UNASSIGNED: A growing corpus of research has revealed that circular RNAs (circRNAs) have become increasingly important for the growth of malignancies in recent years. CircRNAs as ideal candidates for breast cancer (BC) therapeutic targets is still absent.
UNASSIGNED: In our study, the dysregulated circRNAs in BC progression were explored, we analysed the BC\'s circRNA expression profiles using publicly available datasets (GSE101124 and GSE101122). The expression of circZEB1 in BC and cell lines was investigated by qPCR. RNase and actinomycin D were used to examine the features of circZEB1. The function of circZEB1 was subsequently investigated through the utilisation of colony formation, tube formation, transwell assays, and xenograft animal models.RNA immunoprecipitation (RIP), luciferase reporter assays, immunoprecipitation (co-IP) test in conjunction with LC-MS, and ChIP-seq assay to investigate the molecular mechanism underlying the biological activity of circZEB1 in BC.
UNASSIGNED: Among the circRNAs, we were particularly interested in hsa_circ_0000228, which is spliced from the oncogene ZEB1. In BC cell lines, CircZEB1 expression was upregulated. CircZEB1 knockdown prevented BC cells from migrating and invading, as well as HUVECs from forming tubes and developing. By sponging miR-337-3p, functional testing revealed that circZEB1 promoted O-GlcNAcylation, increased YBX1, and OGT expression. Moreover, circZEB1 overexpression is reversible, in contrast to YBX1 knockdown, which mostly results in the downregulation of multiple oncogenes.
UNASSIGNED: Our study indicate that circZEB1 had oncogenic function in BC by focusing on circZEB1/miR-337-3p/OGT and YBX1. It might be inferred that circZEB1 could be a promising new target for BC treatment.

Tauopathy is a collective term for several neurodegenerative diseases characterized by the intracellular accumulation of hyperphosphorylated microtubule-associated protein Tau (P-tau). Our recent report has revealed the neuroprotective effect of dihydroartemisinin (DHA) on mice overexpressing human Tau (hTau) in the hippocampus by enhancing O-linked-N-Acetylglucosaminylation (O-GlcNAcylation) modification. However, whether DHA can improve synaptic and cognitive function in hTau transgenic mice by specifically promoting Tau O-GlcNAcylation is still unclear. Here, we introduced hTau transgenic mice, a more optimal tauopathy model, to study the effect of DHA on Tau O-GlcNAcylation. We reported that DHA treatment alleviated the deficits of hippocampal CA1 LTP and spatial learning and memory in the Barnes maze and context fear conditioning tests in hTau transgenic mice. Mechanically, we revealed that DHA exerted a significant protective effect by upregulating Tau O-GlcNAcylation and attenuating Tau hyperphosphorylation. Through molecular docking, we found a stable binding between DHA and O-GlcNAc transferase (OGT). We further reported that DHA treatment had no effect on the expression of OGT, but it promoted OGT nuclear export, thereby enhancing OGT-mediated Tau O-GlcNAcylation. Taken together, these results indicate that DHA exerts neuroprotective effect by promoting cytoplasmic translocation of OGT and rebuilding the balance of Tau O-GlcNAcylation/phosphorylation, enhancing O-GlcNAcylation of Tau, suggesting that DHA may be a potential therapeutic agent against tauopathy.

Hepatocellular carcinoma (HCC) presents significant challenges in treatment and prognosis because of its aggressive nature and high metastatic potential. This study aims to investigate the role of the hexosamine biosynthesis pathway (HBP) and its association with HCC progression and prognosis. We identified SPP1 and FOXM1 as hub genes within the HBP pathway, showing their correlation with poor prognosis and late-stage progression. In addition, the analysis uncovered the complex participation of the HBP pathway in nutrients and oxygen reactions, PI3K-AKT signaling, AMPK activation, and angiogenesis regulation. The disruption of these pathways is pivotal in influencing the growth and progression of HCC. Targeting the HBP presents a promising therapeutic approach to modulate the tumor microenvironment, thereby enhancing the efficacy of immunotherapy. In addition, FOXM1 was identified as the HBP pathway regulator, influencing cellular O-GlcNAcylation level and VEGF secretion, thereby promoting angiogenesis in HCC. Inhibition of O-GlcNAcylation significantly hindered angiogenesis, which is suggested as a potential avenue for therapeutic intervention. Our research demonstrates the practicality of using the HBP-related gene as a prognostic marker in liver cancer patients and suggests targeting FOXM1 as a novel avenue for personalized therapy.

Hepatocellular carcinoma (HCC) is one of the most prevalent and deadly tumors; however, its pathogenic mechanism remains largely elusive. In-depth researches are needed to reveal the expression regulatory mechanisms and functions of the RNA-binding protein RALY in HCC. Here, we identify RALY as a highly expressed oncogenic factor that affects HCC cells proliferation both in vitro and in vivo. O-GlcNAcylation of RALY at Ser176 enhances its stability by protecting RALY from TRIM27-mediated ubiquitination, thus maintaining hyper-expression of the RALY protein. Mechanistically, RALY interacts with USP22 messenger RNA, as revealed by RNA immunoprecipitation, to increase their cytoplasmic localization and protein expression, thereby promoting the proliferation of HCC cells. Furthermore, we develop a novel RALY protein degrader based on peptide proteolysis-targeting chimeras, named RALY-PROTAC, which we chemically synthesize by linking a RALY-targeting peptide with the E3 ubiquitin ligase recruitment ligand pomalidomide. In conclusion, our findings demonstrate a novel mechanism by which O-GlcNAcylation/RALY/USP22 mRNA axis aggravates HCC cells proliferation. RALY-PROTACs as degraders of the RALY protein exhibit potential as therapeutic drugs for RALY-overexpressing HCC.

O-linked N-acetylglucosamine protein modification (O-GlcNAcylation) is a dynamic post-translational modification (PTM) involving the covalent binding of serine and/or threonine residues, which regulates bone cell homeostasis. Reactive oxygen species (ROS) are increased due to oxidative stress in various pathological contexts related to bone remodeling, such as osteoporosis, arthritis, and bone fracture. Autophagy serves as a scavenger for ROS within bone marrow-derived mesenchymal stem cells, osteoclasts, and osteoblasts. However, oxidative stress-induced autophagy is affected by the metabolic status, leading to unfavorable clinical outcomes. O-GlcNAcylation can regulate the autophagy process both directly and indirectly through oxidative stress-related signaling pathways, ultimately improving bone remodeling. The present interventions for the bone remodeling process often focus on promoting osteogenesis or inhibiting osteoclast absorption, ignoring the effect of PTM on the overall process of bone remodeling. This review explores how O-GlcNAcylation synergizes with autophagy to exert multiple regulatory effects on bone remodeling under oxidative stress stimulation, indicating the application of O-GlcNAcylation as a new molecular target in the field of bone remodeling.

The tumor microenvironment (TME) consists of tumor cells, non-tumor cells, extracellular matrix, and signaling molecules, which can contribute to tumor initiation, progression, and therapy resistance. In response to starvation, hypoxia, and drug treatments, tumor cells undergo a variety of deleterious endogenous stresses, such as hypoxia, DNA damage, and oxidative stress. In this context, to survive the difficult situation, tumor cells evolve multiple conserved adaptive responses, including metabolic reprogramming, DNA damage checkpoints, homologous recombination, up-regulated antioxidant pathways, and activated unfolded protein responses. In the last decades, the protein O-GlcNAcylation has emerged as a crucial causative link between glucose metabolism and tumor progression. Here, we discuss the relevant pathways that regulate the above responses. These pathways are adaptive adjustments induced by endogenous stresses in cells. In addition, we systematically discuss the role of O-GlcNAcylation-regulated stress-induced adaptive response pathways (SARPs) in TME remodeling, tumor progression, and treatment resistance. We also emphasize targeting O-GlcNAcylation through compounds that modulate OGT or OGA activity to inhibit tumor progression. It seems that targeting O-GlcNAcylated proteins to intervene in TME may be a novel approach to improve tumor prognosis.

O-GlcNAcylation, as a post-translational modification, can modulate cellular activities such as kinase activity, transcription-translation, protein degradation, and insulin signaling by affecting the function of the protein substrate, including cellular localization of proteins, protein stability, and protein/protein interactions. Accumulating evidence suggests that dysregulation of O-GlcNAcylation is associated with disease progression such as cancer, neurodegeneration, and diabetes. Recent studies suggest that O-GlcNAcylation is also involved in the regulation of osteoblast, osteoclast and chondrocyte differentiation, which is closely related to the initiation and development of bone metabolic diseases such as osteoporosis, arthritis and osteosarcoma. However, the potential mechanisms by which O-GlcNAcylation regulates bone metabolism are not fully understood. In this paper, the literature related to the regulation of bone metabolism by O-GlcNAcylation was summarized to provide new potential therapeutic strategies for the treatment of orthopedic diseases such as arthritis and osteoporosis.

Glycophagy has evolved from an alternative glycogen degradation pathway into a multifaceted pivot to regulate cellular metabolic hemostasis in peripheral tissues. However, the pattern of glycophagy in the brain and its potential therapeutic impact on ischemic stroke remain unknown. Here, we observed that the dysfunction of astrocytic glycophagy was caused by the downregulation of the GABA type A receptor-associated protein like 1 (GABARAPL1) during reperfusion in ischemic stroke patients and mice. PI3K-Akt pathway activation is involved in driving GABARAPL1 downregulation during cerebral reperfusion. Moreover, glycophagy dysfunction-induced glucosamine deficiency suppresses the nuclear translocation of specificity protein 1 and TATA binding protein, the transcription factors for GABARAPL1, by decreasing their O-GlcNAcylation levels, and accordingly feedback inhibits GABARAPL1 in astrocytes during reperfusion. Restoring astrocytic glycophagy by overexpressing GABARAPL1 decreases DNA damage and oxidative injury in astrocytes and improves the survival of surrounding neurons during reperfusion. In addition, a hypocaloric diet in the acute phase after cerebral reperfusion can enhance astrocytic glycophagic flux and accelerate neurological recovery. In summary, glycophagy in the brain links autophagy, metabolism, and epigenetics together, and glycophagy dysfunction exacerbates reperfusion injury after ischemic stroke.

Protein posttranslational modifications are important factors that mediate the fine regulation of signaling molecules. O-linked β-N-acetylglucosamine-modification (O-GlcNAcylation) is a monosaccharide modification on N-acetylglucosamine linked to the hydroxyl terminus of serine and threonine of proteins. O-GlcNAcylation is responsive to cellular stress as a reversible and posttranslational modification of nuclear, mitochondrial and cytoplasmic proteins. Mitochondrial proteins are the main targets of O-GlcNAcylation and O-GlcNAcylation is a key regulator of mitochondrial homeostasis by directly regulating the mitochondrial proteome or protein activity and function. Disruption of O-GlcNAcylation is closely related to mitochondrial dysfunction. More importantly, the O-GlcNAcylation of cardiac proteins has been proven to be protective or harmful to cardiac function. Mitochondrial homeostasis is crucial for cardiac contractile function and myocardial cell metabolism, and the imbalance of mitochondrial homeostasis plays a crucial role in the pathogenesis of cardiovascular diseases (CVDs). In this review, we will focus on the interactions between protein O-GlcNAcylation and mitochondrial homeostasis and provide insights on the role of mitochondrial protein O-GlcNAcylation in CVDs.

O-linked-β-D-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation), which is dynamically regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), is a post-translational modification involved in multiple cellular processes. O-GlcNAcylation of proteins can regulate their biological functions via crosstalk with other post-translational modifications, such as phosphorylation, ubiquitination, acetylation, and methylation. Liver diseases are a major cause of death worldwide; yet, key pathological features of the disease, such as inflammation, fibrosis, steatosis, and tumorigenesis, are not fully understood. The dysregulation of O-GlcNAcylation has been shown to be involved in some severe hepatic cellular stress, viral hepatitis, liver fibrosis, nonalcoholic fatty acid liver disease (NAFLD), malignant progression, and drug resistance of hepatocellular carcinoma (HCC) through multiple molecular signaling pathways. Here, we summarize the emerging link between O-GlcNAcylation and hepatic pathological processes and provide information about the development of therapeutic strategies for liver diseases.