Ulcerative colitis (UC) is a chronic, relapsing inflammatory disorder of the colonic mucosa. Its pathogenesis reflects a multifactorial interplay among genetic susceptibility, environmental triggers, dysregulated microbial metabolism, and breakdown of epithelial barrier homeostasis. Contemporary management emphasizes mucosal healing, yet many patients reach a therapeutic ceiling with existing agents. The reviewed work positions the mTOR signaling pathway and its downstream control of glycolysis as central immunometabolic determinants that may offer new mechanistic insights and therapeutic targets for UC.
mTOR (mechanistic target of rapamycin) operates as an evolutionarily conserved serine/threonine kinase that integrates nutrient availability, growth factor input, energy status, and oxygen tension to regulate cell growth, autophagy, and immune-lineage decisions. In UC, mTOR coordinates glycolytic reprogramming across immune and epithelial compartments, linking luminal nutrient cues and microbial signals with inflammatory output. This immunometabolic coupling influences the balance between pro-inflammatory effector programs and regulatory mechanisms, and it is implicated in the collapse of mucosal tolerance and impaired epithelial repair described in UC.
mTOR signals through two distinct complexes with complementary roles. mTORC1 senses amino acids, growth factors, ATP/AMP ratios, and oxygen via lysosomal localization, and it cooperates with transcriptional regulators such as HIF-1α and c-Myc to upregulate glycolytic gene expression. The mTORC1–eIF4E axis promotes HIF-1α translation and protein stabilization, driving genes like GLUT1, HK2, PFKFB3, and LDHA, while mTORC1 enhances c-Myc translation and stability to induce broad glycolytic programs.
Conversely, mTORC2 primarily responds to growth factor signaling and impinges on metabolic regulation through AKT phosphorylation (Ser473). Activated AKT facilitates transcriptional programs (for example, SREBP1c and glucokinase expression) and post-translational modulation of metabolic enzymes via GSK3β, thereby coordinating glucose phosphorylation, uptake, and downstream glycolytic flux. In certain contexts, the mTORC2–AKT axis also interfaces with rate-limiting glycolytic regulators such as PFKFB family members.
The intestinal inflammatory microenvironment in UC is shaped by modulation at several key glycolytic nodes. Three central control points highlighted are: (1) transmembrane glucose uptake via GLUT1/3, (2) rate-limiting phosphorylation by HK2 with mitochondrial tethering, and (3) the oligomeric-state–dependent dual roles of PKM2 in metabolism and transcriptional regulation. These nodes determine whether glucose-derived carbons are committed to ATP generation or diverted into biosynthetic branches that support inflammatory cell function and epithelial remodeling.
Transmembrane glucose transport is a prerequisite for glycolytic activation, and GLUT1 and GLUT3 are principal mediators. GLUT3 has higher substrate affinity and transport velocity, conferring an advantage in low-glucose microenvironments. Stabilized HIF-1α and c-Myc transcriptionally drive GLUT1/3 expression, while PI3K/AKT signaling promotes membrane translocation and activation of GLUT1. Upregulation of these transporters in UC mucosa facilitates accelerated glycolytic flux that parallels observations in proliferative pathologies.
Hexokinase 2 (HK2) catalyzes the irreversible conversion of glucose to glucose-6-phosphate, marking the first rate-limiting step of glycolysis. Unlike other isoforms, HK2 preferentially localizes to the outer mitochondrial membrane via interaction with VDAC, giving it privileged access to mitochondrial ATP and accelerating glycolytic throughput. This mitochondrial tethering also exerts anti-apoptotic effects by stabilizing the outer membrane and limiting cytochrome c release. HK2 expression is regulated by signaling cascades including PI3K/AKT, MAPK, and NF-κB, and HK2 can act as a signaling node influencing mTORC1 activity and immune microenvironment remodeling. Under inflammatory stress, GSK3β-mediated phosphorylation can detach HK2 from mitochondria, altering energy coupling and contributing to neutrophil apoptosis and oxidative responses.
Pyruvate kinase M2 (PKM2) serves as a gatekeeper that dictates whether glycolytic carbon flows toward pyruvate/ATP production or is redirected to biosynthetic pathways. The tetrameric PKM2 form is catalytically active and drives conversion of phosphoenolpyruvate to pyruvate, while dimeric PKM2 exhibits low enzymatic activity, enabling accumulation of upstream intermediates for the pentose phosphate and serine synthesis pathways. Critically, dimeric PKM2 can translocate to the nucleus to act as a transcriptional coactivator and protein kinase, linking metabolic state to gene expression. Post-translational modifications—including phosphorylation, acetylation, and oxidation—shift PKM2 oligomeric balance in the UC mucosal milieu. Complementary regulation of LDHA (for example, Tyr10 phosphorylation) supports lactate production under inflammatory conditions.
The review compiles biomarkers connecting glycolytic activity to UC clinical features (Table 1). Reported associations include: peripheral/tissue PKM2 levels correlating with disease scores and inflammatory markers; elevated fecal lactate in active UC linked to mucosal acidosis and worse remission rates; tissue HIF-1α as a spatial-temporal marker distinguishing epithelial repair from immune-mediated damage; increased PDK2 indicating mitochondrial dysfunction and poorer remission; GLUT1 expression reflecting high metabolic activity; and elevated HK2 as an early indicator of mucosal metabolic remodeling preceding endoscopic lesions. The source lists these biomarkers and their clinical correlations but does not provide interventional outcome data within this text.
By portraying the mTOR–glycolysis axis as a rheostat that shifts tissues from immunosurveillance to pathogenic inflammation, the review argues for therapeutic strategies that selectively target metabolic checkpoints in specific cell types rather than broad systemic mTOR inhibition. Cell-selective modulation could theoretically dampen pro-inflammatory effector programs (neutrophil oxidative burst, NETosis, M1 macrophage polarization, Th17 pathogenicity) while preserving or restoring regulatory T cell function and epithelial metabolic fitness. The source summarizes mechanistic rationale and potential precision approaches but does not report clinical trial results or specific therapeutic efficacy outcomes.
The mTOR–glycolysis axis integrates nutrient and inflammatory signals to reprogram immune and epithelial metabolism in UC. Key nodes—GLUT1/3, HK2, and PKM2—mediate the metabolic-transcriptional shifts that underpin pro-inflammatory activation and barrier dysfunction. Translational strategies proposed in the review favor cell-specific metabolic checkpoint targeting; however, the source focuses on mechanistic synthesis and biomarker associations rather than clinical intervention data.