Ulcerative colitis (UC) is a chronic, non-specific
inflammatory bowel disease (IBD) that is characterized by
persistent inflammation and ulceration of the colonic mucosa.
Patients with UC typically present with abdominal pain, diarrhea
and stools containing blood and mucus (1). Although the precise pathogenesis of
UC remains to be fully elucidated, it is generally understood to
result from the multifactorial interplay of environmental factors,
immune dysregulation, gut microbiota imbalance and genetic
predispositions (2).
Histopathological features include inflammatory cell infiltration
within the lamina propria and excessive secretion of
proinflammatory cytokines such as IL-6 and TNF-α (3). Globally, the prevalence of UC is
~10.6 per 100,000 individuals (4),
driven by an aging population and improved diagnostic recognition.
With disease progression, the risk of colonic malignancy also
increases (5). In Asian
populations, westernization of diets has been identified as a key
contributor to the increasing prevalence. Evidence from a large
cohort of 500,000 Chinese participants highlights two high-risk
dietary patterns associated with increased risk of UC: i) The
traditional Northern diet, consisting of high wheat and low rice
intake; and ii) a modern diet rich in animal-based foods and
fruits. Notably, frequent egg consumption was associated with
increased susceptibility to late-onset UC, whereas spicy food
intake showed a protective association (6). Similarly, a Japanese study has
attributed the pathogenesis of UC to reduced intake of dietary
fiber, fermented foods containing probiotics and plant-based
nutrients, accompanied by higher consumption of refined
carbohydrates and animal fats (7).
Pan-Asian analyses further support these findings, indicating that
‘Westernized’ diets, characterized by elevated refined sugar, red
meat and linoleic acid, promote UC development, while fiber-rich
fruits and vegetables exert protective effects (8).
Mechanistically, these dietary factors are
considered to impair gut barrier integrity, alter gut microbial
composition and amplify proinflammatory signaling cascades. Acute
severe colitis is experienced by ~15% of patients with UC, with
>30% ultimately requiring colectomy (9). Therapeutically, monoclonal antibodies
targeting key cytokines have been increasingly used to manage
corticosteroid-refractory UC (10–12).
However, their long-term efficacy is limited by adverse effects and
the gradual loss of therapeutic response in some patients (13), underscoring the need for continued
investigation into UC pathogenesis and the development of novel
treatment strategies.
The receptor for advanced glycation end products
(RAGE), first identified in 1992, is a transmembrane protein
belonging to the immunoglobulin (Ig) receptor superfamily (10). Structurally, RAGE comprises three
domains, extracellular, transmembrane and intracellular, and exists
in both membrane-bound and soluble forms. Owing to its unique
molecular configuration, RAGE is one of the few pattern recognition
receptors capable of binding both pathogen-associated molecular
patterns and damage-associated molecular patterns (DAMPs).
Initially discovered for its ability to interact with AGEs
implicated in diabetes (14), RAGE
has since been shown to bind a wide array of non-glycation ligands,
including protein S100 (S100) calgranulins, high-mobility group box
1 (HMGB1) and amyloid β (Aβ) protein (15). Although this is most abundantly
expressed in lung tissue, RAGE signaling contributes to the
pathogenesis of numerous chronic inflammatory diseases affecting
multiple organs, including diabetic vascular complications
(16), cardiovascular disease
(17), cancer (18), Alzheimer's disease (AD) (19) and various infection-related and
autoimmune disorders (20).
Previous studies have revealed elevated RAGE expression in UC
(21) and Crohn's disease
(22). Furthermore, several DAMP
ligands, including calprotectin (23), lactoferrin (24), S100A calgranulins (25) and HMGB1 (26), are recognized biomarkers of disease
activity and prognosis in IBD. Other receptor systems implicated in
UC, including toll-like receptors (TLRs) (27), C-type lectin receptors (28) and nucleotide-binding
oligomerization domain-like receptors (29), have been well characterized.
However, the contribution of RAGE to UC pathogenesis and its
potential as a therapeutic target remain inadequately understood.
The present review, therefore, highlights the pathobiological
importance of RAGE in UC, summarizing previous advances in clinical
and translational research and exploring its implications for
targeted therapeutic intervention.
Currently, the primary pharmacologic options for
treating UC include corticosteroids, aminosalicylates,
immunomodulators and antibiotics. However, the widespread clinical
application of these drugs is constrained by high costs, notable
toxicities and frequent disease recurrence (30). Although a previous study has
explored dose de-escalation strategies using immunomodulators such
as thiopurines and methotrexate, these regimens have shown limited
efficacy in patients with moderate-to-severe UC compared with
biologic therapies and small-molecule targeted drugs (31). To address these limitations, a new
generation of small-molecule targeted therapies has been developed,
offering distinct advantages such as high oral bioavailability,
reduced risk of immunogenicity and lower manufacturing costs
(32). These agents represent a
promising alternative to conventional biologics in UC management.
Approaches primarily targeting cellular subsets or broad immune
modulation are beyond the scope of the present discussion and are
therefore not included in the classification stated in the present
review.
The IL-12 family has unique heterodimeric cytokines,
including the IL-12, IL-23, IL-27 and IL-35 cytokines; this
heterodimeric property confers a unique set of connectivity and
functional interactions in these cytokines (33). Despite their similar structural
features, the members of the IL-12 family have distinct properties.
Among them, IL-12 and IL-23 play key roles in intestinal
homeostasis and inflammation and are involved in the pathogenesis
of IBD (34). The main
contributions of IL-12 and IL-23 to UC pathogenesis are the
induction of T helper (Th)1 and Th17 cell differentiation,
respectively (35); thus, the
inflammatory effects of IL-12 and IL-23 provide a theoretical
rationale for the development of blocking agents targeting UC.
Inhibitors targeting IL-12/23 attenuate the Th1/Th17-mediated
adaptive immune response, which is a notable contributor to UC
pathogenesis (36).
JAK is a non-receptor tyrosine protein kinase
located downstream of different inflammatory cytokines. As an
intracellular-signaling mediator, JAK interacts with STAT so as to
induce phosphorylation of STAT and activate the target
transcription molecules (11). The
JAK/STAT pathway is an important signaling pathway that allows
extracellular proinflammatory cytokines to relay inflammatory
signals to the nucleus via membrane receptors. Several cytokines
that are notably associated with immunity and intestinal stromal
cell homeostasis, such as IL-6, IL-10, IL-2 and IL-22, as well as
cytokines that act as mediators of pathological responses in UC,
such as IFN-γ, IL-12, IL-23 and IL-9, are dependent on
JAK/STAT-mediated signaling (37,38).
When JAK/STAT signaling is blocked, the nucleus cannot receive
extracellular chemical signals, which reduces inflammation. Thus,
JAK inhibitors can simultaneously block multiple inflammatory
pathways. Demonstrably, JAK inhibitors can broadly affect the
immunopathogenesis of UC, influencing factors such as the
inflammatory response, intestinal epithelial barrier and fibrosis
(11).
The diversity of therapeutic targets identified thus
far underscores the multifactorial nature of UC pathogenesis.
Agents targeting cytokines, such as TNF-α (39–52)
and IL-12/23 (40,53–56),
intracellular signaling pathways, such as the JAK/STAT pathway
(57–67), epithelial barrier integrity, such
as mucin-2, phosphodiesterase 4 (PDE4) inhibitors (68,69)
and lymphocyte trafficking, for example sphingosine 1-phosphate
receptor (70–74), have demonstrated clinical efficacy
in mediating UC (11,12,72,75),
with the detailed clinical trial data of these targeted agents
systematically summarized in Table
SI (39–56,58–74);
however, these therapies typically modulate discrete components of
the inflammatory cascade or adaptive immune response. By contrast,
RAGE represents a distinct signaling axis, primarily activated by
DAMPs generated during tissue stress and injury (76). Functioning as a sensor of
persistent inflammation and cellular injury, RAGE activation
amplifies oxidative stress, perpetuates chronic inflammation and
contributes to fibrotic remodeling, key pathological processes not
fully addressed by current biologics or small molecule inhibitors
(77). The following sections
examine the mechanistic role of RAGE and its ligands in UC
pathogenesis and discuss the potential of targeting this axis as a
novel therapeutic strategy.
The RAGE gene is located on chromosome 6 within the
major histocompatibility complex class III region, which harbors
numerous genes that are important to both adaptive and innate
immune function (78). RAGE is a
50–55 kDa type I transmembrane glycoprotein composed of an
extracellular region containing three Ig-like domains, a variable,
a constant 1 and a constant 2 domain (Fig. 1). Ligand binding predominantly
occurs within the variable domain (79). The extracellular region adjoins a
single transmembrane segment, followed by a short, charged
cytoplasmic tail, the latter being important for intracellular
signal transduction (80,81). Notably, truncation of this
cytoplasmic domain abolishes downstream RAGE signaling and markedly
attenuates RAGE-mediated pathological effects (82,83).
In addition to the membrane-bound full-length RAGE (FL-RAGE), two
soluble isoforms, soluble RAGE (sRAGE) and endogenous secretory
RAGE (esRAGE), have been identified. The former arises from
proteolytic cleavage of membrane-bound RAGE, whereas esRAGE is
produced through alternative mRNA splicing. Both soluble forms can
bind circulating RAGE ligands, acting as ‘decoy’ receptors that
prevent ligand engagement with FL-RAGE and thereby dampen
inflammatory signaling (84,85).
Interactions between cell-surface RAGE and its
ligands initiate a cascade of intracellular events that promote
proinflammatory phenotypes both in vitro and in vivo,
implicating this pathway in the pathophysiology of numerous
diseases (84). In addition to
binding endogenous DAMPs, RAGE can also be activated by
pathogen-associated molecular patterns such as bacterial
lipopolysaccharide (86), viral
proteins (87), parasite-derived
proteins (88) and bacterial DNA
(76). Ligand engagement activates
multiple downstream signaling networks, including the
diaphanous-related formin 1 (89),
MAPK (90), PI3K/Akt (91) and toll-interleukin 1 receptor
domain-containing adaptor protein (92) pathways, culminating in NF-κB
activation. Notably, RAGE signaling forms a self-sustaining
positive feedback loop with NF-κB: Inflammatory stimuli activate
NF-κB, which subsequently upregulates RAGE expression, further
amplifying and prolonging inflammatory responses (93).
RAGE expression has been detected in diverse cell
types, including endothelial cells (ECs), vascular smooth muscle
cells, monocytes and macrophages, granulocytes, adipocytes and
various tumor cells (94).
Aberrant RAGE expression has also been implicated in the
pathogenesis of numerous diseases, such as diabetes (95), atherosclerosis (96), rheumatoid arthritis (97), AD (19), cardiovascular diseases (98) and chronic immune-mediated and
inflammatory disorders (84).
Furthermore, RAGE has been associated with tumor initiation and
progression across multiple types of cancer (99).
The binding of RAGE ligands to membrane-bound RAGE
initiates receptor activation and triggers a cascade of
intracellular signaling events. Increasing evidence identifies RAGE
as an important mediator in the pathogenesis of numerous chronic
inflammatory disorders (100–102). Multiple molecular mechanisms
appear to contribute to disease initiation and persistence in
patients with UC, particularly those amplifying proinflammatory
signaling (103,104). Notably, both RAGE and its ligands
exhibit elevated expression in intestinal epithelial cells from
patients with UC and experimental colitis models, and are localized
predominantly in inflamed mucosal regions (105–108). This interaction of RAGE and its
ligands plays an important role in sustaining mucosal injury and
perpetuating intestinal inflammation.
In UC, chronic inflammation and mucosal damage
promote the accumulation of AGEs, which interact with RAGE to
exacerbate inflammatory signaling. AGEs are naturally formed during
aging however, their formation is accelerated under conditions of
hyperglycemia and oxidative stress, such as in diabetes mellitus
(81). The binding of AGEs to RAGE
activates the NF-κB and MAPK signaling pathways (90), stimulating the release of
proinflammatory cytokines, including IL-6 and TNF-α, thereby
aggravating mucosal inflammation and driving UC progression
(21). AGEs are generated through
the Maillard reaction, a non-enzymatic process in which reducing
sugars react with proteins, lipids or DNA (109). This reaction proceeds from the
formation of reversible Schiff bases and Amadori intermediates to
stable, irreversible AGEs via oxidative rearrangements (110). Given that diabetes is a frequent
comorbidity among patients with UC (111), strategies aimed at glycemic
control, through dietary interventions, hypoglycemic agents or
inhibition of glycation reactions, may effectively suppress AGE
production and attenuate intestinal inflammation. Inhibitors of AGE
synthesis, including aminoguanidine, which has been evaluated in
acetic acid- (112) and
TNF-α-induced rat and murine colitis models (113), metformin, tested in oxazolone-
(114), acetic acid- (115) and dextran sulfate sodium
(DSS)-induced models (116), and
pioglitazone, previously assessed in acute and chronic DSS-driven
murine colitis (117,118), consistently alleviate
inflammation and reduce colonic mucosal injury across experimental
settings. Although some clinical evidence supports these findings,
translational validation remains limited (119).
Another therapeutic strategy involves preventing
AGE-RAGE binding, which can be achieved via soluble receptor
analogs, receptor antagonists or post-receptor signaling
inhibitors. In UC, blockade of this binding suppresses inflammatory
cascades, preserves mucosal integrity and modulates immune
responses (120). Statins, for
instance, interrupt the positive feedback loop between the AGE-RAGE
axis and C-reactive protein expression, thereby reducing
inflammation and oxidative stress (121). Statins, as a potential preventive
and therapeutic strategy for UC, have been shown to attenuate
colitis severity in animal models (122–124). However, clinical investigations
evaluating the disease-modifying and preventive potential of
statins in UC have yielded limited and inconsistent findings
(125–127). Current epidemiologic evidence is
insufficient to support the use of statins for the prevention or
treatment of UC (128).
Low-molecular-weight heparin acts as a competitive
RAGE antagonist by displacing AGE ligands, leading to notable
anti-inflammatory and antioxidant effects in UC, as supported by
clinical evidence (129–131). Collectively, AGEs contribute to
UC pathogenesis through multiple mechanisms that sustain
inflammation and tissue injury. Elucidating these pathways may
yield novel therapeutic targets and provide mechanistic insight
into AGE-RAGE-mediated intestinal pathology.
HMGB1 was the second ligand identified to bind RAGE
following the discovery of AGEs (132). HMGB1 is a highly-conserved
nuclear protein comprising two N-terminal DNA-binding domains and
an acidic C-terminal domain. It is broadly expressed in multiple
tissues, including the brain, heart, lungs, liver, spleen, kidneys
and lymphatic organs, and can be localized in the nucleus,
cytoplasm and extracellular milieu (133). Under resting conditions, HMGB1
predominantly resides within the nucleus; however, upon stimulation
by lipopolysaccharide, 5′-C-phosphate-G-3′ DNA, TNF-α or IL-1,
various immune cells, particularly monocytes and neutrophils,
actively secrete HMGB1 (134).
Passive release also occurs from necrotic cells (134). Both actively and passively
released HMGB1 can bind high-affinity receptors such as TLR2, TLR4
and RAGE on target cells (135–137). These interactions drive immune
cell activation, cytokine release and downstream inflammatory
cascades (138,139). RAGE-HMGB1 binding activates
multiple tumor-associated signaling pathways, including the ERK1/2,
p38 MAPK and NF-κB pathways, thereby promoting cancer progression
and metastasis (140).
In the context of UC, blockade of HMGB1/TLR4 or
HMGB1/RAGE signaling markedly attenuates inflammation in
experimental models (141,142).
Clinically, fecal HMGB1 levels correlate strongly with disease
severity and mucosal activity in UC (143–145), highlighting its promise as a
non-invasive biomarker for both overt and subclinical intestinal
inflammation (26,146). Therapeutic strategies targeting
HMGB1 remain in early development, but preclinical evidence
suggests potential efficacy. Pharmacological agents such as
dapagliflozin (141) and several
natural compounds, including isoliquiritin (147), 20(S)-protopanaxadiol saponins
(148) and matrine (149), have demonstrated anti-HMGB1
effects in experimental models. Nonetheless, the majority of these
interventions remain confined to animal experimental stages
(147,148,150), and rigorous clinical validation
is required to confirm their safety, pharmacokinetics and
therapeutic benefit. To date, HMGB1-targeted therapies have not
entered routine clinical practice, although ongoing advances
warrant close attention to emerging evidence.
The S100 protein family constitutes one of the
largest subgroups of calcium-binding proteins, exhibiting distinct
biological functions and tissue-specific expression patterns
(151). Extracellular S100
proteins interact with several receptors, including RAGE, TLR4,
fibroblast growth factor receptor 1 and G-protein coupled receptors
(152). Through these
interactions, they promote the transcription of proinflammatory
mediators such as TNF-α, IL-1β, IL-6 and IL-8, induce reactive
oxygen species generation and regulate apoptosis (102). Although RAGE binding is
considered a common feature of numerous S100 proteins (153), only specific members, including
S100A1, S100A2, S100A4-9, S100A11-13, S100B and S100P, have been
experimentally validated as RAGE ligands in vivo (154). Among these, S100A8/A9, also known
as calprotectin, is predominantly expressed by neutrophils and is
markedly elevated in IBD. The notable stability of calprotectin in
fecal samples has established it as a robust biomarker of
intestinal inflammation (155,156). Functionally, calprotectin
contributes to epithelial barrier dysfunction by disrupting
cytoskeletal organization and tight junction integrity via TLR4-
and RAGE-dependent pathways in endothelial and epithelial cells
(157). Calprotectin further
compromises EC integrity by downregulating junctional proteins and
increasing vascular permeability (158). The quinoline-3-carboxamide
derivative ABR-215757 binds S100A9 and S100A8/A9 complexes,
blocking their interactions with TLR4 and RAGE, thereby exerting
potent anti-inflammatory effects across several experimental models
(159–161). Localized targeting of
calprotectin in UC mucosa using monoclonal antibodies represents a
promising therapeutic strategy, supported by successful outcomes in
preclinical models of atherosclerosis (162).
Beyond HMGB1 and S100 proteins, several other
endogenous RAGE ligands have been identified, including Aβ
(15), lysophosphatidic acid (LPA)
(163), phosphatidylserine
(164), complement protein C1q
(165) and islet amyloid
polypeptide (166). Although the
involvement of DAMPs in UC remains insufficiently characterized,
emerging evidence suggests that they contribute to disease
pathogenesis or to comorbid conditions associated with UC. For
instance, modulation of adrenergic receptor signaling can preserve
intestinal barrier integrity in UC partly through the presenilin
1/β-secretase-1/Aβ axis, conferring antioxidant, anti-inflammatory
and antifibrotic effects (164).
Similarly, bamboo leaf flavonoids downregulate Aβ expression in the
brain, ameliorating both AD and UC-like inflammation (167). Furthermore, inhibition of the
autotaxin/LPA axis reduces chronic intestinal inflammation by
suppressing Th17 cell differentiation (168,169). Despite these insights, to the
best of our knowledge, no current studies have directly
demonstrated that these ligands exert anti-UC effects specifically
through RAGE signaling. Further mechanistic and translational
investigations are therefore warranted to delineate their roles
within RAGE-dependent inflammatory networks.
Ligand binding to RAGE activates multiple downstream
signaling cascades implicated in the pathogenesis of UC (Fig. 2). These include the Ras/MEK/ERK1/2S
(170), stress-activated protein
kinase/JNK (171), MAPK/p38
(172), PI3K/AKT (173), JAK/STAT (174), Rho GTPase (175) and vascular endothelial growth
factor (VEGF) (176) pathways.
Collectively, these cascades activate the transcription factors
NF-κB, STAT3, activator protein 1 and early growth response-1,
which subsequently induce the synthesis and secretion of vascular
cell adhesion protein 1, intercellular adhesion molecule 1, matrix
metalloproteinase-2, IL-1, IL-6 and TNF-α (15,177–180). DAMP-mediated RAGE activation
drives UC pathogenesis via three interconnected mechanisms: i) Rho
GTPase modulation alters gut microbiota composition and
metabolites, promoting disease progression (175); ii) JAK/STAT signaling regulates
inflammatory mediators and immune cell activation (181); and iii) MAPK pathway activation
induces mitochondrial dysfunction (182), autophagy (183), oxidative stress (184) and apoptosis (185). Collectively, these pathways
underscore the central role of RAGE in UC pathogenesis by
orchestrating inflammation, disrupting intestinal barrier integrity
and dysregulating immune responses. Thus, identifying and
characterizing RAGE-associated downstream targets may offer novel
insights into UC pathophysiology and reveal new therapeutic
strategies.
Angiogenesis, the formation of new capillaries from
pre-existing blood vessels in adult tissues, is a multistep process
involving EC proliferation, migration, differentiation, lumen
formation and maturation, ultimately expanding the microvascular
network (186,187). This process represents a
double-edged sword: While important for wound healing and tissue
repair, it also contributes to pathological tissue remodeling in
cancer and chronic inflammatory diseases. Beyond oncology,
angiogenesis plays a key role in several chronic inflammatory
disorders such as atherosclerosis, rheumatoid arthritis and
psoriasis (188–193). Although angiogenesis has been
implicated in UC (194),
quantitative characterization of mucosal vascular remodeling during
active inflammation remains limited. However, increasing evidence
from clinical and experimental studies demonstrates notable
angiogenesis in UC and Crohn's disease, with elevated vascular
density associating with IBD severity (195–200).
In UC, the colonic mucosa undergoes recurrent cycles
of ulceration and regeneration. This dynamic process increases
local neovascularization and enhances the recruitment of
leukocytes, nutrients and oxygen to inflamed regions (194,201). The expansion of the vascular
network during inflammation is accompanied by notable structural
and functional changes in blood vessels. Functionally, these
changes promote inflammation through several mechanisms: i)
Enhanced leukocyte infiltration; ii) augmented nutrient delivery
that sustains metabolically active immune responses; and iii) EC
activation, which drives local cytokine, chemokine and
metalloproteinase production (202). Consequently, angiogenesis and
inflammation form a self-perpetuating, chronic cycle.
Hypoxia serves as a central trigger in
inflammation-induced angiogenesis. Inflammatory and immune cells
migrate to hypoxic sites, where they release angiogenic mediators,
including growth factors, cytokines, proteases and nitric oxide,
which stimulate EC activation and vascular remodeling. The
resulting neovascularization amplifies inflammation by increasing
the delivery of oxygen, nutrients and inflammatory mediators to
affected tissues (203,204). In UC, this excessive angiogenesis
enlarges the endothelial surface area and enhances vascular
permeability, promoting plasma extravasation and worsening IBD
severity (199). Notably, the
neovessels formed during active UC differ from those generated
during normal physiological angiogenesis. UC-induced vessels are
structurally immature, highly permeable, poorly perfused, prone to
stenosis and thrombosis and display hypersensitivity to growth
factors, features that exacerbate mucosal injury and sustain
chronic inflammation (205,206). Collectively, inflammation and
angiogenesis in UC exist in a reciprocal, self-amplifying
relationship that drives disease progression (207–210).
Angiogenesis is coordinated through a balance of
pro- and anti-angiogenic molecules. Although the VEGF family is a
central player, the angiogenic cascade in UC involves the complex
interplay of multiple factors, receptors and isoforms (211). VEGF is the most extensively
studied angiogenic factor in IBD, with elevated levels in
circulation and the intestinal mucosa associating with disease
activity (212,213). The VEGF family comprises several
isoforms, such as VEGF-A, -B, -C, -D and -E, and placental growth
factor (PlGF), which exert their effects primarily by binding to
three tyrosine kinase receptors: VEGFR1, VEGFR2 and VEGFR3
(214). Although VEGFR2 is the
primary mediator of pathological angiogenesis, driving EC
proliferation, permeability and survival, the roles of other
receptors and isoforms are increasingly recognized. VEGFR1, which
has a higher affinity for VEGF-A than other isoforms but weaker
tyrosine kinase activity than other VEGFRs, acts as a decoy
receptor, thereby fine-tuning the availability of VEGF for VEGFR2
(215). The VEGF2 ligands, VEGF-B
and PlGF, are upregulated in inflammation and modulate
VEGFR1-specific signaling, influencing monocyte recruitment and
inflammatory angiogenesis (216).
Furthermore, the neuropilin (NRP) co-receptors NRP1 and NRP2, which
bind specific VEGF-A isoforms, enhance VEGFR2-signaling complex
formation and signaling potency (217).
The specific splice variants of VEGF-A are notably
important. The pro-angiogenic VEGF-Axxx isoforms, such as
VEGF-A164, dominate in the inflammatory milieu of UC (218). By contrast, the anti-angiogenic
VEGF-Axxxb isoforms, such as VEGF-A164b, are often downregulated,
creating a permissive environment for neovascularization (57). Previous evidence suggests that
restoring the balance of isoforms toward VEGF-A164b can ameliorate
experimental colitis (57).
VEGF-C, primarily known for lymphangiogenesis via VEGFR3, can also
contribute to blood vessel angiogenesis in chronic inflammation
(219).
Under the inflammatory environment of UC, cytokines
such as TNF-α and IL-1β can activate the RAGE-signaling pathway,
which, in turn, promotes the expression and release of VEGF
(21). Alterations in the
extracellular matrix and oxidative stress, both hallmarks of UC,
further amplify RAGE activation and its downstream pro-angiogenic
signals (77,177,220). The downstream signaling of VEGFR2
exhibits notable crosstalk with RAGE-activated pathways. VEGFR2
activates the ERK1/2/MAPK pathway via Ras, which is important for
EC proliferation and migration (221). VEGFR2 also activates PI3K,
leading to the activation of AKT, a central regulator of cell
survival, and small GTPases such as Rac, which guides cytoskeletal
dynamics and EC motility (222,223). Notably, both RAGE and VEGFR2
signaling converge on NF-κB activation, creating a feed-forward
loop that amplifies the production of proinflammatory cytokines and
sustains the angiogenic response (224). Supporting this interconnection,
neutralizing RAGE has been shown to markedly inhibit AGE-induced
activation of both the VEGF and NF-κB pathways (224), while RAGE silencing also inhibits
VEGF expression and angiogenesis in colorectal cancer models
(225).
Beyond VEGF, other angiogenic factor families are
active in UC. The angiopoietin (Ang)/Ang-1 receptor (Tie2) system
is important for vascular maturation and stability. Ang-1, produced
by pericytes, activates Tie2 to promote vessel quiescence and
integrity (226). In UC, the
balance is shifted toward Ang-2, which is stored in and released
from endothelial Weibel-Palade bodies upon inflammatory stimuli.
Ang-2 acts as a context-dependent antagonist of Tie2, destabilizing
vessels, priming them to be more responsive to VEGF and promoting
vascular leakage and inflammation (227). Platelet-derived growth factors
(PDGFs), particularly PDGF-BB produced by ECs and platelets, are
important for recruiting pericytes and vascular smooth muscle cells
in order to stabilize newly formed vessels. PDGF-BB is also
associated with M1 macrophages and has demonstrated notable
potential diagnostic value for active IBD (228).
Despite the central role of VEGF and its synergistic
partners in UC angiogenesis, drug development targeting VEGF has
predominantly focused on oncology. The majority of mechanistic
insights into the RAGE/VEGF axis are derived from diabetes-related
lesions and tumors (229–231). Consequently, there is a notable
gap in the comprehension of the precise mechanisms and therapeutic
potential involved in targeting the RAGE/VEGF network and its
associated angiogenic factors, specifically in UC. Future research
should therefore explore multi-target strategies that co-regulate
RAGE, specific VEGF isoforms and parallel pathways such as the
Ang-2/Tie2 pathway to achieve effective vascular normalization in
UC.
RAGE knockdown is safe in animal models, supporting
the feasibility of developing RAGE-targeted drugs (232). However, to the best of our
knowledge, no anti-RAGE drug has been approved for the treatment of
UC to date. Several investigations are exploring strategies that
interfere with RAGE activation, including antagonistic ligands,
RAGE gene deletion or small-molecule inhibitors (120,233,234). Among these, FPS-ZM1 (77,235) binds to the V-type domain of RAGE,
thereby preventing its interaction with multiple ligands such as
AGEs (84,236–238), HMGB1 (84,239–241), S100B (84,242) and Aβ (243). Other RAGE antagonists or
inhibitors (Table SII) (84,236–244), including azeliragon, alagebrium
and Tanshinone IIA (241,243,244), have been primarily developed for
other RAGE-related conditions, such as neurodegenerative disorders,
diabetes, tumors and inflammatory diseases (237,245,246). As aforementioned, angiogenesis is
a multifactorial process involving numerous cells, molecules and
signaling pathways, all of which may serve as potential therapeutic
targets in UC (21,208,210). Beyond conventional
anti-inflammatory agents, such as 5-aminosalicylic acid
derivatives, glucocorticoids and biologics, which indirectly
modulate VEGF-mediated angiogenesis (247,248), direct anti-VEGF therapies have
gained attention as potential adjunctive treatments. Representative
agents include receptor tyrosine kinase inhibitors, such as
axitinib and sunitinib, and monoclonal antibodies such as
bevacizumab, as well as investigational compounds such as
rapatinib, hesperidin and sorafenib (249–251). These agents inhibit VEGF
activity, suppress new vessel formation and consequently reduce
vascular density and permeability in the colonic mucosa, leading to
attenuation of inflammatory responses and tissue injury (247–251). Despite these promising
mechanisms, clinical outcomes of antiangiogenic drugs in UC remain
suboptimal, and further preclinical and clinical studies are
warranted to validate their efficacy and safety.
Although numerous innovative drugs and biologics
have been approved for UC treatment in previous years, the complex
multifactorial pathogenesis of UC continues to limit therapeutic
efficacy. Furthermore, individualized therapy in UC remains
underdeveloped, and the lack of reliable prognostic biomarkers
complicates the selection of optimal therapeutic regimens (40,47,50,54).
Although sRAGE and esRAGE function as both biomarkers and natural
inhibitors of RAGE-mediated pathology, their large recombinant
protein structures hinder their practical use as therapeutic
agents. Consequently, current research is increasingly focused on
developing small-molecule inhibitors that can selectively target
the extracellular ligand-binding domains of RAGE or its
intracellular signaling cascades (252–254).
Nevertheless, several key questions remain
regarding the long-term safety, pharmacodynamics and physiological
impact of RAGE blockade in humans. Further studies are required to
elucidate the molecular properties of potent RAGE inhibitors and to
clarify the systemic consequences of chronic RAGE inhibition. In
parallel, although VEGF-based antiangiogenic therapies have been
successfully used in clinical trials against various tumors
(255–257), their application in chronic
inflammatory diseases such as UC is still in its infancy.
Antiangiogenic therapy may represent a promising adjunctive
approach to preventing inflammation recurrence and persistence in
UC. Given that angiogenesis involves multiple interdependent steps,
regulated by growth and survival factors, adhesion molecules and
proteases, intestinal angiogenesis in UC provides a
multidisciplinary array of potential pharmacological targets
(258–260). Despite being generally considered
low in toxicity, antiangiogenic agents warrant comprehensive
evaluation to determine their effects on normal physiological
angiogenesis and mucosal healing dynamics. Consequently, combined
targeting of RAGE ligands and VEGF may offer a synergistic and
effective therapeutic strategy for UC. Translation to clinical
applications will require careful evaluation of human tolerability
and maintaining an appropriate physiological-pathological
angiogenesis balance.
Not applicable.
The present article is supported by the Anhui Provincial Health
Research Program (grant nos. AHWJ2023A20431 and AHWJ2023A20431) and
Clinical Research Project of Anhui University of Chinese Medicine
(grant no. 2024YFYLCZX35).
Not applicable.
CX designed the manuscript concept. CX and YL wrote
the manuscript. KH, LW, YH, DZ and FH participated in writing and
reviewing the manuscript. All authors read and approved the final
version of the manuscript. Data authentication is not
applicable.
Not applicable.
Not applicable.
The authors declare that they have no competing
interests.
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