OGT as a metabolic-epigenetic integrator in cancer: context-dependent mechanisms and therapeutic vulnerabilities

Abstract

Background

Accumulating evidence shows that specific dietary elements and metabolic conditions significantly regulate gene expression through epigenetic processes. These observations link the etiology of metabolic disorders and cancer to nutrient-dependent epigenetic reprogramming. In this context, O-GlcNAc transferase (OGT) functions as a context-dependent nutrient sensor and metabolic-epigenetic integrator.

Main text

This enzyme participates in the “histone code” by regulating gene expression and modulating chromatin remodeling. In Drosophila melanogaster, OGT is a bona fide Polycomb group (PcG) protein; however, in mammals it functions as a context-dependent, non-canonical modulator of PRC2 activity rather than a canonical PcG member. OGT interacts with Ten-Eleven Translocation (TET) family proteins, which are involved in DNA hydroxylation. This suggests that O-GlcNAcylation serves as a critical bridge between dietary influences and epigenetic regulation. Evidence from animal models supports a significant role for OGT in polycomb-dependent gene silencing. Notably, OGT modifies all core histones and may constitute a vital component of the histone code. Aberrant O-GlcNAcylation of signaling proteins, metabolic enzymes, and transcriptional regulators can drive oncogenesis by dysregulating cellular proliferation, survival, and metabolic reprogramming. However, the effects of O-GlcNAcylation are not uniformly pro-oncogenic; context-dependent, tumor-suppressive, and protective functions have also been reported, underscoring the need for nuanced, cancer type-specific interpretation. OGT interacts with diverse epigenetic factors including HCF-1, TET, mSin3A, HDAC, and BAP1, linking the cellular metabolic state to the epigenetic profile of cancer cells.

Conclusions

In this review, we critically evaluate OGT’s role in cancer epigenetics within a metabolism-epigenetics-signaling crosstalk framework, and discuss OGT inhibitor development and the challenges of therapeutic translation, including selectivity and bioavailability.

Background

Cancer remains one of the leading causes of morbidity and mortality worldwide and is frequently limited by therapeutic resistance (WHO 2025). According to the World Health Organization (WHO), more than 19 million new cancer cases and 10 million cancer-related deaths were forecasted to occur in 2025 globally, leading to a sharp rise in incidence and mortality. While survival rates have improved through earlier detection and refined therapeutics, resistance to treatment continues to limit outcomes in many malignancies. The mechanisms displaying resistance are multifactorial, involving mutations in drug targets, activation of efflux transporters, epigenetic remodeling, and dynamic adaptation by cancer stem cells (Siegel et al. 2025; CDC 2026; Bhol et al. 2025; Jia et al. 2025). Crucially, among these mechanisms, epigenetic plasticity has become a particularly tractable but underutilized therapeutic vulnerability. Unlike genetic mutations, epigenetic changes are reversible, enzyme-mediated, and closely linked to the cell’s metabolic state, which makes them appealing targets for intervention strategies that go beyond traditional cytotoxics.

The term “epigenetic reprogramming” describes heritable modifications in gene expression that cannot be linked to changes in the DNA sequence. Because epigenetic plasticity allows tumor cells to dynamically rearrange transcriptional programs in response to therapeutic pressure — including chemotherapy, targeted therapies, and immunotherapy — thereby avoiding drug-induced cell death, these alterations are crucial for cancer initiation, development, metastatic dissemination, and acquired resistance to therapy. Here, “resistance to treatment” refers specifically to the capacity of tumor cells to epigenetically reprogram gene expression in response to selective pressure from anti-cancer agents, a mechanism distinct from, but often co-occurring with, genetic mutation-based resistance (Bhol et al. 2025; Jia et al. 2025). Importantly, epigenetic states are dynamic and controlled by cellular metabolism and nutrient availability. This process is known as nutrient-driven epigenetics. Essential metabolites including acetyl-CoA, SAM, and UDP-GlcNAc act as direct substrates for chromatin-modifying enzymes, connecting the cell’s metabolic milieu to its gene expression landscape (CDC 2026; Vaschetto 2024; Klibaner-Schiff et al. 2024).

O-linked N-acetylglucosamine glycosylation (O-GlcNAcylation) is one of the most metabolically sensitive post-translational modifications (PTMs). Like phosphorylation, O-GlcNAcylation operates as a dynamic and reversible cycle: OGT installs the modification and OGA removes it. OGT is the sole enzyme that adds O-GlcNAc to serine and threonine residues of nuclear and cytoplasmic proteins; OGA is the sole enzyme that hydrolyzes it. The net O-GlcNAc stoichiometry of a cell therefore reflects the balance between OGT and OGA activities. In addition to being crucial for stem cell maintenance, cell-cycle regulation, and stress responses, OGT is necessary for embryonic development (germline knockout is fatal in mice). Beyond development, OGT plays broad roles in disease: dysregulated O-GlcNAcylation has been linked to type 2 diabetes and insulin resistance through impaired insulin signaling, to neurodegeneration (including Alzheimer’s disease via tau O-GlcNAcylation), and to cancer, where OGT overexpression or OGA downregulation drives oncogenic signaling (Chatham et al. 2021; Zhao et al. 2025a, b). Dysregulation of this cycling system, most commonly through OGT overexpression or OGA downregulation, is a hallmark of multiple cancer types (Wang et al. 2025a, b, c; Hu et al. 2022). OGT is becoming more widely acknowledged as a key epigenetic integrator in many, though not all, cancer types (Wang et al. 2025a, b, c; Zhao et al. 2025a, b). Nevertheless, O-GlcNAcylation does not uniformly promote oncogenesis; context-dependent and tumor-suppressive functions have also been documented, underscoring the need for careful, cancer-type-specific interpretation. Metabolic status, OGT isoform subcellular localization, and the predominant oncogenic drivers each shape this context-dependency. Although more than 160 reviews indexed in PubMed address O-GlcNAcylation and cancer, most focus on individual cancer types, discrete signaling pathways, or the inhibitor landscape alone. The unifying framework of the current review sets it apart by integrating three aspects that are rarely discussed together: (i) OGT functions as an epigenetic regulator via chromatin-modifying complexes (PRC2/EZH2, TET proteins, HCF-1, NSL); (ii) OGT as a metabolic sensor that translates HBP flux into oncogenic and tumor-suppressive signaling outputs in a context-dependent manner; and (iii) the translational gap between preclinical OGT inhibitor development and clinical readiness, including previously underreported challenges such as immune cell toxicity and the complete absence of clinical trial data. This review offers an updated, critically analytical synthesis that provides a framework for prioritizing OGT as a therapeutic target in metabolically defined cancer subtypes by explicitly resolving conflicting findings across cancer models. Therefore, this review tackles conflicting discoveries in the field, critically evaluates OGT’s role in cancer within this unifying metabolism-epigenetics-signaling crosstalk framework, and evaluates the current state of OGT inhibitors along with the translational obstacles they face.

O-linked N-acetylglucosamine transferase (OGT) structure

The human OGT gene, which codes for an enzyme that is roughly 117 kDa and has 1,046 amino acids per monomer, is found on chromosome Xq13.1. It has shown that point mutations in OGT itself cause X-linked intellectual disability in humans, underscoring the crucial reliance of normal neurodevelopment on O-GlcNAcylation (Vaidyanathan et al. 2017). The structure consists of two main components: (i) a GT-B glycosyltransferase fold at the C-terminus with two Rossmann-like lobes separated by a metazoan-specific interdomain region; and (ii) a right-handed superhelix composed of 13.5 tetratricopeptide repeats (TPRs) at the N-terminus, lined by a “asparagine ladder” that enables sequence-independent substrate recognition through hydrogen bonding to the peptide backbone. A flexible linker permits hinge-like conformational changes that gate substrate access (Fig. 1) (Zhang et al. 2022; Chatham et al. 2021). Crucially, the TPR domain facilitates protein-protein interactions with OGT’s regulatory partners, including TET2, HCF-1, and PRC2 complex components, and is not just a passive scaffold. Different from the UDP-GlcNAc active site, this dual function, substrate recognition and interaction partner docking, makes the TPR domain an appealing surface for allosteric inhibitor design and explains why different TPR-length isoforms have varied biological roles and interactomes.

Fig. 1.

Structural organization and domain architecture of OGT: The human OGT ribbon illustrates the C-terminal GT-B glycosyltransferase catalytic domain and the N-TPR domain, which forms an elongated superhelix. Hinge-like conformational changes that regulate substrate access to the active site are shown by the flexible linker between the domains. UDP spheres are displayed in the catalytic cleft

Alternative splicing produces three primary isoforms of OGT, which are referred to as short OGT (sOGT, 2.5 TPRs; cytoplasm), mitochondrial OGT (mOGT, 9 TPRs; inner mitochondrial membrane), and nucleocytoplasmic OGT (ncOGT, 13.5 TPRs; nucleus and cytoplasm). These isoforms share the same catalytic C-terminal domain. The isoforms show varied substrate selectivity and interactome profiles (Zhang et al. 2022; Chatham et al. 2021) due to their variable TPR levels and consequent amphipathic groove shape (Fig. 2). Because ncOGT regulates the glycosylation of nucleus substrates, including as transcription factors, TET proteins, and histones, it is the most common type that is related to cancer. Although mOGT has been demonstrated to influence mitochondrial protein function, its precise role in cancer cell metabolism is still poorly understood (Chatham et al. 2021). sOGT, with its truncated TPR domain, is restricted to the cytoplasm and has a distinct, more limited substrate repertoire compared to ncOGT (Zhang et al. 2022). The differential subcellular distribution of OGT isoforms is therefore a structural basis for the context-dependency observed in O-GlcNAc biology across cancer types.

Fig. 2.

Structural organization and functional domains of human OGT A Heterotrimeric composition demonstrating two 110 kDa subunits and one 78 kDa subunit B Domain of three OGT isoforms

The catalytic process is carried out by an ordered sequential bi-bi mechanism, where the peptide substrate binds after UDP-GlcNAc. The two important catalytic residues that are clearly identified in Fig. 3 are H498, which serves as the catalytic base, and K842, which stabilizes the departing UDP moiety (Zhao et al. 2025a, b; Zhang et al. 2022; Chatham et al. 2021). According to structural research, the OGT active site forms a ternary complex when both UDP-GlcNAc and the peptide substrate attach to it, adopting a more confined shape (Zhang et al. 2022). The observed difficulties of attaining high cellular potency with UDP-mimetic analogs alone, which bind only a portion of the active site, is consistent with this conformational change. Additionally, the metazoan-specific interdomain region, absent in bacterial OGT homologs, contributes to the substrate specificity of human OGT (Chatham et al. 2021). These structural features offer crucial mechanistic context for understanding the limitations and opportunities in OGT inhibitor design, as discussed in "OGT and Inhibitors" section.

Fig. 3.

Proposed catalytic mechanism of O-GlcNAc transferase (OGT). Note: Catalytic residues H498 (general base) and K842 (UDP-stabilizing residue) are explicitly labeled in each panel of the figure to clarify mechanistic steps. Left Panel: After binding of the UDP-GlcNAc to the active site, the peptide substrate places its acceptor hydroxyl group in close proximity to the sugar’s anomeric carbon. With its orientation toward this hydroxyl, H498 functions as a general base, abstracting the proton and changing the –OH into a more reactive alkoxide nucleophile. K842 is positioned close to the UDP diphosphate at the same time, creating hydrogen-bonding and stabilizing electrostatic interactions. Middle Panel: Once deprotonated, the activated oxygen on the peptide attacks the anomeric carbon of the GlcNAc. This forms oxocarbenium-like transition state. During this step, the bond between the sugar and UDP begins to break. K842 helps stabilize the accumulating negative charge on the UDP moiety as it departs and H498 remains protonated after acting as the base. Right Panel: The new glycosidic bond between the sugar and the peptide is fully formed, yielding the glycosylated product. UDP is released as the leaving group, its departure facilitated by prior stabilization from K842. H498 returns to its original state (after proton transfer equilibrates), ready for another catalytic cycle

OGT in epigenetic regulation

Histone O-GlcNAcylation and chromatin dynamics

Adapter proteins such as Sp1, Trak1/Milton, and mSin3A attract OGT to particular signaling complexes or chromatin loci. Additionally, the enzyme forms three key functional complexes that have been described in the literature (Fig. 4): the OGT–URI–PP1 complex (metabolic stress response), the OGT–TET complex (DNA demethylation and epigenetic control), and the NSL/KANSL complex (histone H4 acetylation) ( Sepulveda et al. 2025).

Fig. 4.

(A) OGT structural organization showing the TPR domain and GT-B fold catalytic domain. (B) The three major OGT complexes: OGT-URI-PP1, NSL, and OGT-TET complexes

Every core histone is tagged with O-GlcNAc by OGT. Histone H2B serine 112 (H2BS112-GlcNAc), the most thoroughly studied site, controls gene activation and nucleosome dynamics. The competitive interaction between O-GlcNAcylation and phosphorylation at similar or nearby serine/threonine sites is a fundamental regulatory concept. Elevated O-GlcNAc can reduce phosphorylation-dependent signaling as OGT and kinases fight for overlapping substrate locations, and vice versa. For instance, O-GlcNAcylation and H2BS112 phosphorylation are mutually exclusive at H2BS112, and metabolic flow via the HBP regulates the ratio of these marks. Mechanistically, this competition is governed by at least three non-mutually exclusive principles: (i) steric occlusion, whereby the bulky O-GlcNAc moiety physically prevents kinase access to the same or adjacent residue; (ii) shared scaffold competition, in which OGT and kinases are recruited to the same chromatin loci through overlapping adaptor proteins (e.g., mSin3A), such that elevated HBP flux favors OGT occupancy over kinase docking; and (iii) nutrient-driven shifts in relative enzymatic activity, where high UDP-GlcNAc concentrations under nutrient-replete conditions increase OGT catalytic rate and tip the modification balance away from phosphorylation (Zhao et al. 2025a, b; Dupas et al. 2023; Cheng et al. 2024). Similarly, cross-talk between O-GlcNAcylation and phosphorylation has been documented on H3S10, H3T32, and multiple sites on H3 and H4 tails, with consequences for mitotic progression and transcriptional regulation (Zhao et al. 2025a, b; Dupas et al. 2023). OGT stabilizes the NSL HAT complex and directly connects nutrient flux to histone H4 acetylation and chromatin accessibility by glycosylating NSL3/KANSL3 (Sepulveda et al. 2025; Xu et al. 2022; Dupas et al. 2023). Furthermore, it has been revealed that OGT-mediated O-GlcNAcylation of H3T32 controls heterochromatin structure under nutritional stress, and glycosylation of the H4 tail affects how it interacts with chromatin readers, which modifies the status of chromatin compaction. All of these results highlight histone O-GlcNAcylation as a layer of the histone code that is sensitive to nutrients and interacts with acetylation and phosphorylation to regulate transcriptional output.

PRC2 and polycomb-mediated gene silencing

In Drosophila melanogaster, OGT (the product of the super sex combs gene, sxc) is a bona fide Polycomb group (PcG) protein whose loss causes homeotic transformations similar to classical PcG mutations (Gambetta et al. 2009). In mammals, OGT is not classified as a canonical PcG member; rather, it works as a context-dependent modulator of PRC2 activity through direct O-GlcNAcylation of complex subunits (Myers et al. 2011). OGT O-GlcNAcylates EZH2, PRC2’s catalytic subunit, along with EED and other accessory subunits, increasing H3K27 trimethylation (H3K27me3) and encouraging the silence of tumor suppressor and developmental genes. By preventing proteasomal degradation, O-GlcNAcylation of EZH2 improves protein stability and boosts PRC2 enzymatic output. OGT-dependent stabilization of EZH2 in cancer settings enhances H3K27me3-mediated silencing at tumor suppressor loci such CDH1 and CDKN2A (p16/p14ARF), which promotes tumor growth and immune evasion (Fig. 5). Mechanistically, de-repression of developmental regulators results from decreased OGT activity, which also lowers EZH2 protein levels and compromises the integrity of the PRC2 complex. Crucially, EZH2’s interaction with PRC2 cofactors and its recruitment to particular genomic loci through contact with long non-coding RNAs are also impacted by O-GlcNAcylation. Notably, a study demonstrated that OGT regulates p21 levels and cell proliferation through the FoxM1–Skp2 axis, providing mechanistic insight into how OGT-PRC2 crosstalk can influence cell cycle checkpoints beyond direct H3K27me3 deposition (de Queiroz et al. 2022). These findings collectively support OGT as a non-canonical regulator of Polycomb-mediated gene silencing in mammals, with direct relevance to epigenetic reprogramming in cancer.

Fig. 5.

OGT regulates PRC2 function. (1) OGT is associated with the PRC2 complex, which includes EZH2, SUZ12, EED, and RbAp46/48. (2) OGT O-GlcNAcylates EZH2 on serine/threonine residues, enhancing H3K27 trimethylation (H3K27me3) on nucleosomes and promoting repression of developmental genes. (3) In cancer, OGT-dependent stabilization of EZH2 strengthens H3K27me3-mediated silencing at tumor suppressor loci, contributing to tumor progression

TET proteins and DNA demethylation

OGT forms mutually stabilizing partnerships with TET2 and TET3 through physical contacts and co-localization at transcription start sites (Deplus et al. 2013).

Loss of TET2 leads not only to aberrant DNA methylation but also to reduced recruitment of OGT and diminished histone O-GlcNAcylation at affected loci, highlighting the close functional coupling between DNA hydroxymethylation and O-GlcNAc signaling pathways (Chen et al. 2013). TET proteins and OGT coordinate chromatin modification and transcriptional regulation through their physical and functional interactions (Deplus et al. 2013). In parallel, 5-hydroxymethylcytosine (5hmC), generated by TET-mediated oxidation of 5-methylcytosine, works both as a stable epigenetic mark and an intermediate in active DNA demethylation enriched at active enhancers and gene bodies of transcribed genes (Wu & Zhang, 2017; Zheng et al. 2024). As recently reported, OGT simultaneously constrains TET catalytic activity genome-wide in heterochromatin to prevent erroneous de-repression of transposable elements, positioning OGT as a rheostat of DNA methylation fidelity that must balance active demethylation at promoters with heterochromatin maintenance (Sepulveda et al. 2025).

HCF-1 processing and cell-cycle control

One of OGT’s most unusual biochemical roles is the proteolytic processing of Host Cell Factor-1 (HCF-1). The correct G1/S-phase transition depends on the proteolytic maturation of HCF-1, a chromatin-associated transcriptional co-regulator essential for cell-cycle progression. OGT catalyzes the site-specific cleavage of HCF-1 at its proteolytic repeat (PRO) domains, resulting in non-covalently linked N- and C-terminal subunits. This cleavage reaction is mechanistically distinct from conventional proteolysis because it is catalyzed directly by OGT rather than by a separate protease. Mature HCF-1 links OGT activity to transcriptional control and chromatin modification by participating in SET1/MLL histone H3K4 methyltransferase complexes, Sin3 histone deacetylase, and NSL histone acetyltransferase complexes.In cancer models, disruption of OGT-dependent HCF-1 processing impairs E2F-regulated transcriptional programs, delays cell-cycle progression, and can reduce cellular proliferation and survival (Lazarus et al. 2013; Daou et al. 2011; Janetzko and Walker 2014). Since HCF-1 is frequently overexpressed in cancer and drives transcription of proliferative target genes including CCND1 and MYC, OGT-dependent HCF-1 processing represents a direct mechanism through which elevated HBP flux sustains tumor cell proliferation. Consistent with this, OGT-dependent HCF-1 activity has been shown to promote lung cancer progression (Srivastava et al. 2025). Furthermore, HCF-1 co-occupies promoters of oncogenic targets together with OGT and the SET1/MLL complex, establishing O-GlcNAcylation-dependent HCF-1 processing as an epigenetic vulnerability with direct relevance to cancer (Sugeedha et al. 2021).

High O-GlcNAcylation in cancer

O-GlcNAcylation across cancer types

The expression patterns and important functional effects of increased OGT/O-GlcNAcylation in the main human cancers are mentioned in Table 1. Hyper-O-GlcNAcylation frequently promotes pro-oncogenic characteristics such as invasion, metastasis, proliferation, and treatment resistance across multiple solid tumor types, though this review focuses on solid malignancies for which functional mechanistic data are available; hematologic cancers represent an important parallel literature not covered here. As introduced in "Background" section, O-GlcNAc cycling is controlled by the opposing actions of OGT, which installs the modification, and OGA (encoded by MGEA5), which hydrolyzes it; the net cellular O-GlcNAc level reflects the balance of these two enzymatic activities. OGT overexpression, OGA downregulation, or increased HBP flux can all lead to elevated O-GlcNAc levels in tumors; differentiating between these mechanisms has significant implications for therapeutic targeting. Higher O-GlcNAc levels in liver cancer, for example, might co-occur with variable or even decreased OGT expression, indicating that substrate-level metabolic changes or OGA downregulation rather than OGT overexpression are the main cause (Sampson et al. 2025; Dai et al. 2025; Hu et al. 2022; Wang et al. 2025a, b, c). This is a notable example of context-dependence. These differences highlight how important it is to distinguish between changes in OGT activity, OGA activity, and net O-GlcNAc flux when analyzing cancer datasets and to avoid confusing higher O-GlcNAc with OGT overexpression.

Table 1.

Cancer type expressions and OGT/O-GlcNAcylation’s functions

Cancer Types	OGT/ O-GlcNAC Expression	Mechanisms/ Effects	Sources
Breast	↑/↑	OGT stabilizes c-MYC (T58 glycosylation), promotes FoxM1-driven proliferation, activates AKT/mTOR via O-GlcNAcylation; RUNX1 glycosylation confers CDK4/6 inhibitor resistance; OGT-c-MYC axis drives chemoresistance in TNBC; OGT targets FoxM1 to drive breast tumorigenesis; tumor promoting	● Kozal and Krześlak 2023; ● Caldwell et al. 2010; ● Zhou et al. 2025; ● Li and Zhang, 2026
Lung	↑/↑	YEATS2 O-GlcNAcylation promotes ATAC complex chromatin association and tumorigenesis; HCF-1 glycosylation activates proliferative transcription; context-dependent due to variability in KRAS/EGFR driver background; mostly tumor promoting	● Zhao et al. 2025a, b ● Srivastava et al. 2025
Prostate	↑/↑	OGT O-GlcNAcylates OR51F2 to enhance malignant phenotype; CDK1 downregulation and AR protein reduction upon OGT inhibition; c-MYC stabilization; OGT inhibition reduces AR protein levels, implicating OGT in androgen signalling; tumor promoting	● Itkonen et al. 2016 ● Xu et al. 2025
Liver	-/↑	PRDX1 O-GlcNAcylation stabilizes protein and activates LRP6-Wnt signaling to promote metastasis; OGT expression variable/decreased while O-GlcNAc elevated suggesting OGA downregulation as primary driver; context dependent	● Dai et al. 2025 ● Hu et al. 2022
Colon	↑/↑	NONO O-GlcNAcylation regulates paraspeckle assembly and drives cell proliferation; glycosylation-related gene signatures predict poor prognosis; OGT promotes Wnt/β-catenin signaling; tumor promoting	● Kim et al. 2025 ● Chen et al. 2025
Gastric	↑/↑	Hypoxia-induced circPRELID2 promotes metastasis via PCBP1 O-GlcNAcylation facilitating ZEB2 translation; elevated O-GlcNAcylation promotes cell-cycle dysregulation via CDK2/cyclin D1 and ERK1/2 pathways; tumor promoting (limited but consistent evidence)	● Zhang et al. 2025 ● Lu et al. 2022
Esophageal	↑/↑	O-GlcNAcylation of RSK4 antagonizes GSK3β-mediated phosphorylation, stabilizing RSK4 and enhancing radioresistance; O-GlcNAcylation broadly implicated in therapeutic resistance; context dependent (radioresistance mechanism validated in ESCC)	● Liu et al. 2026a, b ● Lu et al. 2022
Laryngeal	↑/↑	OGT/OGA gene and protein expression altered in laryngeal squamous cell carcinoma; elevated O-GlcNAc correlates with advanced T-stage and poor prognosis; specific substrates include glycosylation-dependent stabilization of proliferative transcription factors; context dependent (limited molecular mechanistic data; OGA downregulation implicated as primary driver)	● Starska et al. 2015 ● Lu et al. 2022
Pancreatic	↑/↑	KRAS-driven O-GlcNAcylation of CLDN18.2 enhances progression and reduces efficacy of CLDN18.2-targeted therapy; METTL3 O-GlcNAcylation stabilizes protein to promote HMGB1 degradation and gemcitabine resistance; tumor promoting	● Liu et al. 2026a, b ● Wang et al. 2025a, b, c
Bladder	↑/↑	GFPT2/O-GlcNAcylation/c-Myc axis promotes progression via increased HBP flux and c-Myc glycosylation-dependent stabilization; glycoprotein biomarker alterations identified for detection; context dependent (c-Myc stabilization and HBP upregulation mechanistically validated; broader substrate map emerging)	● Xie et al. 2026 ● Khan et al. 2026
Endometrial	↑/↑	Elevated glucose activates HBP/Wnt/β-catenin axis via O-GlcNAcylation, linking hyperinsulinemia to endometrial cancer risk; context dependent (hyperglycemia-driven O-GlcNAcylation mechanism well-supported; protective roles under nutrient deprivation also reported)	● Zhou et al. 2016

Context-dependent and tumor-suppressive roles of O-GlcNAcylation

The O-GlcNAc cycling mechanism and AMPK signaling interact in a bidirectional and context-dependent way. According to research, AMPK can phosphorylate O-GlcNAc transferase (OGT), affecting its subcellular location and global O-GlcNAcylation patterns. This connects the control of protein glycosylation networks with energy stress (Bullen et al. 2014; Cheng et al. 2024). On the other hand, OGT-mediated O-GlcNAcylation of Raptor at Thr700 activates mTORC1 by facilitating its interaction with Rag GTPases, linking O-GlcNAc signaling to mTOR-dependent nutrient sensing (Xu et al. 2023; Cheng et al. 2024). All of these results point to an integrated nutrient-sensing network where O-GlcNAc cycling and AMPK operate together to control metabolic adaptation, with results that are strongly influenced by cellular energy balance and environmental factors. Critically, the tumor-suppressive arm of this crosstalk is context-specific: AMPK-mediated phosphorylation of OGT and consequent attenuation of global O-GlcNAcylation has been observed primarily under conditions of severe glucose limitation (< 2 mM glucose in vitro) or pharmacological energy stress (e.g., AICAR or metformin treatment), conditions that elevate the AMP: ATP ratio and maximally activate AMPK (Bullen et al. 2014; Cheng et al. 2024). Under such nutrient-deprived conditions, reduced OGT activity limits O-GlcNAc-dependent stabilization of oncoproteins such as c-MYC and SREBP-1, thereby engaging a metabolic checkpoint that restrains tumor cell proliferation. By contrast, in nutrient-replete tumor microenvironments — characteristic of hyperglycemic or hyperinsulinemic states — AMPK activity is suppressed, OGT-driven O-GlcNAcylation predominates, and the net effect is pro-oncogenic. This metabolic dichotomy underscores why O-GlcNAcylation must be interpreted in the context of the prevailing nutrient and energy status of the tumor.

O-GlcNAcylation has been identified as a crucial post-translational modification that controls the stability, activity, and stress response of p53. Early mechanistic research revealed that p53 is O-GlcNAcylated at Ser149, which strengthens p53 tumor suppressor function by increasing p53 stability under stressful conditions by blocking phosphorylation at Thr155 by the COP9 signalosome, which otherwise drives ubiquitination and proteasomal degradation of p53 (Yang et al. 2006). As further highlighted in recent integrative analyses of p53 regulation in cancer biology, this regulatory mechanism reflects broader principles of post-translational cross-talk within the p53 network, where phosphorylation and O-GlcNAcylation dynamically compete to control protein stability and transcriptional activity (Wang et al. 2024). Importantly, O-GlcNAcylation of p53 at Ser149 and its tumor-suppressive consequences are most pronounced under genotoxic or metabolic stress conditions — including oxidative stress, DNA damage, and glucose deprivation — in which OGT activity is transiently elevated as part of a broad cellular stress-response program (Yang et al. 2006; Wang et al. 2024). In nutrient-replete, rapidly proliferating cancer cells, this protective O-GlcNAcylation event may be outcompeted by constitutively active oncogenic kinases and ubiquitin ligases that override p53 stability, explaining why the tumor-suppressive role of O-GlcNAcylation at this site is context-dependent rather than universal.

Multiple recent studies demonstrate that acute or sustained stress triggers a rapid increase in O-GlcNAcylation that contributes to cellular adaptation and survival signaling programs, with broad redistribution of O-GlcNAc across nuclear, cytoplasmic, and mitochondrial proteins. In this context, O-GlcNAc signaling interacts with important stress-adaptive transcriptional regulators, such as FOXO family transcription factors and hypoxia-inducible factor 1α (HIF-1α), which regulate oxidative stress reactions, metabolic reprogramming, and survival signaling in low oxygen or nutrient availability (Housley et al. 2008; Wang et al. 2024).

OGT, nutrition, and cancer epigenetics

The HBP produces UDP-GlcNAc, the necessary OGT substrate, by combining UTP, glutamine (amine donor via GFAT), acetyl-CoA (for N-acetylation), and glucose (carbon backbone) (Zhao et al. 2025a, b; Zhang et al. 2022; Chatham et al. 2021; Sepulveda et al. 2025; Xu et al. 2022; Dupas et al. 2023). In cancer cells, HBP flux is substantially elevated and intracellular UDP-GlcNAc concentrations increase significantly, leading to hyper-O-GlcNAcylation of key oncoproteins (Chatham et al. 2021; Zhao et al. 2025a, b). For example, O-GlcNAcylation at T58 stabilizes c-MYC by blocking T58-directed phosphorylation and subsequent proteasomal degradation, substantially extending its protein half-life (Chatham et al. 2021; Li and Zhang, 2026); AKT is modified at T308/S473 regulatory regions by OGT, enhancing kinase activity and downstream mTORC1 and FOXO suppression (Zhao et al. 2025a, b; Chatham et al. 2021); and SREBP-1 is stabilized at serine residues within its transactivation domain, driving lipogenic gene expression including FASN and ACC1 to support tumor biomass (Zhao et al. 2022).

On a molecular level, hyperinsulinemia promotes mTORC1-dependent GFAT upregulation and OGT membrane recruitment via PIP3-binding proteins, creating a feedforward loop whereby elevated insulin signaling increases HBP flux and O-GlcNAcylation, which in turn sustains oncogenic insulin/IGF-1 signaling. Epidemiologically, high glycemic-index diets and chronic hyperinsulinemia are associated with elevated risk of colorectal and endometrial cancers (Chatham et al. 2021; Cheng et al. 2024).

OGT reciprocally O-GlcNAcylates AMPK α- and γ-subunits, attenuating AMPK energy-sensing function and establishing a bidirectional crosstalk between these two metabolic master regulators. AMPK counterbalances this axis by phosphorylating OGT to reroute its substrate specificity and by inhibiting SREBP-1 and mTORC1 (Hu et al. 2022; Kozal and Krześlak 2023) (Fig. 6).

Fig. 6.

OGT acting as as a metabolic–epigenetic integrator linking HBP activity to oncogenic signaling and epigenetic reprogramming in cancer. Glucose and glutamine/acetyl-CoA serve as major substrates for the HBP, with GFAT functioning as the rate-limiting enzyme that generates UDP-GlcNAc, the donor substrate required for O-GlcNAcylation. In cancer cells, increased HBP flux increases OGT activity, promoting O-GlcNAc modification of proteins involved in both oncogenic signaling and epigenetic regulation. The epigenetic arm involves H2B Ser112 glycosylation, TET2/3 co-regulation, stabilization of the PRC2/EZH2 complex and HCF-1–SET1/MLL-mediated transcriptional activation, which influence chromatin remodeling, DNA methylation dynamics, and gene expression. The oncogenic arm includes O-GlcNAc-dependent RAS/MAPK pathway enhancement, stabilization of c-MYC, activation of PI3K/AKT/mTOR signaling, and increased NF-κB/SREBP-1 activity, promoting proliferation, apoptosis resistance, invasion, and metastasis. OGT activity is further integrated into cellular energy sensing through reciprocal crosstalk with AMPK and mTORC1, leading to a regulatory feedback network that coordinates nutrient availability with cancer-associated transcriptional and signaling programs. Solid arrows indicate metabolic or signaling flow, whereas flat-headed lines indicate inhibitory regulation

NF-κB represents an additional oncogenic effector through which O-GlcNAcylation promotes tumor survival. O-GlcNAcylation of the p65/RelA subunit at Thr322 and Thr352 stabilizes the NF-κB transcriptional complex and facilitates its nuclear translocation, thereby sustaining transcription of pro-survival and pro-inflammatory target genes including BCL-2, BCL-XL, XIAP, cyclin D1, and IL-6 (Ma et al. 2013; Allison et al. 2012). In cancer cells with constitutively elevated O-GlcNAc, this mechanism creates a direct link between HBP nutrient flux and apoptosis resistance. Conversely, OGA-mediated removal of these O-GlcNAc marks attenuates NF-κB transcriptional activity and sensitizes cells to apoptotic stimuli, reinforcing the therapeutic rationale for modulating O-GlcNAc cycling in NF-κB-dependent malignancies such as diffuse large B-cell lymphoma, triple-negative breast cancer, and pancreatic ductal adenocarcinoma.

OGT and inhibitors

The epigenetic and metabolic mechanisms established in the preceding sections provide the therapeutic rationale for OGT targeting. Because OGT sits at the intersection of chromatin regulation and HBP-derived nutrient flux, its inhibition is predicted to concurrently reverse hyper-O-GlcNAcylation of oncoproteins (c-MYC, AKT, and NF-κB), destabilize the PRC2/EZH2 complex and relieve tumor-suppressor gene silencing, impair HCF-1 maturation and reduce E2F-driven proliferation, and disrupt TET–OGT cooperation at active promoters. This pleiotropy represents both a therapeutic opportunity, multi-pathway blockade from a single target — and a liability, given the risk of on-target toxicity in normal tissues that depend on the same epigenetic machinery. Downstream mechanistic read-outs identified in earlier sections, including H3K27me3 levels, 5hmC abundance, c-MYC protein stability, and AKT kinase activity, represent candidate pharmacodynamic markers for future inhibitor studies. Understanding this mechanistic context is prerequisite for designing informative preclinical studies and interpreting existing potency and selectivity data. Most inhibitor candidates developed prior to 2015 were not demonstrated to selectively or efficiently inhibit OGT. The absence of effective and targeted OGT inhibitors is one of the major challenges to validating OGT as a therapeutic target. For instance, early studies with substrate-mimicking peptides and UDP analogs such as UDP-5 S-GlcNAc (1) and UDP-S-GlcNAc (2) (Fig. 7) showed low cell permeability and limited efficacy (Balsollier et al. 2021; Ortiz-Meoz et al. 2015). This modification where sulfur is substituted for the endocyclic oxygen of the N-acetylglucosamine ring or between the ring and the phosphate, changes the sugar moiety’s steric and electronic characteristics and lowers enzymatic turnover while preserving active-site binding. The highly polar and negatively charged UDP scaffold results in low membrane permeability, which limits the usefulness of these analogs mainly to in vitro research and limits their cellular efficacy (Balsollier et al. 2021). It is noteworthy that UDP-5 S-GlcNAc (IC₅₀ = 8 µM) was characterized as a bisubstrate-mimicking competitive inhibitor of OGT with sub-micromolar binding affinity in biochemical experiments, but with no cellular activity because of its charged phosphate groups (Gloster et al. 2011). Similar poor membrane penetration was shown by UDP-S-GlcNAc (IC₅₀ = 78.8 µM). These early findings pushed the field toward non-nucleotide scaffolds and showed that direct UDP-mimicry is an inadequate technique for cell-active OGT inhibition.

Fig. 7.

UDP analogs structures. (1) UDP-5 S-GlcNAc (IC₅₀ = 8 µM); (2) UDP-S-GlcNAc (IC₅₀ = 78.8 µM). Previously studied OGT inhibitors: (3) Alloxan (IC₅₀ = 100 µM in islet-based assay; 18 µM in recombinant enzyme assay); (4) BZX (IC₅₀ = 11.9 µM); (5) OSMI-1 (IC₅₀ = 2.7 µM); (6) OSMI-4 (EC₅₀ = 3 µM); (7) ST045849 (IC₅₀ = 53 µM); (8) L01 (IC₅₀ = 21.8 µM); (9) 3b (IC₅₀ = 116 µM) and (10) 6b (IC₅₀ = 144.5 µM), the two most effective candidates of the fragment-based drug design published study (Weiss et al. 2021)

Alloxan (3) (Fig. 7) holds the distinction of being the first OGT inhibitor ever described, reported in 2002 as a synthetic uracil analogue that inhibits OGT by competing with the UDP-GlcNAc donor substrate (Konrad et al. 2002). Despite early promise, alloxan displayed considerable off-target effects — most notably pancreatic beta-cell toxicity — and lacked the selectivity needed to distinguish OGT from other glycosyltransferases. Additionally, several early small-molecule candidates exhibited unfavorable pharmacokinetic properties, including rapid metabolic clearance and the inability to cross cellular membranes at therapeutically relevant doses (Balsollier et al. 2021; Ortiz-Meoz et al. 2015).

High-throughput screening (HTS) based assays have been employed to identify small-molecule inhibitors of OGT. One compound identified through HTS is BZX (4) (Fig. 7), a covalent, irreversible OGT inhibitor that cross-links active-site residues Lys842 and Cys917 via an S-thiocarbamate mechanism, thereby permanently inactivating the enzyme (Ortiz-Meoz et al. 2015; Borodkin et al. 2014). It shows IC₅₀ = 11.9 µM, but was found to have potential cytotoxicity and off-target effects that limit its utility as a selective chemical probe. The OSMI series’ medicinal chemistry evolution serves as an example of the iterative optimization needed to produce cell-active OGT inhibition. The first cell-permeable OGT inhibitor to be widely used was OSMI-1 (5) (Ortiz-Meoz et al. 2015), identified by HTS of over 4,000 compounds. It showed an IC₅₀ of 2.7 µM in biochemical experiments. Notably, OSMI-1’s precise binding mode and mechanism of inhibition at the molecular level remain unresolved crystallographically, complicating rational scaffold optimization. Furthermore, OSMI-1 has been shown to inhibit NK cell cytotoxicity and T-cell effector function in vitro, findings with direct relevance to the immune toxicity concerns discussed in "Clinical Translation Challenges" section. OSMI-2 and OSMI-3, analogs with better aqueous solubility but only slight increases in potency, were subsequently identified by modifying the fundamental quinolinone-sulfonamide scaffold (Martin et al. 2018). In cellular O-GlcNAc-reduction assays, OSMI-4 (6), which incorporated a fluorinated benzenesulfonamide extension and a methyl-quinoline core substitution, achieved an EC₅₀ of 3 µM with a substantially improved selectivity profile over earlier OSMI analogs and a panel of glycosyltransferases (Balsollier et al. 2023). OSMI-4 validated the scaffold for further tuning and exhibited on-target activity in several cancer cell lines. Together, these advances have significantly accelerated the field of selective OGT inhibition, with accumulating evidence that OGT inhibition can sensitize cancer cells to chemotherapy and overcome drug resistance.

Through cell viability assays, ST045849 (7) was identified to significantly inhibit the viability of LNCaP and PNT2 cells after 96 h of treatment (Fig. 7). Compound (7) led to sustained decrease of c-MYC at 24, 48 and 96 h time-points. The expression levels of CDK1, the gene found to be most down-regulated upon OGT inhibitor treatment, were also reduced by this compound. Treatment with OSMI-1 led to a maximal 60% decrease in CDK1 mRNA and decreased c-MYC expression by 40% at 24 and 48 h post-treatment (Itkonen et al. 2016). Increased expression of CDK1 predicts prostate cancer recurrence after surgery with high significance. OGT inhibition also decreased AR protein expression (Itkonen et al. 2016).

High-throughput screening (HTS) has proven to be a productive strategy for identifying OGT inhibitors. Using newly developed assay platforms, structure-based optimization yielded low-nanomolar OGT inhibitors by profiling a core scaffold across approximately 1,400 commercially available analogs (Martin et al. 2018). This effort produced cell-permeable OGT inhibitors representing substantial potency improvements over initial hits (Martin et al. 2018). These compounds reduced O-GlcNAcylation in breast epithelial cells and inhibited proliferation and invasion of MCF-10 A-ErbB2 cells, a non-tumorigenic breast epithelial line overexpressing ErbB2/HER2 used as a model of oncogene-driven transformation.

Furthermore, a small series of derivatives were designed to define the structure-activity relationships of the most potent and synthetically adaptable hit (Loi et al. 2022). The chosen hit contained a uridine-mimetic scaffold with an IC₅₀ of 7 µM, representing an alternative non-OSMI chemotype for further optimization toward sub-micromolar, cell-active OGT inhibitors.

Among the several methods used to find selective OGT inhibitors, fragment-based drug design has shown promise (Weiss et al. 2021). To increase potency and selectivity, this approach starts with tiny chemical fragments that bind to the target protein weakly and are then methodically expanded. The first OGT inhibitors developed via fragment growth methodology were reported based on a 2-hydroxyquinoline-4-carboxamide scaffold. The uridine moiety of UDP-GlcNAc was mimicked by the quinolinone core, which was then extended using 4-(aminomethyl)benzoic acid to approach the GlcNAc-binding site. The most effective fragment from the original series, designated F20, displayed an IC₅₀ of 117.6 µM. Extended analogs 3b (9) and 6b (10) (Fig. 7) were the series’ most potent inhibitors; both resembled the binding mode of UDP-5 S-GlcNAc as a bisubstrate analog. The shorter analog 3b lost a hydrogen bond with Thr921 but gained an additional interaction with Lys842 (Weiss et al. 2021).

Previous studies have demonstrated that TamR cells were more sensitive to OSMI-1 and ST045849 (Fig. 7), OGT inhibitors, than the parental TamS cells (Barkovskaya et al. 2020). OGT inhibition can suppress cancer cell proliferation in part through induction of DNA damage-induced transcription 3 (DDIT3) and downregulation of mRNAs encoding for cell specific transcription factors that support cell proliferation (Barkovskaya et al. 2020). In addition to that, another study revealed that L01 (8) (Fig. 7) is an amentoflavone derivative and was reported as the major anti-inflammatory compound in the seed of Semecarpus anacardium (Liu et al. 2017). Compound 8 showed remarkable inhibition of OGT activity. As it has a larger topological polar surface area and higher rigidity than UDP, its ring D occupied the entrance of the UDP binding pocket between N557 and A897. Further site-directed mutagenesis to target the potentially important OGT amino acid residue Asn557 followed by an in vitro glycosylation assay showed that N557A influences L01 but not UDP (Liu et al. 2017).

Clinical translation challenges

Before clinical translation is possible, a number of crucial and important issues must be addressed.

Systemic OGT inhibition carries the potential for widespread on-target toxicity because OGT is encoded by a single gene and is ubiquitously required for normal cell function, including in rapidly dividing tissues such as immune cells, intestinal epithelium, and bone marrow. Preclinical studies with OGT knockout models have demonstrated dose-dependent effects on intestinal crypt cells and normal hematopoietic progenitors, highlighting the need to define careful therapeutic windows. In immune cells, O-GlcNAcylation plays important roles in T-cell activation, macrophage polarization and cytokine production: OGT is required for optimal T-cell receptor signaling, and systemic OGT inhibition in vivo has been shown to impair T-cell proliferation and effector function, raising concerns about potential immunosuppression that could counteract anti-tumor immunity. Beyond T cells, OGT-dependent O-GlcNAcylation governs macrophage polarization: its reduction shifts macrophages toward the pro-inflammatory M1 phenotype and amplifies cytokine production (including TNF-α and IL-1β), meaning that systemic OGT inhibition could trigger unintended inflammatory responses in the tumor microenvironment and peripheral tissues. Tumor-targeted delivery systems, such as antibody-drug conjugates (ADCs) that link OGT inhibitors to tumor-antigen-directed antibodies, nanoparticle encapsulation for increased tumor accumulation, and pH-sensitive pro-drugs that release active compounds preferentially in the acidic tumor microenvironment, are some strategies to mitigate this.

In the second place, the majority of OGT inhibitors currently available on the market still have challenging pharmacokinetic and bioavailability characteristics. OSMI-class drugs have significant plasma protein binding and fast metabolic clearance in vivo despite cell permeability, which limits their use in translational research and animal effectiveness models.

Third, patient stratification strategies, for example, employing the OGT: OGA expression ratio or site-specific O-GlcNAc profiling as companion biomarkers, will be critical for clinical implementation given tumor heterogeneity and OGT expression variability across cancer types.

Fourth, combination strategies might offer a way around selectivity restrictions: preclinical data shows OGT inhibition alone can activate tumor-suppressor gene expression and reverse tamoxifen resistance in breast cancer cells (Barkovskaya et al. 2020). In terms of clinical progress, no OGT inhibitor has started clinical trials as of yet. Candidates that concurrently satisfy the requirements of adequate potency (IC₅₀ < 1 µM cellular), selectivity (> 50-fold over related glycosyltransferases), and appropriate pharmacokinetic features for in vivo efficacy investigations are lacking in the field. Notably, robust in vivo pharmacodynamic and antitumor efficacy data for OGT inhibitors in animal models remain sparse, representing a critical translational gap between biochemical potency and clinical readiness that must be addressed before any compound can advance to clinical candidacy.

Prioritizing next-generation chemotypes with enhanced drug-like characteristics is a crucial unmet need, and this indicates a substantial gap between the robust target validation evidence and clinical readiness. Resolving these translational barriers should be the main goal of the upcoming generation of OGT inhibitor research, with a focus on tumor-targeted delivery methods in particular.

Conclusion & future directions

OGT holds a distinct position at the intersection of metabolic signaling, nutrition sensing, and epigenetic control; cancer cells frequently exploit this intersection to maintain growth and avoid apoptosis. Strong mechanistic evidence relating OGT to the stability of oncoproteins, the activity of chromatin-modifying complexes, and the coherence of important signaling cascades (PI3K/AKT/mTOR, RAS/MAPK) supports elevated O-GlcNAcylation as observed, though context-dependent, metabolic feature across multiple cancer types, one that is not universal and whose functional consequences vary with metabolic state, tissue of origin, and oncogenic driver. OGT inhibitors confront specific challenges on their path to the clinic, despite strong preclinical support. Resolution is needed for context-dependent toxicity, bioavailability, and selectivity.

Future directions warranting investigation include: (i) structure-based design exploiting the TPR allosteric surface of OGT for isoform-selective inhibitors that spare essential cytoplasmic functions; (ii) context-specific OGT targeting prioritized in metabolically defined subtypes — particularly HBP-high, hyperinsulinemia-driven, and MYC-amplified cancers — where the therapeutic window is predicted to be widest; (iii) resolving the OGT–EZH2 axis in PRC2-dependent cancers as a synthetic lethal vulnerability, combining OGT inhibition with EZH2 inhibitors already in clinical use; (iv) multi-omics characterization of acquired resistance mechanisms emerging under sustained OGT inhibition; and (v) clinical biomarker development utilizing site-specific O-GlcNAc profiling, the OGT: OGA expression ratio, and liquid biopsy-based readouts to enable patient stratification. The HBP–OGT–O-GlcNAc axis is a high-priority therapeutic vulnerability that merits ongoing investment in structural biology, medicinal chemistry, and translational research, especially in malignancies caused by hyperinsulinemia, obesity, or MYC amplification.

Abbreviations

AMPK

AMP-activated protein kinase

AKT

Protein kinase B

BAP1

BRCA1-associated protein 1

CAPES

Coordination for the Improvement of Higher Education Personnel

CNPq

National Council for Scientific and Technological Development

EC₅₀

Half-maximal effective concentration

EZH2

Enhancer of zeste homolog 2

FAPESP

São Paulo Research Foundation

FOXO3

Forkhead box O3

GFAT

Glutamine–fructose-6-phosphate amidotransferase

H2BS112-GlcNAc

O-GlcNAcylation of histone H2B at serine 112

H3K27me3

Trimethylation of histone H3 at lysine 27

H3K4me3

Trimethylation of histone H3 at lysine 4

HBP

Hexosamine biosynthesis pathway

HCF-1

Host cell factor 1

HDAC

Histone deacetylase

HIF-1α

Hypoxia-inducible factor 1-alpha

HTS

High-throughput screening

IC₅₀

Half-maximal inhibitory concentration

IGF-1

Insulin-like growth factor 1

MAPK

Mitogen-activated protein kinase

MGEA5

Meningioma expressed antigen 5 (gene encoding OGA)

mOGT

Mitochondrial OGT

mSin3A

Mammalian switch-independent 3 A

mTOR

Mechanistic target of rapamycin

mTORC1

mTOR complex 1

ncOGT

Nucleocytoplasmic OGT

NF-κB

Nuclear factor kappa-light-chain-enhancer of activated B cells

NSL

Non-specific lethal complex

O-GlcNAc

O-linked N-acetylglucosamine

OGA

O-GlcNAcase (the enzyme that removes O-GlcNAc modifications, encoded by MGEA5)

OGT

O-GlcNAc transferase

PI3K

Phosphatidylinositol 3-kinase

PIP3

Phosphatidylinositol (3,4,5)-trisphosphate

PRC2

Polycomb repressive complex 2

PTM

Post-translational modification

RAS

Rat sarcoma virus oncogene

SAM

S-adenosylmethionine

SET1/MLL

SET domain-containing protein 1/mixed lineage leukemia

sOGT

Short OGT

SREBP-1

Sterol regulatory element-binding protein 1

TET

Ten-eleven translocation

TPR

Tetratricopeptide repeat

UDP-GlcNAc

Uridine diphosphate N-acetylglucosamine

WHO

World Health Organization

ESCC

Esophageal squamous cell carcinoma

TNBC

Triple-negative breast cancer

DLBCL

Diffuse large B-cell lymphoma

PDAC

Pancreatic ductal adenocarcinoma

ADC

Antibody-drug conjugate

DDIT3

DNA damage-inducible transcript 3

Authors’ contributions

M.E. and G.H.G.T conducted the systematic literature search and performed the analysis. M.E. and G.H.G.T wrote the main manuscript text and M.E. prepared figures. G.H.G.T was project coordinator and review the manuscript.

Funding

This work was supported by the Brazilian funding agencies CNPq (grant numbers 313782/2025-3, 436791/2018-8, 310232/2017-1, and 441004/2023-7), FAPESP (grant numbers #2024/08603-0, #2022/03521-0, and 2017/25543-8), and CAPES. The funding bodies had no role in the design of the study, collection, analysis, or interpretation of data, or in writing the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.