Unraveling the pleiotropic roles of the mTOR-glycolytic axis in ulcerative colitis: from immunometabolic dysregulation to mucosal barrier remodeling

Abstract

Ulcerative colitis (UC) is a chronic, relapsing inflammatory disorder of the colonic mucosa, whose pathogenesis is intricately linked to metabolic reprogramming within both immune and epithelial compartments. The mechanistic target of rapamycin (mTOR) signaling pathway serves as a central immunometabolic hub that integrates nutrient availability, microbial cues, and inflammatory signals to orchestrate glycolytic flux, thereby profoundly shaping the functional plasticity of diverse intestinal cell populations. This review systematically delineates, from a cell-type-specific perspective, the divergent regulatory roles of the mTOR-glycolysis axis in intestinal immunity and mucosal barrier homeostasis. We first outline the core molecular architecture of mTORC1/mTORC2-driven glycolytic reprogramming, highlighting key regulatory nodes including GLUT1/3-mediated glucose uptake, HK2-dependent rate-limiting phosphorylation, and PKM2-governed metabolic-transcriptional switching. Subsequently, we examine how aberrant mTOR-glycolysis axis activation in neutrophils, macrophages, type 3 innate lymphoid cells, and CD4+ T effector subsets propagates a feed-forward inflammatory loop—exacerbating oxidative burst, NETosis, M1 polarization, and Th17 pathogenicity—while simultaneously undermining the metabolic fitness and suppressive integrity of regulatory T cells. Moreover, we discuss the metabolic rewiring of intestinal epithelial cells via the mTOR-glycolysis axis, which compromises barrier integrity, disrupts epithelial regeneration, and initiates a “metabolic-secretory” crosstalk that perpetuates mucosal inflammation. Collectively, this review positions the mTOR-glycolysis axis as a rheostat governing the transition from homeostatic immunosurveillance to pathogenic inflammation in UC, and proposes that cell-selective metabolic checkpoint targeting—rather than broad systemic inhibition—represents a promising precision strategy for future therapeutic intervention.

1. Introduction

Ulcerative colitis (UC) is a chronic, idiopathic inflammatory bowel disease (IBD) characterized by a relapsing-remitting course of colonic mucosal inflammation. Typically, the disease process originates in the rectum and propagates proximally in a continuous fashion, involving variable extents of the colon (1). Although the incidence of UC has historically predominated in Western nations, its global epidemiological landscape is undergoing a profound transition. While trends in high-income countries have begun to plateau, newly industrialized regions—including Asia, Latin America, and Africa—are witnessing a rapid and disproportionate surge in disease prevalence (2). The pathogenesis of UC is widely conceptualized as a multifactorial process wherein environmental triggers and dysregulated microbial metabolic signatures converge in genetically susceptible individuals to incite a chronic, aberrant immune response against the colonic mucosa, ultimately culminating in the collapse of epithelial barrier homeostasis (3). To date, the triad of intestinal epithelial barrier integrity, host immune reactivity, and gut microbial metabolic homeostasis remains pivotal in both the pathogenesis and therapeutic landscape of UC. The management paradigm has undergone a fundamental shift from reactive symptom control toward proactive, target-driven strategies centered on “mucosal healing”. Nevertheless, conventional pharmacological interventions—including aminosalicylates, corticosteroids, immunomodulators, and biologics—encounter a formidable “therapeutic ceiling,” with a significant subset of patients exhibiting primary non-response or secondary loss of response to existing biologics and small-molecule inhibitors (4). Therefore, elucidating UC pathogenesis from novel mechanistic perspectives and identifying innovative therapeutic targets are of paramount importance for overcoming the limitations inherent in current clinical interventions.

mTOR is a highly conserved serine/threonine kinase that acts as a pivotal immunometabolic hub. It integrates extrinsic signals, including nutrient availability and immune challenges, to coordinate essential cellular processes such as growth, autophagy, and immune cell lineage specification (5). Emerging evidence indicates that the mTOR signaling pathway integrates luminal nutrient cues with host immune inputs to modulate the reciprocal balance between pro-inflammatory T helper 17 (Th17) and regulatory T (Treg) cells. Dysregulation of this signaling axis precipitates the breakdown of intestinal immune tolerance and exacerbates the chronic inflammatory milieu characteristic of UC (6). By positioning the mTOR pathway at the nexus of luminal metabolic equilibrium and systemic immune reactivity, fine-tuning this signaling axis offers a dual therapeutic potential: not only to dampen refractory inflammation but also to reinstate metabolic homeostasis within the intestinal epithelial cells of UC patients (7, 8). Beyond its canonical role in bioenergetic replenishment, glycolysis serves as a critical metabolic nexus that shunts glucose-derived carbon intermediates into divergent biosynthetic branches. This redirection fulfills the heightened anabolic demands of cells and fuels the inflammatory effector functions of activated immune subsets (9). Evidence suggests that this metabolic transition toward accelerated glycolysis—commonly termed metabolic reprogramming—functions as a fundamental bioenergetic engine. It governs the pro-inflammatory polarization of mucosal macrophages and the differentiation of Th17 cells, thereby precipitating a cytokine storm and exacerbating the breakdown of intestinal immune tolerance (10). Consequently, the aberrant upregulation of glycolysis within the intestinal microenvironment represents a pivotal pathophysiological driver that transcends mere bioenergetic provision. During UC pathogenesis, the mTOR signaling pathway functions as a central immunometabolic hub, orchestrating glycolytic reprogramming across diverse intestinal cell populations and profoundly impacting both mucosal barrier integrity and intestinal immunity (11). Accordingly, this review adopts a cell-type-specific framework to systematically delineate the divergent regulation of the mTOR-glycolysis axis in intestinal immunity and barrier integrity, aiming to provide novel strategic perspectives and therapeutic avenues for the management of UC.

2. Overview of the core molecular mechanisms governing the mTOR-glycolysis axis

2.1. Molecular mechanisms of synergistic metabolic reprogramming driven by mTORC1 and mTORC2 complexes

mTOR functions through two distinct complexes: mTORC1 and mTORC2. As a central metabolic sensor, mTORC1 integrates diverse cues—including amino acids, growth factors, energy status (ATP/AMP), and oxygen levels—via its precise lysosomal localization. In contrast, mTORC2 primarily responds to growth factor signaling and associates with functional ribosomes to integrate the cellular translational state (12, 13). Mechanistically, mTORC1 synergizes with the core transcriptional networks of HIF-1α and c-Myc to remodel the glycolytic landscape (14). The mTORC1-eIF4E axis not only stimulates the translation of HIF-1α mRNA but also counteracts its VHL-mediated degradation under normoxia through robust protein synthesis. This culminates in the pathological stabilization of HIF-1α protein, thereby driving the transcription of GLUT1, HK2, PFKFB3, and LDHA (15). Simultaneously, mTORC1 enhances both the translation and protein stability of c-Myc by inhibiting its ubiquitination-mediated degradation. In turn, c-Myc directly drives the transcription of virtually all glycolytic enzymes and PDK1, compelling the cells into a lactate-producing mode (16). Through this HIF-1α/c-Myc transcriptional axis, mTORC1 establishes a positive feedback loop that sustains high glycolytic flux, thereby meeting the biosynthetic demands of rapidly proliferating cells (17, 18). mTORC2 modulates glycolytic metabolism through various downstream effector pathways, with the AKT signaling axis serving as the primary regulator. Upon growth factor stimulation, mTORC2 phosphorylates AKT at Ser473; subsequently, activated AKT drives the glycolytic program at both transcriptional and post-translational levels (12). At the transcriptional level, AKT promotes the nuclear translocation of SREBP1c and upregulates glucokinase (GCK) expression, thereby facilitating glucose phosphorylation and channeling glucose-derived carbons into the glycolytic pathway. Post-translationally, mTORC2-activated AKT modulates the activity of GSK3β, whose inactivation relieves the inhibition of multiple downstream metabolic targets (19). In the liver, the mTORC2-AKT-glucokinase-SREBP1c axis orchestrates the coordination of glucose uptake and glycolytic pathways with de novo lipogenesis, thereby coupling carbohydrate catabolism to systemic metabolic homeostasis (20). In the context of cancer, the mTORC2-AKT signaling pathway interacts with PFKFB2, a rate-limiting regulator of glycolysis. PFKFB2 functions by promoting the production of fructose-2,6-bisphosphate, thereby sustaining high glycolytic rates in proliferating cells (21, 22).

2.2. Key regulatory nodes of glycolysis

Intestinal metabolic reprogramming relies on the exquisite modulation of multiple key nodes within the glycolytic pathway (Table 1). Specifically, glucose uptake, HK2-catalyzed rate-limiting phosphorylation, and the dual metabolic and transcriptional roles of PKM2 constitute the core regulatory framework of glycolysis.

Table 1.

Clinical biomarkers related to glycolytic metabolism in UC.

Biomarker	Detection of source	The role in glycolysis metabolism	Correlation with UC clinical manifestations	References
PKM2	Peripheral serum	PKM2 is the rate-limiting enzyme for glycolysis. Under inflammatory conditions, PKM2 transforms from a tetramer to a dimer, thereby inducing the release of pro-inflammatory factors.	It is positively correlated with the Mayo score and CDAI score of UC, as well as the endoscopic activity. It is also significantly correlated with CRP and ESR.	(23)
lactic acid	faeces	Lactic acid is the final product of glycolysis. Accumulation of lactic acid indicates a shift in metabolism towards aerobic glycolysis, leading to acidosis in tissues.	The fecal lactate levels in patients with active ulcerative colitis are significantly elevated. Excessive accumulation of lactate can lead to a decrease in intestinal pH, exacerbate mucosal damage, and indicate a lower clinical remission rate.	(24)
HIF-1α	Intestinal mucosa Biopsy	The upstream regulators and downstream targets of PKM2. It drives the transcription of glycolytic genes such as GLUT1 and LDHA.	Epithelial cells express HIF-1α, which promotes repair, while immune cells express HIF-1α, which mediates damage. This is the core for evaluating the “spatiotemporal metabolic landscape”.	(25)
PDK2	Intestinal mucosa Biopsy	The increase in PDK2 indicates a complete shift of the metabolic flow from the mitochondrial cycle to glycolysis, and it is a driver of tissue inflammation and oxidative stress.	PDK2 is significantly upregulated in patients with active ulcerative colitis. High expression indicates severe mitochondrial dysfunction and a lower rate of clinical remission.	(26)
GLUT1	Intestinal mucosa Biopsy	GLUT1 is the core transporter for cells to take in glucose. Its high expression directly drives a large influx of glucose, providing sufficient substrates for the subsequent glycolysis process.	The expression intensity and spatial distribution of GLUT1 reflect the metabolic requirements of the tissue. In UC, it is a clear biomarker of high metabolic activity of cells.	(27)
HK2	Intestinal mucosa Biopsy	HK2 efficiently utilizes ATP to phosphorylate glucose into 6-phosphoglucose by binding to the outer mitochondrial membrane, thereby irreversibly initiating and maintaining a high glucose glycolysis flux.	The expression of HK2 at the top indicates that the epithelial cells are undergoing severe metabolic remodeling, suggesting that the mucosal barrier is about to develop ulcers or erosions. It can be used as an early biochemical warning indicator before endoscopic examination.	(28)

2.2.1. Glucose uptake: GLUT1/3-mediated regulation of the metabolic gateway

The initiation of glycolysis is predicated on transmembrane glucose transport as a rate-limiting prerequisite, which is primarily mediated by the transporters GLUT1 and GLUT3. Research indicates that while GLUT1 is ubiquitously overexpressed across various malignancies to sustain basal glucose requirements, GLUT3—possessing a five-fold higher substrate affinity and superior transport velocity—affords cancer cells a competitive advantage in glucose acquisition within low-glucose microenvironments (29). Accordingly, dysregulated GLUT1 and GLUT3 expression is considered a major contributor to the malignant evolution of tumors (30). Acting as a “metabolic switch”, the upregulation of GLUT1/3 facilitates accelerated glycolytic flux in UC mucosa, echoing its established role in cancer biology (31). Mechanistically, the transcriptional landscape is dominated by HIF-1α and c-Myc; stabilized HIF-1α under hypoxic conditions directly activates the transcription of these transporters, whereas c-Myc potently augments their levels via synergistic recruitment to the promoter elements (32). Furthermore, the PI3K/Akt signaling pathway orchestrates multi-layered glycolytic reprogramming by facilitating the membrane translocation and activation of GLUT1, while simultaneously phosphorylating a series of downstream metabolic enzymes, including HK2, PFKFB3/4, and PKM2 (33).

2.2.2. HK2: a mitochondrial-bound regulatory node governing rate-limiting phosphorylation

Upon cellular entry, glucose is phosphorylated into glucose-6-phosphate (G6P) by hexokinase 2 (HK2), a reaction that constitutes the first irreversible and rate-limiting step of glycolysis (34). Distinct from other hexokinase isoforms, HK2 is markedly upregulated in tumor cells and possesses an exclusive mitochondrial-tethering capacity. This localization is orchestrated by its N-terminal hydrophobic domain, which mediates the interaction with the voltage-dependent anion channel (VDAC), thereby anchoring HK2 securely to the outer mitochondrial membrane (35). This subcellular compartmentalization endows HK2 with a dual functional edge: it facilitates the privileged access to mitochondrially exported ATP for glucose phosphorylation, thereby markedly accelerating glycolytic flux and fueling anabolism with abundant biosynthetic precursors. Concurrently, by safeguarding the permeability barrier of the outer mitochondrial membrane, HK2 suppresses cytochrome c release, directly antagonizing the intrinsic apoptotic signaling pathway (36). The transcriptional landscape of HK2 is orchestrated by a network of oncogenic cascades, including the PI3K/Akt (37), MAPK (38), and NF-κB (39) pathways. Beyond its canonical enzymatic hallmarks, emerging evidence identifies HK2 as a signaling transducer that modulates mTORC1 activity and drives the remodeling of the immune microenvironment (40). The mitochondrial dissociation of hexokinase 2 (HK2) represents a pivotal event in the immune cell response to acute stress. Under steady-state conditions or in the presence of pro-survival signaling, Akt suppresses GSK3β activity to maintain the mitochondrial localization of HK2 (41). Conversely, under inflammatory stress, activated GSK3β directly phosphorylates HK2 at residues Thr473 and Ser465, triggering its detachment from the mitochondria. This translocation not only impairs efficient energy coupling but also serves as a critical molecular switch orchestrating neutrophil apoptosis and the oxidative burst (42).

2.2.3. PKM2: a dual-function metabolic and transcriptional hub governed by oligomeric state switching

The terminal regulatory gatekeeper of glycolysis is presided over by Pyruvate Kinase M2 (PKM2), which is distinguished by its ability to execute dual metabolic and transcriptional programs through reversible oligomeric switching. In its highly active tetrameric state, PKM2 catalyzes the irreversible conversion of phosphoenolpyruvate (PEP) to pyruvate, propelling glycolytic carbon flux toward its terminal stage for efficient ATP production. Conversely, when PKM2 dissociates into low-activity dimers, upstream glycolytic intermediates accumulate and are shunted into the pentose phosphate pathway and serine synthesis pathway. This metabolic rewiring provides essential biosynthetic building blocks—including nucleotides, amino acids, and lipids—to sustain the biomass demands of rapidly proliferating tumor cells (43). More pivotally, the dimeric form of PKM2 undergoes nuclear translocation, where it assumes non-canonical roles as both a transcriptional coactivator and a protein kinase (44). In the UC intestinal mucosal inflammatory microenvironment, the equilibrium between PKM2 tetramers and dimers is exquisitely regulated by a diverse repertoire of post-translational modifications (PTMs), FGFR1-mediated Tyr105 phosphorylation (45), Lys305 acetylation (46), and ROS-induced Cys358 oxidation collectively inhibit PKM2 activity (47), thereby diverting metabolic flux toward biosynthetic pathways. Concurrently, pro-inflammatory signaling triggers LDHA phosphorylation at the Tyr10 residue. This modification enhances the binding affinity of LDHA for its substrate NADH, accelerating the conversion of pyruvate to lactate to sustain the rapid energetic demands of immune cells under stress (48). Beyond rapid regulatory mechanisms such as phosphorylation and oxidation, the control of protein stability for key metabolic enzymes is a cornerstone of immune cell metabolic reprogramming. PFKFB3, a master regulator of glycolysis, is highly expressed during immune cell activation to drive ATP production. However, its intracellular abundance is stringently governed by the ubiquitin ligase complex APC/C-Cdh1, which mediates PFKFB3 ubiquitination and subsequent proteasomal degradation, effectively constraining glycolytic flux (49). In the intestinal inflammatory microenvironment, dysregulation of this degradation mechanism can lead to persistent metabolic hyperactivation in neutrophils or macrophages, ultimately exacerbating oxidative stress and tissue damage.

2.3. spatiotemporal orchestration of immunometabolism: reshaping immune cell fate decisions via the mTOR-glycolysis axis

While evolutionarily linked by a common catalytic subunit, mTORC1 and mTORC2 function as non-redundant modulators of glycolytic flux within the immune system. This divergence in function is rooted in their differential recruitment of upstream cues and effector substrates, ultimately leading to lineage-specific physiological outcomes (50). mTORC1 functions as a nutrient-sensitive initiator that orchestrates effector-associated glycolytic programs. In CD8+ cytotoxic T lymphocytes (CTLs) and T helper 17 (Th17) cells, TCR engagement alongside co-stimulation triggers mTORC1 activation, which selectively enhances the transcription of HIF-1α mRNA via the S6K1/4E-BP1 signaling axis (51). The accumulated HIF-1α protein complexes with c-Myc to co-activate the glucose transporter GLUT1 and rate-limiting glycolytic enzymes, thereby establishing a high glycolytic flux that is indispensable for clonal expansion and the production of effector cytokines (52). Conversely, in regulatory T cells (Tregs), the inhibition of mTORC1 activity is indispensable for maintaining Foxp3 stability. Unrestrained mTORC1-driven glycolysis compromises their suppressive capacity, underscoring the pivotal role of mTORC1-mediated metabolic regulation as a central arbiter in the fate decisions between effector and regulatory lineages (53). In contrast, mTORC2 is largely dispensable for the acute glycolytic burst in effector cells, yet it serves as a distinct requirement for metabolic adaptation during differentiation and memory formation. Genetic ablation of mTORC2 via Rictor deletion in CD8+ T cells fails to perturb effector-phase glycolysis but severely impairs the generation of long-term memory cells. This indicates that the nexus between mTORC2 and metabolic reconfiguration is decoupled from mTORC1-driven glycolysis and is inextricably linked to cell survival and memory potential (54). Alternatively activated (M2) macrophages harbor a signature mTORC2-dependent glycolytic program. In this state, mTORC2 synergizes with the IL-4/STAT6 signaling axis to drive the induction of the transcription factor IRF4, which subsequently transactivates glycolytic genes essential for M2 polarization and tissue-repair functions (55).

Consequently, mTORC1 functions as a master switch, coupling nutrient sensing to rapid pro-inflammatory glycolysis; in contrast, mTORC2 serves as a context-dependent regulator that fine-tunes glycolytic programs in alignment with the specific bioenergetic and biosynthetic demands of the immune response, thereby meeting the specialized requirements of memory, regulatory, and homeostatic immunity (56) (Figure 1).

Figure 1.

The different roles of mTOR1 and mTOR2 in regulating glycolysis-driven processes. (A) Differential mTOR Complex Sensing. (B) mTORC1-driven Transcriptional Feed forward Loop via HIF/c-Myc Axis. (C) mTORC2-driven Post-translational Landscape on AKT Node. (D) The Three Gatekeepers of Glycolysis. (E) Above metabolic pathways into spatiotemporal Immune Fate. (mTORC1, mammalian target of rapamycin; PKM2, pyruvate kinase M2 type; GLUT1/3, glucose transporter 1/3; HIF-1α, hypoxia-inducible factor-1 α; AKT, protein kinase B; SREBP1c, sterol regulatory element binding protein 1c; GSK3 β, glycogen synthase kinase 3 β; c-Myc,Myelocytomatosis viral oncogene homolog; IRF4, Interferon Regulatory Factor 4; HK2, Hexokinase 2; PFKFB2, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2).

3. Metabolic dysregulation of the mTOR-glycolysis axis in immune cells: a driver of inflammation

3.1. Neutrophils

As the premier rapid-response effectors of the innate immune system, neutrophils undergo massive transepithelial migration to counter microbial invasion within the gut. However, their unbridled activation and the release of a pro-inflammatory secretome often pivot from protective surveillance to become a primary catalyst for mucosal collateral damage (57, 58). Loss of Farnesoid X receptor (FXR) function in neutrophils establishes a pathological feed-forward loop, wherein unrestrained mTORC1 signaling drives metabolic reprogramming toward glycolysis. This heightened glycolytic flux directly fuels a suite of pro-inflammatory effector functions—including excessive reactive oxygen species (ROS) production, neutrophil extracellular trap (NET) formation, and augmented chemotaxis—which collectively exacerbate intestinal mucosal injury (59, 60). Recent studies demonstrate that pharmacological intervention with INT-747 (obeticholic acid), a semi-synthetic bile acid-derived FXR agonist, markedly suppresses mTORC1-mediated glycolytic flux and dampens inflammatory effector responses in neutrophils derived from IBD patients. This modulation effectively re-establishes neutrophil homeostasis and alleviates intestinal inflammation (61). In the pathogenesis of UC, the intestinal inflammatory microenvironment drives neutrophil metabolic reprogramming by activating the mTOR/HIF-1α signaling pathway (62, 63), orchestrating a metabolic shift from oxidative phosphorylation toward a PFKFB3-mediated, high-flux glycolytic state (64). This immunometabolic dysregulation not only significantly enhances the ROS burst and the release of NETs but also perpetuates mucosal barrier injury and inflammatory infiltration through the sustained activation of the ‘mTOR-glycolysis-NETs’ axis (65). Collectively, these findings identify the mTOR-glycolysis axis as a pivotal metabolic switch governing neutrophil pro-inflammatory activation in UC.

3.2. Macrophages

As indispensable gatekeepers of mucosal homeostasis, intestinal macrophages leverage their profound functional plasticity to orchestrate an exquisite equilibrium between immunological tolerance toward the commensal microbiota and vigilant immunosurveillance against enteric pathogens (66, 67). The mTOR signaling axis functions as a pivotal metabolic rheostat within macrophages, wherein mTORC1 and mTORC2 orchestrate distinct yet interconnected bioenergetic programs (68) (69). mTORC1 serves as a primary engine driving glycolytic flux by enhancing the translation of HIF-1α and c-Myc; conversely, mTORC2 functions as a metabolic gatekeeper of glucose utilization, modulating Akt-dependent glucose uptake and channeling metabolic intermediates toward either biosynthetic or oxidative pathways (70). This “mTOR-centered metabolic switch” ultimately dictates the functional plasticity of macrophages, bridging the fundamental gap between nutrient sensing and immune polarization (71). Emerging evidence indicates that Dioscin modulates the mTORC1/HIF-1α and mTORC2/PPAR-γ signaling axes to suppress aerobic glycolysis while augmenting fatty acid oxidation, thereby driving M2 macrophage polarization to alleviate intestinal inflammation in UC (72). Furthermore, ZNF667 acts as a negative regulator of the aerobic glycolytic switch; by thwarting mTOR-mediated metabolic reprogramming, it dampens the LPS-induced pro-inflammatory burst in macrophages, effectively depriving bioenergetically demanding inflammatory responses of their fuel and restoring metabolic homeostasis (73). Within the intricate intestinal microenvironment of UC, macrophages integrate signals from hypoxia, pathogen-associated molecular patterns (PAMPs), and pro-inflammatory cytokines to trigger the hyperactivation of the mTORC1 signaling pathway. This culminates in a pathological metabolic rewiring toward aerobic glycolysis, characterized by the stabilization of HIF-1α and the upregulation of key rate-limiting enzymes, including PKM2 and PFKFB3 (63, 74). This shift skews macrophages toward a pathogenic M1 phenotype, leading to the profuse secretion of IL-1βand IL-6 (75). Furthermore, the accumulation of glycolytic byproducts, notably lactate, in the extracellular milieu establishes a feed-forward loop that reinforces mTOR activity and suppresses anti-inflammatory regulators (72, 76). Such mTOR-glycolysis axis-driven immunometabolic disequilibrium not only disrupts macrophage homeostatic maintenance but also represents a core molecular mechanism fueling the chronicity of intestinal inflammation and persistent mucosal barrier impairment in UC. Taken together, mTOR-driven aerobic glycolysis acts as a master immunometabolic regulator governing macrophage phenotypic plasticity. Strategic manipulation of this metabolic switch allows for the redirection of macrophage polarization, thus intercepting diverse pathological progressions ranging from hyper-inflammatory cascades to the maturation of the tumor microenvironment.

3.3. Type 3 innate lymphocytes

As quintessential homeostatic sentinels at the intestinal interface, group 3 innate lymphoid cells (ILC3s) integrate microbiota-derived metabolites and neuroendocrine cues via the RORγt-dependent IL-22/IL-17 cytokine axis, thereby precisely orchestrating mucosal barrier integrity and antimicrobial defense (77, 78). Regarding the clinical progression of UC, Gregory F. Sonnenberg posits that the impaired capacity of ILC3s to orchestrate IL-22/IL-23-driven epithelial regenerative programs directly precipitates the collapse of mucosal reparative potential and the perpetuation of colonic tissue injury (79). Intriguingly, this perspective stands in stark contrast to the earlier findings of Lauren A. Zenewicz and more recent evidence from Nicolas Serafini, both of whom concluded that ILC3s confer protection against inflammatory bowel disease in murine models (80, 81). In the context of the mTOR-glycolysis axis in ILC3s, Surace et al. elucidated that ILC3 effector potency is fundamentally anchored in an mTOR-responsive metabolic circuit. This circuit synchronizes accelerated glycolysis with mitochondria-derived redox signaling, thereby furnishing the indispensable bioenergetics and regulatory cues required for the RORγt-driven orchestration of mucosal cytokines (82). Furthermore, research by Sepahi et al. demonstrated that gut microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), calibrate the metabolic thresholds of ILC3s via G protein-coupled receptors (GPCRs) and the mTOR signaling pathway (83). Collectively, the functional dichotomy of ILC3 subsets (NCR+ versus NCR−) is governed by metabolic plasticity driven by the mTOR-glycolysis axis, which dictates the phenotypic transition from protective IL-22 production to a pathogenic IFN-γ-secreting profile during intestinal inflammation (84). During the stable phase of the disease, NCR+ ILC3s utilize moderate glycolysis to support RORγt expression and IL-22 secretion, thereby facilitating tissue repair. However, under the metabolic constraints of chronic inflammation—such as hypoxia or glucose deprivation—heightened glycolytic activity may trigger the conversion of ILC3s into a pathogenic ‘ex-ILC3’ phenotype. These cells switch to IFN-γ production, effectively shifting from protective mediators to inflammatory amplifiers. Conversely, during the acute phase of UC, NCR− ILC3s recruit massive neutrophil infiltration and induce pro-inflammatory chemokine release via IL-17, further exacerbating mucosal tissue injury (85).

3.4. CD4+T cells

T cell populations serve as the principal orchestrators of the intestinal adaptive immune landscape, conferring a requisite spatiotemporal precision to mucosal immunosurveillance (86). This role is fundamental to sustaining the delicate equilibrium between systemic immune tolerance and protective, defensive inflammation (87, 88). The intestinal T-cell compartment is characterized by a sophisticated hierarchical architecture, with a phenotypic spectrum spanning from innate-like intraepithelial lymphocytes (IELs) providing rapid mucosal cytotoxicity to specialized effector cell populations residing in the lamina propria (LPLs) (89) (90). Within the pathological microenvironment of UC, the mTORC1 and mTORC2 signaling pathways serve as central molecular switches that cooperatively orchestrate CD4+ T cell differentiation and plasticity. The metabolic remodeling mediated by these pathways is a fundamental determinant of intestinal immune homeostasis. Specifically, mTORC1 acts in concert with HIF-1α to augment glycolytic flux, thereby driving the pro-inflammatory polarization of Th1 and Th17 cells (91). Conversely, mTORC2 specifically induces Th2 cell development via the Akt signaling axis while finely tuning the suppressive capacity and stability of regulatory T (Treg) cells. The resulting immunometabolic dysregulation, triggered by aberrant mTOR signaling, is characterized by the pathogenic expansion of effector T cells—driven by an over-reliance on glycolysis—and a pathological shift of the Th17/Treg balance toward a pro-inflammatory phenotype under severe metabolic stress. These alterations underpin the persistent mucosal immune activation and non-resolving inflammation observed in UC patients (92, 93).

The divergent differentiation of these CD4+ T cells in the intestinal microenvironment of UC—most notably the pivotal Th17/Treg immunological axis—is synergistically orchestrated by the commensal metabolome and site-specific transcriptional networks, thereby sustaining the delicate equilibrium of the intestinal immune microenvironment (94, 95). Research indicates that the mTOR-HIF-1α signaling axis dictates the reciprocal interconversion between Th17 and Treg cells through the precise modulation of glycolytic flux (96). While mTORC1-mediated induction of aerobic glycolysis is indispensable for the anabolic demands and epigenetic remodeling associated with Th17 pathogenicity, its hyperactivation paradoxically destabilizes the Foxp3+ suppressive program (97, 98). This metabolic bifurcation is dictated by the strategic orchestration of glycolytic enzymes and nutrient transporters, thereby fueling Th17 lineage commitment at the expense of Treg-mediated immune tolerance (99). In the pathogenesis of UC, Wang et al. identified the mTOR-HIF1α axis as a critical metabolic fulcrum that fuels the intestinal inflammatory cascade. This axis exacerbates disease by skewing CD4+ T cell fate toward glycolysis-dependent Th17 pathogenicity while simultaneously undermining the suppressive integrity of the Treg pool—a pathological process that can be reversed through mTOR inhibition (100). Liu et al. demonstrated that Astragalus polysaccharides (APS) attenuate mTOR/HIF-1α-mediated glycolytic flux, thereby steering T-cell differentiation toward a Foxp3-driven immunotolerant phenotype and ultimately ameliorating colonic inflammation (101). Yang et al. proposed that GPR120 signaling effectively redirects CD4+ T cell fate from pathogenic Th17 infiltration toward an IL-10-producing regulatory phenotype by suppressing the mTOR-driven glycolytic program, thereby restoring intestinal homeostasis (102). In summary, the mTOR-glycolysis axis serves as a metabolic conduit that skews the immune landscape toward a pro-inflammatory state. By empowering pathogenic Th17 lineage at the cost of Treg stability, this axis sustains a metabolic bias that prevents the healing of intestinal mucosal lesions (103).

In conclusion, On the pro-inflammatory axis, mTORC1 activation orchestrates the metabolic reprogramming of Th17 cells, M1-polarized macrophages, and neutrophils. Notably, neutrophils harness a glycolytic burst to fuel their key effector functions, including chemotaxis, degranulation, and the release of NETs. This process is mediated by the mTOR/HIF-1α signaling cascade, with the magnitude of glycolytic induction positively correlating with the severity of acute tissue injury. Conversely, on the homeostatic and reparative front, mTORC2 signaling is indispensable for maintaining the metabolic flexibility and immunosuppressive potency of Treg cells and M2 macrophages, thereby indirectly fortifying intestinal barrier integrity and facilitating mucosal healing. although the mTOR-glycolysis axis represents a foundational pillar for advancing immunometabolic therapeutic strategies in UC (Table 2), the inherent spatiotemporal complexity and cellular heterogeneity of the intestinal landscape remain critical determinants. Given the immense clinical potential yet to be tapped, this axis should be strategically integrated into the development of precisely targeted interventions.

Table 2.

The role and mechanism of mTOR and glycolysis in regulating immune cells in the intestinal microenvironment of UC.

Research approach	Animal model	Target cell	Research mechanism	References
in vivo	DSS-induced Colitis	Macrophages, Neutrophils	Glucocorticoids drive intestinal inflammation by activating epithelial-specific mTORC1, which in turn modulates macrophage and neutrophil responses.	(62)
in vivo	DSS-induced Colitis	Macrophages, Neutrophils	Biomimetic Pd@M nanozymes modulate macrophage polarization and neutrophil infiltration by neutralizing oxidative stress and thwarting glycolytic reprogramming.	(63)
in vivo and in vitro	DSS-induced colitis	Macrophages	Dioscin modulates the mTORC1/HIF-1α and mTORC2/PPAR-γ signaling axes to suppress aerobic glycolysis, thereby facilitating M2 macrophage polarization.	(72)
in vivo and in vitro	DSS-induced Colitis	Macrophages	Tiliroside reprograms macrophage polarization by targeting HIF-1α-dependent aerobic glycolysis.	(74)
in vivo and in vitro	DSS-induced Colitis	Macrophages	XHCF orchestrates the M1-to-M2 macrophage phenotypic switch through AMPK-mediated metabolic reprogramming, which is characterized by the suppression of HK2-dependent glycolysis.	(75)
in vitro	–	Th17 cells, Treg cells	The mTOR/HIF-1α signaling axis drives the pathogenesis of ulcerative colitis (UC) by promoting glycolysis-dependent Th17 polarization and impairing Treg fitness; notably, this pathological process can be reversed through mTOR inhibition.	(100)
in vivo	DSS-induced Colitis	Treg cells	Astragalus polysaccharide (APS) modulates Treg cell responses by suppressing aerobic glycolysis and the mTOR/HIF-1α signaling axis.	(101)
in vivo	DSS-induced Colitis、Salmonella typhimurium-induced infectious colitis、Rag(-/-) mice	CD4+ T cells	GP420 orchestrates an mTOR-dependent metabolic-transcriptional axis that synergistically elevates Blimp1 expression and reinforces glycolytic flux, thereby augmenting the IL-10-producing capacity of CD4+ T cells.	(102)
in vivo and in vitro	DSS-induced Colitis	Macrophages	The Myo1F/Integrin-αVβ3/mTOR axis drives macrophage-mediated colonic inflammation by coupling intercellular adhesion to pro-inflammatory M1 polarization.	(104)
in vivo	DSS-induced Colitis	Macrophages	Apremilast perturbs mucosal macrophage immunity by modulating the PDE4-dependent crosstalk of PKA/Epac with the NF-κB, PI3K-mTOR, and JAK-STAT signaling cascades.	(105)
in vivo and in vitro	DSS-induced Colitis	Macrophages	Cinnamaldehyde attenuates UC by suppressing ROS generation, AKT/mTOR signaling, and NLRP3 inflammasome activation, while simultaneously downregulating the expression of miR-21 and miR-155 within the colon and macrophages.	(106)
in vitro	–	Macrophages	Macrophage MMP12 expression is governed by a glycolysis-dependent metabolic crosstalk between the AMPK and mTORC1 pathways.	(107)
in vivo and in vitro	DSS-induced Colitis	Dendritic cells, Th17 cells	The mTORC2 signaling axis drives pro-inflammatory Th17 responses in UC by orchestrating Rac1/Cdc42-mediated cytoskeletal remodeling and the subsequent migration of dendritic cells.	(108)
in vivo and in vitro	DSS-induced Colitis	Macrophages	ES100-PIP/GA NC reprograms the macrophage polarization landscape by augmenting mTOR-mediated M2 polarization while simultaneously attenuating HIF-1α-dependent M1 activation.	(109)
in vivo and in vitro	DSS-induced Colitis	Macrophages, Intestinal epithelial cells	D-mannose modulates macrophage M1/M2 polarization by activating the AMPK/mTOR signaling axis while directly upregulating epithelial tight junction proteins to reinforce barrier integrity.	(110)
in vivo	DSS-induced Colitis	Macrophages	Bangle (Zingiber purpureum Rosc.) Extractameliorates colonic inflammation by modulating the AMPK/mTOR/NFκB signaling axis, thereby reducing macrophage infiltration in the inflamed colon.	(111)
in vivo	SAMHD1mKO mice	Macrophages	SAMHD1 deficiency unleashes the mTOR signaling pathway, where aberrant mTOR hyperactivation suppresses the MITF-CTSD-mediated lysosomal homeostatic program in macrophages.	(112)
in vivo	DSS-induced Colitis	Macrophages	Berberine promotes M2 macrophage polarization by suppressing the mTOR/HIF-1α axis in a PPAR-γ-dependent manner, thereby augmenting oxidative phosphorylation.	(113)
in vivo	DSS-induced Colitis	Macrophages	Wenyang Decoction orchestrates the macrophage phenotypic switch from M1 to M2 and mitigates oxidative stress by suppressing the PI3K/AKT/mTOR/HIF-1α signaling axis.	(114)
in vivo and in vitro	DSS-induced Colitis	Macrophages	Dehydrocorydaline (DHC) blunts glycolytic flux by dual-targeting the enzymatic activity and formylation of GAPDH, thereby suppressing lactate production and subsequent macrophage activation.	(115)
in vivo and in vitro	DSS-induced Colitis	Macrophages	Shikonin abrogates aerobic glycolysis by suppressing the PKM2-HIF-1α metabolic axis, thereby attenuating macrophage-mediated inflammatory responses.	(116)
in vivo	DSS-induced Colitis	Macrophages	ADMSCs orchestrate a bidirectional Succinate-PGE2 feedback loop to dismantle the HIF-1α-dependent glycolytic engine in macrophages, thereby reinstating immune homeostasis.	(117)
in vivo and in vitro	DSS-induced Colitis	Macrophages	HMGB1 triggers a metabolic switch from fatty acid oxidation to glycolysis through the transcriptional repression of Cpt1a, thereby driving pro-inflammatory M1 macrophage polarization.	(118)
in vivo and in vitro	DSS-induced Colitis	Macrophages	Ginsenoside Rg1-primed ADSCs attenuate pro-inflammatory glycolytic flux in macrophages via the exosomal miR-574-3p/RAS axis.	(119)
in vivo	DSS-induced Colitis	Macrophages	Total flavonoids from Cynanchum chinense synergistically orchestrate Keap1-Nrf2-mediated mucosal barrier repair, suppress glycolysis-driven macrophage metabolic reprogramming, and reshape gut microecological homeostasis.	(120)
in vivo	DSS-induced Colitis、Fats(-/-) mice	Macrophages	FATS attenuates pro-inflammatory macrophage polarization and mucosal injury by modulating HIF-1α-mediated glycolytic flux.	(121)
in vivo and in vitro	DSS-induced Colitis	Macrophages	IPA orchestrates a macrophage M1-to-M2 phenotypic switch in colitis by suppressing JNK/MAPK-mediated glycolysis and augmenting PPAR-γ-dependent lipid metabolism.	(122)
in vivo、in vitro and clinical samples	DSS-induced Colitis	Macrophages	EBV/MHV-68 infection hijacks macrophage glucose metabolism to elicit NLRP3/GSDMD-mediated pyroptosis.	(123)
in vivo and in vitro	DSS-induced Colitis	Macrophages	Impaired PDH-dependent glucose oxidation fuels M1 macrophage-mediated colitis under thiamine deficiency.	(124)
in vivo	DSS-induced Colitis	Macrophages	DOPS activates the SENP1-SIRT3 axis to curtail macrophage glycolysis and foster M2 polarization.	(125)
in vivo	DSS-induced Colitis	Neutrophils	Glutamine suppresses the PI3K/Akt/mTOR signaling axis, thereby abrogating neutrophil infiltration and mitigating associated colonic oxidative damage.	(126)
in vivo and clinical samples	DSS-induced Colitis	Neutrophils	Spleen tyrosine kinase (Syk) orchestrates neutrophil effector functions—including NETosis and oxidative stress—via the mTOR/Rubicon-dependent autophagy pathway.	(127)
in vivo	DSS-induced Colitis	Neutrophils	Atractylenolide-I suppresses neutrophil-derived S100A9 release and subsequently activates the AMPK/mTOR signaling axis to reinstate tight junction protein expression.	(128)
in vivo	DSS-induced Colitis	Th17 cells, Treg cells	Resveratrol dampens the HIF-1α/mTOR/STAT3 signaling cascade to orchestrate Th17/Treg homeostasis.	(129)
in vivo	DSS-induced Colitis	Th17 cells, Treg cells	BL-hIL-10 rectifies the Th17/Treg imbalance by targeting a convergent mTOR-STAT3-HIF-1α signaling network.	(130)
clinical sample	–	Th17 cells, Treg cells	CCR6 signaling orchestrates iTreg-to-Th17 lineage plasticity via the Akt/mTOR/STAT3 axis.	(131)
in vivo and clinical sample	DSS-induced Colitis	Th17 cells	Hyperactivated epithelial mTORC1 drives the recruitment of pathogenic Th17 cells by initiating a STAT3-dependent COX-2 transcriptional program.	(132)
in vivo	DSS-induced Colitis	Th17 cells	The synergistic combination of empagliflozin and metformin activates the AMPK signaling pathway, thereby suppressing the mTOR/NLRP3 inflammasome axis and subsequent Th17 cell polarization.	(133)
in vivo	DSS-induced Colitis	Th17 cells, Treg cells	PD-L1-EVs rectify Th17/Treg dyshomeostasis and multidimensional mucosal injury by targeting the PI3K/Akt/mTOR signaling axis.	(134)
in vivo	DSS-induced Colitis	Th17 cells, Treg cells	Cinnamtannin D1 re-establishes Th17/Treg homeostasis by engaging the AMPK/mTOR signaling axis.	(135)
in vivo	DSS-induced Colitis	Th17 cells, Treg cells	Butyrate recalibrates Th17/Treg immune homeostasis through cAMP-PKA/mTOR-mediated immunomodulation.	(136)
in vivo and in vitro	DSS-induced Colitis	Th17 cells, Treg cells, Intestinal epithelial cells	Artesunate promotes HMGCS2-dependent ketogenesis by activating the AMPK/mTOR signaling axis, thereby restoring Th17/Treg homeostasis and intestinal epithelial barrier integrity.	(137)
in vivo and in vitro	DSS-induced Colitis	Th17 cells, Treg cells	Senkyunolide selectively inhibits Th17 cell glycolysis and restores Th17/Treg homeostasis by triggering the PHD2-mediated proteasomal degradation of HIF-1α.	(138)
in vivo and in vitro	DSS-induced Colitis	Th17 cells, Treg cells	DIM suppresses Th17 pathogenicity and bolsters Foxp3 stability via the lactate-STAT3 and HIF-1α/TIP60 signaling cascades.	(139)
in vivo	DSS-induced Colitis、TNBS-induced Colitis	Th17 cells, Treg cells	D5, a novel cinnamyl alcohol ester derivative, selectively suppresses Th17-driven glycolysis and reinstates the Th17/Treg immune balance through the covalent activation of PKM2 at the Cys424 residue.	(140)
in vivo and in vitro	DSS-induced Colitis	Th17 cells, Treg cells	Inhibition of HSP90β triggers GLUT1 ubiquitination and suppresses glycolysis, which subsequently drives Foxp3 epigenetic remodeling via the lactate-STAT5-TET2 axis, ultimately inducing Th17-to-Treg transdifferentiation.	(141)
in vivo and in vitro	DSS-induced Colitis	Th17 cells, intestinal epithelial cells	Phascolarcto bacterium depletes luminal succinate, thereby attenuating SUCNR1-mediated glycolytic remodeling in both epithelial and Th17 cells.	(142)
in vivo	DSS-induced Colitis	Dendritic cells, Intestinal epithelial cells, CD4+ T cells	Colon-targeted delivery of MFGE8-enriched ERC-derived exosomes reconfigures intestinal epithelial cell survival and CD4+ T cell proliferation while suppressing dendritic cell maturation through the PI3K/AKT/mTOR signaling axis.	(143)

4. Metabolic rewiring of the mTOR-glycolysis axis in intestinal epithelial cells: from barrier breakdown to impaired mucosal repair

The mTOR signal pathway functions as a central metabolic rheostat within the intestinal epithelium, exquisitely orchestrating the coupling of luminal nutrient sensing with mucosal regeneration kinetics and autophagy-driven proteostasis to safeguard intestinal barrier integrity (137, 144). The metabolic landscape of intestinal epithelial cells (IECs) is governed by a finely tuned glycolytic program that functions as a fundamental bioenergetic checkpoint, orchestrating mucosal niche remodeling and adaptive barrier responses under both homeostasis and inflammatory stress (145). Serving as an integrated ‘‘metabolic-effector’’ hub in IECs, the mTOR-glycolytic signaling axis couples nutrient sensing with pathogenic metabolic reprogramming upon aberrant activation, ultimately dictating the phenotypic transition from mucosal homeostasis to inflammatory barrier collapse (146). Inflammation is characterized by a metabolic switch that favors aerobic glycolysis and lactate production. Specifically, apical HK2 expression serves as a hallmark of severe metabolic remodeling in epithelial cells, heralding imminent mucosal ulceration or erosion. This suggests that dysregulated epithelial HK2 expression acts as a driver of exacerbated intestinal inflammation (28). Concurrently, PDK2 is significantly upregulated in patients with active UC, where its overexpression signals profound mitochondrial dysfunction within IECs (147). Crucially, these pathological processes are triggered by the activation of the upstream mTOR signaling pathway. The resulting cellular metabolic derangement within the microenvironment ultimately culminates in the collapse of the mucosal barrier.

It’s worth noting that various agents, including halogenated acylaminopyridine-based molecules (P2281) (148), the flavonoid derivative 3”,4”,5”-trihydroxyflavone (THF; NJK16003) (149), heat shock factor 2 (HSF2) (150), Metrnl (151), and inulin-type fructans (CP-A) (152), function as potent mTOR inhibitors. These candidates safeguard the mucosal barrier by antagonizing the mTOR signal pathway, which subsequently attenuates IEC apoptosis and potentiates autophagy to facilitate tissue repair. Concurrently, Palmatine (PAL) (153) and barley leaf (154) have been shown to restore the IEC barrier by suppressing glycolytic metabolic reprogramming, thereby ameliorating the clinical symptoms of UC. Despite extensive characterization of the mTOR signal pathway and glucose metabolism as standalone regulators of IEC homeostasis (Table 3), evidence regarding their functional crosstalk within a unified mTOR-glycolysis axis remains conspicuously scarce.

Table 3.

The role and mechanism of mTOR and glycolysis in regulating intestinal epithelial cells in the intestinal microenvironment of UC.

Research approach	Animal model	Target cell	Research mechanism	References
in vivo and in vitro	DSS-induced Colitis	Macrophages, Intestinal epithelial cells	D-mannose activates the AMPK/mTOR signaling axis to modulate macrophage M1/M2 polarization while simultaneously upregulating tight junction proteins in epithelial cells directly.	(110)
in vivo and in vitro	DSS-induced Colitis	Th17 cells, Treg cells, Intestinal epithelial cells	Artesunate promotes HMGCS2-dependent ketogenesis by activating the AMPK/mTOR signaling axis, thereby restoring Th17/Treg homeostasis and intestinal epithelial barrier integrity.	(137)
in vivo and in vitro	DSS-induced Colitis	Th17 cells, Intestinal epithelial cells	Phascolarcto bacterium depletes luminal succinate, thereby attenuating SUCNR1-mediated glycolytic remodeling in both epithelial and Th17 cells.	(142)
in vivo	DSS-induced Colitis	Dendritic cells, Intestinal epithelial cells, CD4+ T cells	Colon-targeted delivery of MFGE8-enriched ERC-derived exosomes reconfigures intestinal epithelial cell survival and CD4+ T cell proliferation while suppressing dendritic cell maturation through the PI3K/AKT/mTOR signaling axis.	(143)
in vivo and in vitro	DSS-induced Colitis	Intestinal epithelial cells	P2281, a novel mTOR inhibitor, attenuates mTOR-driven T-cell activation and safeguards the intestinal epithelial crypt architecture against inflammatory destruction.	(148)
in vivo and in vitro	DSS-induced Colitis	Intestinal epithelial cells	NJK16003 safeguards intestinal epithelial cells against apoptosis and inflammatory damage by harnessing an mTOR-dependent autophagy program.	(149)
in vivo、in vitro and clinical samples	DSS-induced Colitis、HSF2(-/-) mice	Intestinal epithelial cells	Butyrate-mediated epigenetic induction of HSF2 promotes intestinal epithelial autophagy via the PI3K/Akt/mTOR signaling axis.	(150)
in vivo	DSS-induced Colitis、Metrnl(-/-) mice	Intestinal epithelial cells	Metrnl-dependent activation of the AMPK/mTOR/p70S6K signaling axis sustains protective autophagy in intestinal epithelial cells.	(151)
in vivo and in vitro	TNBS-induced Colitis	Intestinal epithelial cells	CP-A suppresses the mTOR/p70S6K signaling axis to attenuate the production of pro-inflammatory cytokines in intestinal epithelial cells.	(152)
in vivo and in vitro	DSS-induced Colitis	Intestinal epithelial cells	Palmatine reinforces intestinal barrier integrity by suppressing excessive glycolysis in intestinal epithelial cells through the direct targeting and upregulation of ENO3.	(153)
in vivo	DSS-induced Colitis	Intestinal epithelial cells	Barley leaf drives inosine enrichment, which activates the A(2A)R/PPARγ signaling axis and orchestrates cellular metabolic reprogramming to reinforce the intestinal epithelial barrier.	(154)
in vivo	DSS-induced Colitis、PBLD(IEC-/-) mice	Intestinal epithelial cells	Rapamycin fortifies the intestinal epithelial barrier in ulcerative colitis by suppressing the mTOR/TFEB/PBLD signaling axis.	(155)
in vivo	DSS-induced Colitis	Intestinal epithelial cells	During mucosal healing, IECs undergo a rapid metabolic switch toward robust glycolytic ATP production, driven by mitochondrial fusion and augmented respiratory flux, to bridge the bioenergetic deficit elicited by colitis.	(156)
in vivo、in vitro and clinical samples	(Crt-/-) mice	Intestinal epithelial cells	Deficiency of the creatine transporter CRT disrupts intestinal epithelial energy homeostasis and triggers glycolytic stress.	(157)
in vivo、in vitro and clinical samples	DSS-induced Colitis、Piezo1ΔIEC mice	Intestinal epithelial cells	Upregulated epithelial Piezo1 triggers ferroptosis-dependent barrier dysfunction by modulating the AMPK/mTOR signaling axis.	(158)
in vivo	DSS-induced Colitis	Intestinal epithelial cells	Pingwei San attenuates the PI3K/AKT/mTOR signaling cascade, thereby augmenting autophagy-mediated mucosal protection in intestinal epithelial cells.	(159)
in vivo、in vitro and clinical samples	DSS-induced Colitis、Klf5ΔIEC rats	Intestinal epithelial cells	GPR35 orchestrates a KLF5-centered transcriptional program via the PI3K-AKT-mTOR axis to govern the proliferation and migration of intestinal epithelial cells.	(160)

5. Integrated cross-cell-type analysis

Beyond its role as a mere structural conduit, the intestinal epithelium operates in concert with mucosal immune cell populations as an interdependent functional entity. Within this nexus, reciprocal molecular signaling and metabolic feedback loops exquisitely orchestrate the spatiotemporal transition between homeostatic immunosurveillance and effector inflammatory responses (161, 162).

5.1. Intestinal epithelial cells and macrophages

The homeostatic tethering between intestinal epithelial cells and resident lamina propria macrophages characterizes a distinct, niche-dependent crosstalk (163, 164). Specifically, epithelium-derived instructive signals, such as CSF1 and TGF-β, reprogram macrophages toward a non-inflammatory, ‘pro-resolving’ phenotype; in turn, these macrophages provide paracrine trophic support to reciprocally modulate epithelial progenitor proliferation and mucosal wound healing (165). Emerging evidence indicates that the mTORC1 signaling axis orchestrates a functional bifurcation of the mucosal inflammatory secretome, driving intestinal epithelial Caco-2 cells and THP-1-derived macrophages to exhibit distinct, if not diametrically opposed, cytokine expression patterns under identical metabolic stimuli (166). At the metabolic level, alcohol-induced mitochondrial impairment in intestinal epithelial cells precipitates a dose-dependent bioenergetic crisis, necessitating a compensatory glycolytic shift that culminates in barrier collapse. This structural failure, in synergy with the subsequent translocation of microbial PAMPs and epithelium-derived metabolic stress signals, collectively orchestrates the pro-inflammatory reprogramming of intestinal macrophages (167). Taken together, these findings underscore that the mTORC1-glycolysis signaling axis not only coordinates the symbiotic tethering between intestinal epithelial cells and pro-resolving macrophages under homeostasis but also potentially dictates the phenotypic transition toward a pathological pro-inflammatory landscape by driving a ‘metabolic-secretory’ bifurcation in response to mitochondrial stress and glycolytic reprogramming.

5.2. Intestinal epithelial cells and T cells

A bidirectional crosstalk exists between intestinal epithelial cells (IECs) and mucosal CD4+ T cell subsets. Evidence demonstrates that IECs, acting as unconventional MHC II-expressing antigen-presenting cells, fine-tune bacteria-reactive CD4+ T cell responses by differentially modulating effector and regulatory Th subsets. Conversely, CD4+ T cell-derived cytokines—most notably IL-22 produced by Th17/Th22 cells—activate STAT3 signaling to reinforce epithelial barrier integrity through the upregulation of antimicrobial peptides and tight junction component (168, 169). Focusing on the mTOR signaling pathway, Yingshu Luo et al. demonstrated that the SARS-CoV-2 spike protein exploits the CEACAM5-Galectin-9 interface to dismantle the homeostatic crosstalk between the intestinal epithelium and T cells. In this context, aberrantly released Galectin-9 acts as a ‘molecular wedge’ that impairs mTOR-mediated metabolic fitness in resident T cells, ultimately precipitating a feed-forward loop of mucosal barrier disintegration (170). Regarding metabolic rewiring, Daniela Parada Venegas highlights that SCFAs orchestrate a ‘‘metabolic-epigenetic’’ rheostat, channeling epithelial bioenergetics toward oxidative phosphorylation to foster a glucose-sparing microenvironment. This niche selectively facilitates the HDAC inhibition-dependent expansion of regulatory T cells (Tregs) while curtailing the metabolic surge of pathogenic T cells, ultimately reinstating mucosal harmony in the context of IBD (171). Collectively, these insights suggest that the reciprocal crosstalk between IECs and CD4+ T cells is evidently orchestrated by an mTOR-glycolytic metabolic rheostat. This axis appears to function as a fundamental nexus that integrates immunological signals and bioenergetic cues to sustain mucosal homeostasis.

5.3. Intestinal epithelial cells and other immune cells

Far from being mere static physical barriers, IECs function as critical ‘immune sentinels.’ Upon mucosal perturbation, IECs mount a localized, bioactive secretome comprising chemokines and cytokines, thereby precisely orchestrating the rapid spatiotemporal influx of neutrophils (172, 173). Acting as a pivotal immunomodulatory interface, the intestinal epithelium transduces luminal microbial cues into potent paracrine signals, thereby orchestrating B cell class switch recombination and IgA plasmablast differentiation. This regulatory cascade ensures the targeted deployment of secretory IgA (sIgA), a prerequisite for sustaining commensal homeostasis (174, 175). Furthermore, the mucus-mucin matrix synthesized by goblet cells and IECs functions as a dynamic immunomodulatory scaffold. It actively modulates the mucosal niche by facilitating DCs sampling via specialized goblet cell-associated antigen passages (GAPs), while simultaneously conferring a tolerogenic imprint on these sentinel cells through MUC2-mediated signaling pathways (176). While the reciprocal signaling between the intestinal epithelium and diverse immune subsets has been preliminarily delineated, the mechanistic contribution of the mTOR-dependent glycolytic pathway to this homeostatic interplay remains elusive, representing a critical knowledge gap within the contemporary immunometabolic paradigm.

6. Conclusion and prospect

The burgeoning field of immunometabolism has emerged as a pivotal lens for reappraising the multifactorial etiology of UC, centered on the intricate interplay between bioenergetic pathways and immune dysregulation (177). Compelling evidence suggests that the bioenergetic synergy between mTOR pathway activation and glycolytic flux has emerged as a defining hallmark of UC. This interplay serves as a critical molecular determinant, governing both the inflammatory trajectory of the colonic mucosa and its responsiveness to therapeutic intervention (178, 179). At the epicenter of the immunometabolic network, mTOR functions as the master orchestrator that synchronizes intestinal immune homeostasis with bioenergetic balance (180, 181). In this regulatory hierarchy, the glycolytic pathway serves as a pivotal downstream effector, fine-tuning the functional responsiveness of both IECs and immune cell subsets through metabolic reprogramming (182, 183). While clinically approved mTOR inhibitors have been widely utilized in the management of renal transplantation (184), thalassemia (185), and diverse malignancies (186, 187) (Table 4), their application in UC remains clinically restricted. To date, major global regulatory authorities—including the FDA, EMA, and NMPA—have yet to formally approve any mTOR inhibitor as a standalone therapeutic modality for the treatment of UC. However, a comprehensive synthesis that integrates the regulatory influence of the mTOR-glycolysis axis within the intestinal immune microenvironment remains elusive, particularly regarding the intricate metabolic crosstalk between immune cells and IECs. By situating this signaling axis at the immunometabolic interface, we delineate the bioenergetic heterogeneity and interaction dynamics among diverse cellular populations. These insights offer a transformative paradigm in the pathobiology of ulcerative colitis, underscoring the immense potential of targeting metabolic checkpoints as a novel avenue for future therapeutic intervention.

Table 4.

Clinically approved mTOR inhibitors.

Drug name	Approval number	Adaptation to symptoms	References
Sirolimus	NDA 021083 NDA 021110	Organ rejection after kidney transplantation; lymphangioleiomyomatosis	(188, 189)
Temsirolimus	NDA 022088	Advanced renal cell carcinoma	(190)
Everolimus	NDA 022334 NDA 203985 NDA 021560	Tuberous sclerosis syndrome; locally advanced or metastatic pancreatic neuroendocrine tumors that cannot be resected; liver transplantation	(191–193)
nab-Sirolimus	NDA 213174	Locally advanced, unresectable or metastatic malignant perivascular epithelioid cell tumor	(194)

However, prominent side effects, including oral mucositis and myelosuppression, combined with the drawbacks of non-selective systemic immunosuppression, largely preclude the widespread clinical application of conventional mTOR inhibitors for UC treatment. Functioning as the central immunometabolic rheostat within the UC microenvironment, mTOR integrates intraluminal nutrient availability with systemic inflammatory cues. This integration allows it to precisely orchestrate the functional polarization of mucosal immune subsets and the homeostatic renewal of the intestinal epithelium, thereby serving as a master arbiter of intestinal barrier integrity and immunological tolerance (195). The mTOR-glycolysis axis deciphers intraluminal cues to fulfill the bioenergetic requirements of mucosal immune cells. Aberrant overactivation of this circuitry precipitates a homeostatic shift from immune tolerance toward inflammatory exacerbation, particularly during the pathogenesis of UC. Notably, pathological hyperactivation of mTOR-driven glycolytic programs selectively provides the metabolic momentum for the expansion of pro-inflammatory effectors, such as Th17 and M1 cells, while simultaneously antagonizing the lineage stability and immunosuppressive potency of Tregs within the inflamed mucosal niche (53). Future strategies aiming to harness the mTOR pathway for microenvironmental restoration in UC must transition from broad systemic immunosuppression to targeted local reprogramming. Firstly, innovative drug delivery modalities, including rectal administration and pH-dependent colonic release, should be employed to restrict pharmacological activity to the intestinal lamina propria. This spatial targeting is crucial to avoid systemic side effects and prevent the impairment of mucosal healing. Secondly, the development of selective mTOR pathway modulators, particularly mTORC1-specific inhibitors, represents a promising avenue to achieve therapeutic efficacy while preserving the vital regenerative potential of the intestinal epithelium. In addition, the inherent multidimensional complexity and cellular heterogeneity of the intestinal environment pose formidable obstacles to deconstructing the cell-type-specific nuances of the mTOR-glycolysis axis during UC progression. To bridge these knowledge gaps, future endeavors must harness interdisciplinary synergies—integrating single-cell and spatial multi-omics—to chart a comprehensive blueprint of how this immunometabolic axis dictates intestinal homeostasis and drives disease evolution. Such efforts will be pivotal in elucidating spatiotemporal immunometabolic crosstalk and identifying stage-specific therapeutic vulnerabilities within the UC microenvironment.

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. The author declares that the research, creation and publication of this article have all received financial support. This study was funded by the National Natural Science Foundation of China (82575067).

Author contributions

YC: Conceptualization, Writing – original draft. JX: Software, Writing – original draft. LX: Methodology, Writing – original draft. AC: Formal analysis, Writing – original draft. LH: Visualization, Writing – original draft. ZW: Funding acquisition, Writing – review & editing.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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