeted therapeutic interventions across inflammatory and metabolic diseases. In the central panel, α4β7 interacts with its primary ligands, including MAdCAM-1, VCAM-1, and Fibronectin, regulating leukocyte homing, retention, and costimulation. These molecular interactions are fundamental for regulating leukocyte tethering, rolling, and firm adhesion. As depicted in the peripheral panels, dysregulation of the α4β7 axis drives the pathogenesis of diverse multi-organ systemic conditions. The red inhibitory lines highlight the mechanisms of action for current and investigational α4β7-targeted therapies. These include agents blocking specific integrin subunits (e.g, Natalizumab, AJM-300, and CDP323 targeting α4; Etrolizumab targeting β7), agents neutralizing the endothelial ligand (Ontamalimab targeting MAdCAM-1), and agents selectively blocking the α4β7/MAdCAM-1 interaction (Vedolizumab, Abrilumab, and PTG-100). Schematic of α4β7 integrin pathways and therapies across various diseases affecting multiple organs. Overview of α4β7 integrin pathways and therapies in inflammatory and metabolic diseases. Lymphocytes interact with endothelial ligands MAdCAM-1, VCAM-1 and Fibronectin. Therapies: Natalizumab, AJM-300, CDP323 target α4; Etrolizumab targets β7; Ontamalimab targets MAdCAM-1; Vedolizumab, Abrilumab, PTG-100 block α4β7/MAdCAM-1 interaction. Systems affected: Gut & Lymphoid Tissue (GALT) with IBD, GVHD via lymphocyte homing; Liver with NASH via ectopic MAdCAM-1; Pancreas with diabetes via T/B cell migration; Cardiovascular System with atherosclerosis via endothelial activation; Kidneys with lupus nephritis via ILC2 retention; CNS with multiple sclerosis via T cell trafficking; Lungs with asthma via airway remodeling. Abbreviations : AJM-300, carotegrast methyl; CD, Crohn’s disease; CNS, central nervous system; GLP-1, glucagon-like peptide-1; GVHD, graft-versus-host disease; IBD, inflammatory bowel disease; ILC2s, group 2 innate lymphoid cells; MAdCAM-1, mucosal addressin cell adhesion molecule-1; MS, multiple sclerosis; NASH, non-alcoholic steatohepatitis; PSC, primary sclerosing cholangitis; LN, lupus nephritis; T1D, type 1 diabetes; T2D, type 2 diabetes; UC, ulcerative colitis; VCAM-1, vascular cell adhesion molecule-1.

Schematic overview of α4β7 integrin-mediated pathways and targeted therapeutic interventions across inflammatory and metabolic diseases. In the central panel, α4β7 interacts with its primary ligands, including MAdCAM-1, VCAM-1, and Fibronectin, regulating leukocyte homing, retention, and costimulation. These molecular interactions are fundamental for regulating leukocyte tethering, rolling, and firm adhesion. As depicted in the peripheral panels, dysregulation of the α4β7 axis drives the pathogenesis of diverse multi-organ systemic conditions. The red inhibitory lines highlight the mechanisms of action for current and investigational α4β7-targeted therapies. These include agents blocking specific integrin subunits (e.g, Natalizumab, AJM-300, and CDP323 targeting α4; Etrolizumab targeting β7), agents neutralizing the endothelial ligand (Ontamalimab targeting MAdCAM-1), and agents selectively blocking the α4β7/MAdCAM-1 interaction (Vedolizumab, Abrilumab, and PTG-100).

The development of α4β7-targeted therapies has yielded clinical success, most notably with vedolizumab in IBD, and continues to evolve with novel agents such as oral small molecules and peptide antagonists. However, challenges remain, including variability in therapeutic response, the need to preserve beneficial regulatory T cell populations, and the emergence of alternative homing pathways that may limit efficacy. Furthermore, the divergent roles of α4β7 in different tissues and disease contexts, ranging from pathogenic to protective, necessitate careful consideration in therapeutic targeting. These lessons learned from IBD, together with the growing recognition of immune dysregulation as a driver of metabolic and systemic inflammatory disorders, provide a compelling rationale for extending the therapeutic scope of α4β7 blockade beyond the intestinal mucosa.

In this context, the concept of targeting inflammation in metabolic diseases is already supported by clinical evidence, for instance, metformin, a first-line antidiabetic agent, has been shown to exert immunomodulatory and anti-inflammatory effects beyond its glycemic actions. 205 , 206 Such findings underscore the broader feasibility of immune-directed strategies in metabolic disorders. Beyond this conceptual support, strong mechanistic evidence has directly linked α4β7 to the pathogenesis of systemic inflammatory and metabolic diseases beyond IBD, yet dedicated clinical trials for these conditions have not yet been conducted. To translate these preclinical and observational findings into clinical practice, future translational efforts should focus on several key directions. First, systematic profiling of α4β7-expressing immune cells in patients with these conditions, including their frequency, activation status, and tissue-homing signatures, is essential to confirm their functional contribution to disease pathology. Second, early-phase proof-of-concept studies should be designed to enroll patient subgroups with coexisting intestinal inflammation and extraintestinal manifestations, allowing assessment of whether modulation of gut immunity exerts secondary beneficial effects on systemic disease activity. Third, combination regimens that pair α4β7 blockade with other immunomodulatory agents may be explored to enhance therapeutic efficacy or circumvent potential resistance mechanisms. Should these exploratory studies yield positive efficacy signals, rigorous randomized controlled trials will be warranted to definitively establish the clinical benefits and safety profiles of α4β7-targeted therapies in these specific patient populations. Concurrently, basic research should continue to unravel the regulatory mechanisms governing α4β7 expression and function, its interplay with the gut microbiome and metabolic microenvironment, and the discovery of predictive biomarkers for personalized treatment selection. Collectively, these integrated efforts will provide a rational roadmap for extending α4β7-targeted therapies beyond IBD to a broader array of inflammatory, metabolic, and fibrotic disorders.