Interleukin-33/suppression of tumorigenicity 2 signaling in gastric injury: From mechanistic validation to spatiotemporal precision

Abstract

The interleukin (IL)-33/suppression of tumorigenicity 2 (ST2) axis is a key regulator of gastric mucosal injury, contributing to inflammatory amplification, epithelial cell death, and tissue remodeling. Recent studies, including those using ST2-deficient models, have reinforced its pathogenic role in acute gastric injury. However, the current literature still relies predominantly on static endpoint analyses, which are insufficient to explain the dynamic and context-dependent functions of IL-33/ST2 signaling across different stages of tissue damage and repair. In this opinion review, we propose shifting the focus from repeated pathway validation to identifying phase-specific regulatory switches and cell-specific functional transitions. We outline a spatiotemporal framework in which epithelial cells initiate injury through IL-33 release, macrophages and mast cells amplify inflammation in intermediate stages, and regulatory or stromal cells promote tissue repair at later stages. We further discuss how molecular imaging of IL-33, tumor necrosis factor-α, caspase-3, and related mediators may enable real-time in vivo tracking of pathway activity and disease progression. Finally, we address technical considerations in gastric imaging, including tissue penetration, spatial resolution, organ motion, and probe delivery. Integrating dynamic biology with molecular imaging may support spatiotemporal precision intervention in gastric injury.

Key Words: Interleukin-33; Suppression of tumorigenicity 2; Molecular imaging; Gastric injury; Molecular target screening

Core Tip: Current studies have established the involvement of interleukin (IL)-33/suppression of tumorigenicity 2 signaling in gastric injury, but most evidence remains derived from static endpoint analyses. We propose that future progress depends on defining when, where, and in which cell populations this pathway shifts from injury-promoting to repair-associated functions. By integrating phase-specific biology with molecular imaging of IL-33, tumor necrosis factor alpha, cysteine-aspartic protease-3, and related targets, a spatiotemporal framework may be developed to identify therapeutic windows and support precision intervention in gastric mucosal injury.

INTRODUCTION

The interleukin (IL)-33/suppression of tumorigenicity 2 (ST2) axis has become an important focus in studies of mucosal immunity and tissue injury[1-3]. In the gastrointestinal tract, this pathway participates in a broad range of biological processes, including epithelial stress signaling, immune-cell activation, cytokine production, and tissue remodeling[3-5]. In gastric injury, accumulating evidence has implicated IL-33/ST2 signaling in acute inflammatory responses, epithelial cell apoptosis, mucosal repair/barrier-related alterations, and tissue remodeling[6-9].

Recent studies have further strengthened this view by demonstrating that ST2 deficiency attenuates acute gastric mucosal damage, providing important mechanistic support for the pathogenic relevance of this axis[10]. Such work has helped clarify that IL-33/ST2 signaling is not simply an associated inflammatory marker, but may represent a functionally significant regulatory pathway in gastric injury[9,11].

Nevertheless, the field remains conceptually constrained by the way this pathway is typically studied. Most investigations still depend on histology, cytokine quantification, immunoblotting, and apoptosis assays performed at terminal or sparsely sampled time points[6,8]. These approaches are valuable for mechanistic validation, but they capture only static snapshots of a process that is inherently dynamic[12]. They do not fully explain when IL-33/ST2 signaling becomes detrimental, whether its biological output changes during recovery[13], or how the dominant responding cell populations shift over time and across tissue compartments[8].

In our view, the next advance in this field will require a transition from static pathway confirmation to dynamic regulatory analysis, and from endpoint tissue observation to real-time in vivo spatiotemporal tracking[5,14]. This Opinion Review does not aim to revalidate the IL-33/ST2 axis as a pathogenic pathway[1,15]; rather, it argues that the central challenge now is to define its phase-specific regulatory logic and to develop imaging-based tools that can capture this logic in vivo. To illustrate this conceptual shift, we propose the integrated framework shown in Figure 1, which links disease phase, cellular activity, and molecular imaging in a single spatiotemporal model.

Figure 1 Visualizing the spatiotemporal dynamics of interleukin-33/suppression of tumorigenicity 2 signaling to establish a molecular imaging framework for precision intervention in gastric injury. This figure demonstrates how molecular imaging technology reveals the spatiotemporal dynamics of the interleukin (IL)-33/suppression of tumorigenicity 2 (ST2) signaling axis during gastric injury and repair through a three-tiered integrated framework. The top layer presents the core elements of the in vivo imaging platform. Through tail vein injection of targeted molecular probes [e.g., anti- tumor necrosis factor-alpha (TNF-α) probe, caspase-3 probe, IL-33 probe] combined with in vivo imaging equipment, continuous, non-invasive monitoring of the same animal model at different time points is achieved. Dynamic curves displayed on monitors visually represent real-time changes in signal intensity, embodying the core advantages of molecular imaging: Dynamic, real-time, in vivo, and continuous. The middle layer elucidates the molecular mechanisms of the signaling axis. IL-33, released as an alarm signal from damaged epithelial cells, activates downstream pathways by binding to the ST2 receptor. This dual action promotes the production of pro-inflammatory factors like TNF-α and IL-1β by inflammatory cells such as macrophages, while simultaneously activating T cells to generate cytokines like IL-4, IL-5, and IL-13 that participate in tissue repair, revealing the dual role of this signaling axis in inflammation and repair. The bottom layer delineates three critical phases of gastric injury: The injury phase, during which damaged epithelial cells release damage-associated molecular patterns; the inflammatory phase, marked by pathway activation and massive production of pro-inflammatory factors; and the repair phase, involving tissue regeneration and restoration of homeostasis. Each phase corresponds to molecular events in the middle layer and imaging probe activity windows in the top layer. IL: Interleukin; TNF-α: Tumor necrosis factor-alpha; ST2: Suppression of tumorigenicity 2.

IL-33/ST2 SIGNALING AS A CENTRAL AXIS IN GASTRIC MUCOSAL INJURY

IL-33 is a member of the IL-1 cytokine family and is widely regarded as an alarmin released after tissue stress or cellular injury[16]. Under basal conditions, IL-33 is predominantly localized in the nucleus of structural cells, including epithelial and stromal cells[17]. Upon injury, it may be released into the extracellular milieu and engage ST2-expressing target cells, thereby initiating or amplifying local immune responses[18,19].

ST2 is expressed by a broad spectrum of immune and non-immune cells, including macrophages, mast cells, T lymphocytes, fibroblasts, endothelial cells, and, in some contexts, epithelial cells[20,21]. This wide receptor distribution allows IL-33/ST2 signaling to function not only as an inflammatory pathway[22], but also as a coordinator of tissue adaptation and remodeling[23]. In gastric mucosal injury, this signaling axis has been linked to at least three major pathological processes.

First, IL-33/ST2 signaling promotes inflammatory amplification[24]. Activation of ST2-positive effector cells may induce the production of pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α), IL-1β, and IL-6, thereby intensifying local tissue injury[25]. Second, the pathway is associated with epithelial apoptosis and barrier dysfunction, both of which are central to acute gastric mucosal damage[6,26]. Third, IL-33/ST2 may also participate in stromal activation and tissue remodeling, indicating that its role extends beyond the initial inflammatory phase[27].

Importantly, however, the biological output of IL-33/ST2 signaling is not uniformly injurious[28]. In other tissue contexts, IL-33 has been reported to support immune regulation, epithelial recovery, and repair-associated responses[29]. This context dependence suggests that the functional meaning of IL-33/ST2 activation in gastric tissue may vary according to injury stage, local cellular composition, and microenvironmental cues[25]. The critical question, therefore, is not simply whether the pathway is activated, but how its function changes over time and across distinct cellular niches.

THE LIMITATIONS OF STATIC ENDPOINT STUDIES

The current body of work has provided substantial mechanistic evidence supporting the involvement of IL-33/ST2 signaling in gastric injury[9,10]. However, repeated demonstration of pathway participation is unlikely, by itself, to resolve the central biological uncertainty of this axis-namely, whether it functions exclusively as a driver of tissue damage or more dynamically as a regulator whose effects depend on disease stage.

Most available studies rely on endpoint analyses performed after injury is already established[5]. Such approaches may accurately detect elevated cytokine levels, increased epithelial apoptosis, or altered histological severity, but they cannot define the temporal sequence of these events[30]. Nor can they clarify whether IL-33 release precedes inflammatory amplification, whether inflammatory signaling persists into the repair phase, or whether distinct cell populations dominate at different time points[31,32].

This limitation is particularly relevant in gastric mucosal injury, which evolves through a sequence of epithelial disruption, inflammatory amplification, and tissue recovery[30,33]. A pathway that is predominantly harmful during acute injury may later contribute to restoration of tissue integrity[1,15]. Accordingly, interventions aimed at broad pathway inhibition are likely to yield different outcomes depending on the timing of administration. Static measurement cannot reliably resolve this problem.

For this reason, the field would benefit from a conceptual shift. Rather than continuing to ask only whether IL-33/ST2 contributes to gastric damage, future studies should define when the pathway is activated, where its activity is concentrated, which cell types mediate its effects at each phase, and how these effects are linked to measurable pathological outcomes. This is precisely the level of resolution that static endpoint studies cannot provide[34,35].

A SPATIOTEMPORAL MODEL OF IL-33/ST2 SIGNALING IN GASTRIC INJURY

We propose that IL-33/ST2 signaling in gastric mucosal injury should be interpreted within a phase-specific framework comprising the injury phase, inflammatory phase, and repair phase[36]. This model does not assume that all biological events occur in strictly discrete intervals[31], but it offers a useful structure for understanding how the functional role of the pathway may evolve.

The earliest phase is characterized by direct epithelial damage caused by factors such as ethanol exposure, acid injury, ischemia, oxidative stress, infection, or nonsteroidal anti-inflammatory drugs[37-39]. In this setting, gastric epithelial cells are likely to serve as an important early source of IL-33 release. As an alarmin, IL-33 signals tissue disruption and initiates downstream immune activation[11]. At this stage, the dominant significance of IL-33 may be its role as an early indicator and trigger of mucosal stress[40].

As injury progresses, innate immune effector cells become increasingly important. Macrophages and mast cells, both of which can express ST2, may respond to IL-33 and amplify local inflammation through the production of TNF-α, IL-1β, IL-6, and other mediators[24,41]. This leads to enhanced leukocyte recruitment, oxidative stress, vascular activation, and epithelial cell death[42,43]. In this phase, IL-33/ST2 signaling may function primarily as a molecular amplifier that links epithelial alarm signaling to broader tissue-destructive inflammation[24].

During later stages, the biological role of the pathway may begin to shift. Regulatory T cells, fibroblasts, stromal cells, and other repair-associated populations may participate in the resolution of excessive inflammation, extracellular matrix remodeling, and restoration of mucosal structure[23,31]. Under these conditions, IL-33/ST2 signaling may contribute less to tissue injury and more to tissue adaptation and repair[27,44]. This possibility is especially important when considering therapeutic inhibition, because suppression of the pathway at a late stage could theoretically interfere with recovery-associated processes.

This phase-oriented interpretation also helps explain why cell-specific functions should not be presented as static properties[45,46]. The same molecule may have different biological implications depending on which cells are active, where those cells are located, and when they dominate the tissue microenvironment[15]. The major cell populations and their proposed phase-specific roles are summarized in Table 1.

Table 1 Function of the interleukin-33/suppression of tumorigenicity 2 signaling pathway in different cell types.

Cell type	Key molecules	Function
Mast cell	TNF-α, IL-1β, IL-6, IL-13, VEGF	Amplification of inflammation, vascular responses, and tissue remodeling; increased cell adhesion and immune cell crosstalk
Th2 cell	IL-4, IL-5, IL-10, IL-13	IL-33 exerts a chemotactic effect on Th2 cells; it promotes the polarization of naive T cells toward the Th2 pathway
Treg cell	FoxP3, ST2	IL-33/ST2 axis promotes Treg expansion; suppresses IL-17 and IFN-γ production
Eosinophil	IL-4, IL-5, IL-9, IL-13, GM-CSF	Dual involvement in pro-inflammatory and immunomodulatory functions
ILC2	IL-6, IL-4, IL-5, IL-9, IL-13	Central amplifier of Type 2 immune responses
Dendritic cell	IL-1β, IL-6, TNF-α, CD80, CD86	IL-33 promotes the polarization of naïve T cells toward Th2 cells by activating dendritic cells
Fibroblast	ERK, p38 MAPK	IL-33 activates fibroblasts (ERK/p38 MAPK–dependent) to produce chemokines and promote eosinophil infiltration
B cell	IL-4R	IL-33 activates B cells during delayed-type hypersensitivity and increases IL-4R+ B cells, facilitating IgE production
Macrophage	IL-1β, IL-6, IL-10, VEGF, MMP9	IL-33-induced STAT1 signaling correlates with IFN-γ output

TNF-α: Tumor necrosis factor alpha; IL: Interleukin; VEGF: Vascular endothelial growth factor; FoxP3: Forkhead box P3; ST2: Suppression of tumorigenicity 2; IFN-γ: Interferon gamma; GM-CSF: Granulocyte-macrophage colony-stimulating factor; CD80: Cluster of differentiation 80; CD86: Cluster of differentiation 86; ERK: Extracellular signal-regulated kinase; p38 MAPK: P38 mitogen-activated protein kinase; IL-4R: Interleukin-4 receptor; MMP-9: Matrix metalloproteinase-9; STAT1: Signal transducer and activator of transcription 1.

AN INTEGRATED CONCEPTUAL FRAMEWORK: FROM PATHWAY BIOLOGY TO IMAGING

The central premise of this review is illustrated in Figure 1, which presents an integrated conceptual framework linking pathological progression, IL-33/ST2 signaling biology, and molecular imaging readouts. Rather than listing cellular functions and candidate imaging targets independently, this framework places them into a unified spatiotemporal model.

As shown in Figure 1, the bottom layer depicts the progression of gastric mucosal injury from the initial injury phase to inflammatory amplification and finally to tissue repair[30,47]. The middle layer summarizes the corresponding biological events of the IL-33/ST2 axis, including epithelial IL-33 release, activation of ST2-positive inflammatory cells, downstream cytokine production, and later engagement of repair-related responses[5,22]. The top layer illustrates the proposed in vivo imaging strategy, in which targeted probes are used for longitudinal tracking of pathway activity in the same subject over time[48,49].

This integrated design addresses a major limitation of conventional endpoint studies. It emphasizes that the significance of IL-33/ST2 signaling cannot be fully understood without considering time, space, and cell type simultaneously[50]. In this sense, Figure 1 is not only a schematic summary, but also a statement of the conceptual shift that we believe the field now requires.

MOLECULAR IMAGING AS A TOOL TO DECODE DYNAMIC IL-33/ST2 ACTIVITY

Molecular imaging offers a unique opportunity to transform abstract mechanistic hypotheses into measurable, time-resolved biological signals[51,52]. In the context of IL-33/ST2 signaling, candidate imaging targets should not be viewed as isolated biomarkers, but rather as functional reporters of distinct stages within the signaling cascade and its downstream pathological consequences[53,54]. As summarized conceptually in Table 2[55-69], these targets collectively allow a spatiotemporal readout of pathway initiation, inflammatory amplification, immune-cell recruitment, epithelial injury, vascular adaptation, and tissue remodeling.

Table 2 Current advances in molecular imaging of the interleukin-33/suppression of tumorigenicity 2 signaling pathway.

Target	Imaging	Label	Research	Disease	Year	Notes	Ref.
IL-33	NA	NA	Preclinical	Acute and chronic viral infection	2021	Although the GFP reporter gene was employed, no in vivo imaging was performed; only traditional fluorescence microscopy was utilized	Aparicio-Domingo et al[55]
ST2	NA	BODIPY	Preclinical	NA	2024	An IL-33 analog was conjugated to a fluorescent dye to bind to ST2. This was only performed at the cellular level without in vivo imaging; attempts at in vivo fluorescence imaging could be pursued	Reese et al[56]
ST2 L	NA	Luciferase reporter gene	Preclinical	Th2-mediated diseases	2001	Autofluorescence imaging is feasible, but the study did not perform in vivo imaging and only conducted ex vivo validation	Carter et al[57]
mTNF	Fluorescence imaging	FITC	Clinical	Crohn’s disease	2014	Detecting TNF to Predict Treatment Response in Crohn’s disease	Atreya et al[58]
CD11b	PET	NA	Preclinical	Gastric cancer	2022	In vivo real-time PET imaging of CD11b	Zhang et al[59]
VEGFR3	Fluorescence imaging	Cy5.5; IRdye800	Preclinical	Cancer lymphatic metastasis	2024	In vivo fluorescence imaging of VEGFR3	Shen et al[60]
caspase-3	MRI	NA	Preclinical	apoptosis-related diseases	2023	Lack of in vivo imaging in animal disease models	Xu et al[61]
MyD88	NA	eGFP, DsRed2	Preclinical	Bacterial Infection	2009	Achieved only at the cellular/lineage level	Hall et al[62]
AP-1	Fluorescence imaging	Luciferase reporter gene	Preclinical	Solar UV-induced inflammatory skin damage	2023	AP-1 is fused to the luciferase gene. The intensity of the fluorescence signal reflects AP-1 transcriptional activity	Snell et al[63]
Neutrophil elastase	Fluorescence imaging, photoacoustic imaging	Hemi-cyanine	Preclinical	Lung cancer	2022	Excitation fluorescence and photoacoustic imaging of human neutrophil elastase	Zhang et al[64]
STAT1	NA	GFP, RFP, luciferase reporter gene	Preclinical	Not a specific disease	2013	Achieved only at the cellular level, with potential for in vivo imaging	Samsonov et al[65]
Caspase-1	NA	TPETH	Preclinical	Inflammation-related diseases	2018	Failure to perform in vivo fluorescence imaging on animals	Lin et al[66]
Caspase-1	NA	Luciferase reporter gene	Preclinical	DSS-induced colitis and secondary neuroinflammation	2021	Fluorescence imaging was performed on excised tissue; no in vivo imaging was conducted	Talley et al[67]
IL-13	NA	eGFP	Preclinical	Allergic airwayinflammation	2016	It is believed that IL-33 regulates IL-13 production via ST2. The study primarily performed fluorescent detection of IL-13 in tissue sections, without conducting in vivo dynamic imaging	Piehler et al[68]
Caspase-3/7	NA	Luciferase reporter gene	Preclinical	Cancer	2018	Data from live imaging not displayed	Pal et al[69]

IL: Interleukin; ST2: Suppression of tumorigenicity 2; ST2 L: Suppression of tumorigenicity 2 ligand; CD11b: Cluster of differentiation 11b; VEGFR3: Vascular endothelial growth factor receptor 3; caspase-3: Cysteine-aspartic protease-3; MyD88: Myeloid differentiation primary response 88; AP-1: Activator protein 1; STAT1: Signal transducer and activator of transcription 1; caspase-1: Cysteine-aspartic protease-1; caspase-7: Cysteine-asparticprotease-7; PET: Positron emission tomography; MRI: Magnetic resonance imaging; NA: Not available; GFP: Green fluorescent protein; RFP: Red fluorescent protein.

Because IL-33 is released from damaged epithelial cells at the earliest stage of tissue injury, probes targeting IL-33 may be particularly informative during the initial injury phase[70]. Such probes could define the onset, magnitude, and spatial distribution of epithelial alarm signaling before full inflammatory amplification occurs[71]. This would provide a more direct and dynamic view of pathway initiation than conventional histological sampling alone[72].

Beyond IL-33 itself, a broader panel of imaging targets may be used to capture the downstream consequences of IL-33/ST2 activation. TNF-α is one of the most relevant effectors of inflammatory amplification and can serve as a useful marker of the intermediate inflammatory phase[58]. In addition, other inflammatory mediators, such as IL-1β and related cytokine signals, may further refine the visualization of innate immune activation[73]. Depending on the biological question, markers associated with myeloid-cell infiltration, such as CD11-related targets, may also be useful for tracking the recruitment and accumulation of inflammatory cells[74]. Together, these probes can help characterize the period during which macrophage- and mast cell-driven tissue injury is most active and spatially heterogeneous.

Caspase-3 is a key executioner of apoptosis and represents an important downstream pathological outcome of mucosal injury[75]. Given the reported reduction of epithelial apoptosis following ST2 deficiency, caspase-3-targeted probes may serve as a non-invasive surrogate for injury severity and therapeutic response[10]. Such imaging can bridge pathway activation with one of its most relevant tissue-level consequences and may help distinguish persistent inflammatory damage from early recovery.

In addition to inflammatory and apoptotic readouts, imaging targets linked to vascular activation and remodeling may provide important complementary information. VEGFR-related markers and other endothelial-associated targets may reflect changes in vascular permeability, angiogenic activity, and stromal adaptation during the transition from inflammation to repair[76]. These signals may be especially useful for evaluating later-stage tissue remodeling and repair-associated changes.

Together, these imaging targets represent a practical multistep framework rather than a single-marker strategy. IL-33 may report pathway initiation[70], inflammatory cytokines such as TNF-α and IL-1β may reflect signal amplification[58,73], caspase-3 may indicate tissue damage execution, myeloid markers may capture inflammatory cell infiltration[75], and vascular or remodeling-associated markers may report later tissue adaptation[76]. Depending on the experimental setting, reactive oxygen species-responsive probes and other activatable imaging agents may further expand this framework by providing information on oxidative stress and microenvironmental injury[77]. Accordingly, the value of molecular imaging lies not in selecting one optimal probe, but in building a tiered biomarker panel that captures the full spatiotemporal trajectory of gastric injury.

WHY REAL-TIME IN VIVO TRACKING IS NECESSARY

Conventional methods such as hematoxylin-eosin staining, immunohistochemistry, Western blotting, enzyme-linked immunosorbent assay, and reverse transcription-polymerase chain reaction remain indispensable for mechanistic validation[78,79]. However, their interpretive power is limited when the biological question concerns temporal transitions or spatial heterogeneity. In most animal studies, tissue must be harvested at predefined time points, and different individuals are used for each stage[80]. This makes it difficult to reconstruct continuous pathway dynamics and to distinguish true phase transitions from inter-individual variation.

Real-time in vivo imaging offers a fundamentally different approach[80]. By allowing longitudinal observation of the same subject, it can generate temporal signal trajectories, define peaks and declines of pathway activity, identify spatially restricted hotspots, and monitor treatment response over time[81,82]. Such information is especially valuable for pathways like IL-33/ST2 that may exert both pathogenic and reparative functions depending on the disease stage.

The implications are not only mechanistic, but also therapeutic. If the pathway is harmful during inflammatory escalation but beneficial during later tissue recovery, then the timing of intervention becomes a critical determinant of efficacy. Dynamic imaging may therefore help define not just whether a target is relevant, but when it is most appropriately modulated.

TECHNICAL FEASIBILITY AND CHALLENGES OF GASTRIC MOLECULAR IMAGING

Although the rationale for molecular imaging is compelling, successful implementation in gastric tissue requires careful consideration of organ-specific constraints[83]. Imaging methods must be adapted to the anatomy and physiology of the stomach rather than extrapolated generically from other tissues. Three issues are especially important: Tissue depth, motion artifacts, and probe delivery.

The stomach is a layered organ in which many relevant events occur in the mucosa and submucosa[84]. Therefore, imaging platforms must provide adequate tissue penetration while preserving sufficient spatial resolution to distinguish superficial from deeper wall compartments. Near-infrared region II fluorescence imaging may offer advantages for small-animal studies, with penetration depths in the range of approximately 1-2 cm, making it suitable for superficial gastric imaging under optimized conditions[85]. In future translational settings, endoscopic deployment may further improve mucosal accessibility.

Photoacoustic imaging is also promising because it integrates optical contrast with ultrasound-based depth resolution and can achieve penetration depths of approximately 2-3 cm. This may facilitate improved localization of molecular signals within the gastric wall[86]. By contrast, positron emission tomography and single photon emission computed tomography provide excellent whole-body sensitivity and unrestricted penetration depth, but their spatial resolution may be insufficient for precise wall-layer assignment in the stomach[87].

Motion artifacts caused by gastrointestinal peristalsis are another major obstacle. In this context, fluorescence endoscopy may be particularly advantageous because it enables direct, close-range visualization of the mucosal surface and reduces the impact of whole-organ motion on image quality[52]. In addition, computational approaches such as image registration and machine learning-based motion correction may improve the reliability of serial imaging datasets. These methods will be increasingly important for quantitative longitudinal studies[88].

Probe delivery is equally important. Systemic administration of molecular probes may be limited by blood clearance, nonspecific background accumulation, and poor penetration across the gastric mucus barrier[89]. For this reason, endoscopic local delivery may offer a practical alternative for fluorescence-based probes, allowing direct application to the mucosal surface and increasing local target exposure[90]. Probe design is also critical. Compared with conventional full-length antibodies, small peptides, nanobodies, and related compact affinity ligands generally penetrate tissue more efficiently and may better access mucosal or interstitial targets[91,92]. Optimization of molecular size, charge, pharmacokinetics, and binding affinity will be essential for improving both signal specificity and tissue distribution. Taken together, these considerations indicate that molecular imaging of gastric injury is technically feasible, but only if imaging modality and probe design are selected in a manner tailored to gastric physiology and the spatial biology of the IL-33/ST2 axis.

TOWARD SPATIOTEMPORAL PRECISION INTERVENTION

The broader value of this framework lies in its therapeutic implications. If IL-33/ST2 signaling exerts distinct functions across the injury, inflammatory, and repair phases, then intervention strategies should also become phase-sensitive[19]. Early inhibition may be beneficial if the dominant effect of the pathway is inflammatory amplification and epithelial damage. However, prolonged or untimely blockade could be less effective, or even counterproductive, if the pathway later contributes to mucosal restoration or immune regulation.

This possibility argues for a model of spatiotemporal precision intervention, in which treatment decisions are informed by real-time information about pathway activity, tissue distribution, and disease stage. Within such a framework, molecular imaging would not serve merely as an observational tool, but as a platform for defining therapeutic windows, evaluating treatment response, and distinguishing injurious from potentially reparative pathway activity[87,93].

CONCLUSION

The IL-33/ST2 axis has become an increasingly important focus in gastric injury research because of its involvement in inflammation, epithelial apoptosis, and tissue remodeling. Yet despite growing mechanistic evidence, the field remains limited by an overreliance on static endpoint analyses. This has constrained our ability to understand when the pathway is pathogenic, when it may become repair-associated, and how its cellular effectors shift during disease progression. In our view, future progress depends on two related transitions: From static pathway validation to dynamic regulatory analysis, and from terminal tissue assessment to real-time in vivo spatiotemporal tracking. A framework that integrates phase-specific biology, cell-specific functions, and molecular imaging may provide a more accurate understanding of IL-33/ST2 signaling in gastric injury. More importantly, it may help establish a foundation for stage-adapted and spatially informed precision intervention.