Science Bulletin
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2026
·
IF 20.7
Dan Zhou,Dingru Li,Caimei Zhong,Qiang Li,Peixian Chen,Shuqing Yang,Herong Liang,Zhiyan Chen,Han He,Hua Zhang,Xiaohong Zeng,Mo Chen,Yingxin Lin,Meng Xu,Xingyin Liu,Mengyun Cai,Yuhua Deng
The gut microbiome is increasingly linked to breast cancer (BC) progression; however, specific microbial metabolites and their direct mechanistic connections to oncogenic signalling remain poorly defined. Here, using multi-omics analyses in treatment-naïve patients with BC, we identified gut microbiota-derived uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) as a circulating oncometabolite associated with therapeutic response. We further showed that Ruminococcus lactaris is a key intestinal commensal capable of de novo UDP-GlcNAc biosynthesis, and that microbial-derived UDP-GlcNAc acts as an independent tumour-promoting metabolite, even though the host hexosamine pathways generate the majority of circulating UDP-GlcNAc pools. Mechanistically, UDP-GlcNAc systemically activates O-GlcNAc transferase (OGT), stabilizing the transcription factor NFIB, and triggers a feed-forward loop that upregulates OGT and the proto-oncogene KIT , thereby driving BC progression. Genetic or pharmacological inhibition of OGT disrupts this signaling axis and suppresses tumour growth, even in the presence of UDP-GlcNAc–producing bacteria. These findings reveal a gut microbiota–metabolite–host signalling circuit, in which a microbial metabolite hijacks a core host post-translational modification pathway to promote BC progression, providing novel opportunities for microbiome-targeted diagnosis and therapy. Gut‑microbiota‑derived UDP‑GlcNAc enters circulation, activates host OGT‑mediated O‑GlcNAcylation to stabilize NFIB. This triggers a feed‑forward loop elevating OGT and proto‑oncogene KIT , driving breast tumor progression. Inhibiting OGT blocks this oncogenic axis even with UDP‑GlcNAc‑producing Ruminococcus lactaris . This reveals a gut‑microbe‑metabolite‑host signaling circuit for breast cancer. Download: Download high-res image (170KB) Download: Download full-size image
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JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
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2026
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IF 2.7
Qiushi Chen,Wangzhirui Cheng,Can Li,Yi Man Eva Fung,Jiaqi Wang,Han Liu,Xuechen Li
Protein glycosylation plays essential roles in various biological processes, and thus determining the glycan structure present on the protein is essential to comprehensively understand these events. However, distinguishing saccharide stereoisomers is challenging, especially when their structures are very similar and their molecular weight and potential glycosylation sites are identical. One representative example is O-linked β-N-acetylglucosamine (O-GlcNAc) and O-linked α-N-acetylgalactosamine (Tn antigen). Traditional biochemistry approaches used in separating O-GlcNAc- and Tn antigen-modified peptides mainly include chemical derivatizations, lectins, and antibodies. However, subsequent mass spectrometry (MS) analysis is still required if one aims to determine the exact glycosylation site. Herein, a straightforward approach using the ratio of relative abundance (RA) of two fragment ions (RA126.055/RA138.055) in higher-energy collisional dissociation (HCD) MS without relying on the traditional biochemistry technique is reported to discriminate between O-GlcNAc and Tn antigen. This ratio was verified by synthetic glycopeptides and proteomic analysis in HeLa cells, where 10 proteins were found to be O-GlcNAcylation and 4 proteins were found to be Tn antigen-modified. Overall, this method can be extensively employed in liquid chromatography–mass spectrometry (LC-MS)-based proteomic studies and thus is of importance in biological and biomedical research.
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Advanced Science
·
2026
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IF 14.1
Duoli Xie,Jie Huang,Chunhao Cao,Zhenchao Tang,Xingchen Li,Jianmin Guo,Xinxin Chen,Fang Wang,Dongyi He,Jie Li,Yu Du,Bing He,Jianhua Yao,Aiping Lu,Chao Liang
Rheumatoid arthritis (RA) progression is driven by the pathogenic transformation of stromal fibroblast‐like synoviocytes (FLSs). Using artificial intelligence‐guided analysis of a synovial single‐cell transcriptomic dataset, we identify O‐GlcNAc transferase (OGT) as a key regulator enriched in RA‐FLSs. Gain‐ and loss‐of‐function studies demonstrate that OGT is necessary to drive aggressive FLS phenotypes and exacerbate experimental arthritis. Mechanistically, OGT‐mediated O‐GlcNAcylation stabilizes SAP130, promoting histone deacetylation at the BTG2 promoter. This facilitates the deposition of repressive histone methylation marks, leading to BTG2 epigenetic silencing and ultimately fueling FLS aggression. To translate this mechanistic insight, we develop an FLS‐targeted proteolysis‐targeting chimera (PROTAC) by conjugating the OGT inhibitor OSMI‐1 to the AS1411 aptamer, which selectively binds surface nucleolin (NCL) overexpressed on pathogenic FLSs and, upon internalization, employs NCL as a molecular bridge to recruit the E3 ligase MDM2 for cell‐selective OGT degradation. This PROTAC suppresses FLS pathogenicity, attenuates arthritis in mice, and demonstrates additive therapeutic benefit when combined with the TNF‐α inhibitor etanercept. Collectively, our work establishes a translational paradigm that progresses from AI‐driven target discovery and mechanistic elucidation to the rational design of a cell‐type‐specific degradation therapy, offering a strategy to overcome the stromal‐driven therapeutic barrier in RA. AI‑guided single‑cell transcriptomics identifies OGT as a key regulator enriched in rheumatoid arthritis fibroblast‑like synoviocytes (RA‐FLSs). Inflammatory stimuli activate the OGT–SAP130 axis, which modulates the H3K27ac/H3K27me3 balance and epigenetically silences BTG2, promoting aggressive transformation of RA‑FLSs. A targeted PROTAC is developed to selectively degrade OGT in pathogenic FLSs, suppressing their aggressive phenotypes for RA therapy.
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Frontiers in Microbiology
·
2026
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IF 5.8
Longzhi Chen,Jianong Wang,Zixuan Zhang,Lixia Pan,Dengfeng Yang,Nan Li,Liyan Yang
Chitin, the second most abundant polysaccharide, is poorly soluble and underutilized, whereas its monomer N-acetylglucosamine (GlcNAc) has broad pharmaceutical applications. Efficient enzymatic conversion of chitin to GlcNAc remains challenging. Chitinibacter mangrovi FCG-7T, a novel chitinolytic strain isolated from mangrove sediments, exhibited exceptional chitin degradation, achieving a hydrolysis zone ratio (H/C) of 4.75 and maintained genetic stability over ten successive passages. Sequential optimization using One-Factor-at-a-Time (OFAT), Plackett-Burman designs (PBD), and Box–Behnken designs (BBD) enhanced chitinase production by 49.43-fold, yielding a final activity of 1.211 U/mL under optimized conditions (pH 7.4, 20 °C, 12 g/L powdered chitin). Purification yielded a 100 kDa bifunctional chitinase CmChi, exhibiting dual chitobiosidase and N-acetylglucosaminidase (NAGase) activities. The purified enzyme showed a specific activity of 7.96 U/mg toward colloidal chitin. CmChi demonstrated a high affinity for colloidal chitin with a Km value of 0.24 mg/mL and retained over 80% stability across a broad pH range 4.0–11.0. Furthermore, CmChi completely converted colloidal chitin to N-acetylglucosamine (GlcNAc) within 48 h and demonstrated tolerance to various reagents, including 1% methanol, acetonitrile, Tween 20, and Tween 80 (v/v). Notably, in cyclophosphamide (CTX)-induced immunosuppressed mice, GlcNAc (200 mg/kg) significantly restored body weight, thymic/splenic indices, and tissue architecture while elevating serum TNF-α, IL-2, IgG, and IgM (p < 0.05). This study establishes CmChi as an efficient biocatalyst for industrial GlcNAc production and validates the immunomodulatory potential of GlcNAc, highlighting its dual applicability in biotechnology and immunotherapy.
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Marine Drugs
·
2026
·Vol. 24
·期 8
·290
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IF 5.7
Zhuling Shao,Luya Wang,Xin Wang
A novel, uniform acid heteropolysaccharide with a molecular weight of 13.14 kDa was isolated from the fermented broth of the mangrove endophytic fungusPenicillium janthinellumN29, designated as PJ3-1. A structural analysis showed that PJ3-1 is a straight-chain heteropolysaccharide containing GlcN, GlcNAc, Glc and GlcA in the ratio of 12.23:1.79:10.93:1.00. PJ3-1 markedly inhibits α-glucosidase activity and relieves insulin resistance in HepG2 cells. It alleviates lipid peroxidation and upregulates the activities of endogenous antioxidant enzymes. In addition, it also significantly scavenges hydroxyl radicals, ferrous ions, superoxide anions, DPPH radicals and ABTS radicals and enhances reducing power in a dose-dependent manner. Collectively, these findings suggest that PJ3-1 has the potential to serve as a natural antioxidant and hypoglycemic agent for functional food or pharmaceutical applications.
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Experimental Hematology & Oncology
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2025
·Vol. 14
·期 1
·1-17
·
IF 13.5
Ren Xueting,Wu Jinpeng,Li Jing,Zhai Zhen,Li Xiang,Guan Feng,Wang Meng,Ma Xiaobin,Tan Zengqi,Kang Huafeng,Lin Shuai
Background The abundance of PD-L1 on the surface of tumor cells is a critical factor in sensitizing these cells to T cell-mediated immune killing. While abnormal glycosylation of PD-L1 is known to influence its expression and function, the precise regulatory mechanisms remain unclear.Methods This study utilized bioinformatics analysis to explore the role of MGAT3, a key gene involved in the formation of the bisecting GlcNAc structure, in breast cancer (BC). Experimental approaches were employed to increase bisecting GlcNAc levels in BC cells, followed by assessments of PD-L1 expression, CD8+ T cell-mediated cytotoxicity, extracellular vesicle (EV)-associated PD-L1, and PD-L1/PD-1 interaction. Additionally, forskolin, a bisecting GlcNAc agonist, was combined with anti-PD-L1 antibody to evaluate its antitumor effects in vivo.Results MGAT3 was found to be expressed at low levels in BC tissues but positively correlated with CD8+ T cell infiltration. Elevating bisecting GlcNAc levels in BC cells significantly enhanced the cytotoxic efficacy of CD8+ T cells. High bisecting GlcNAc modification promoted PD-L1 degradation via the lysosomal pathway, reducing PD-L1 expression and its binding to PD-1. Furthermore, increased bisecting GlcNAc levels reduced PD-L1 in tumor cell-derived EVs, impairing the EVs’ ability to block CD8+ T cells and indirectly enhancing T cell cytotoxicity. The combined use of forskolin and anti-PD-L1 antibody significantly increased CD8+ T cell abundance and activity, achieving a more effective antitumor response in vivo.Conclusion sThese findings demonstrate that enhancing bisecting GlcNAc modification in BC cells promotes PD-L1 degradation and inhibits its binding to PD-1, thereby boosting CD8+ T cell-mediated cytotoxicity, providing a promising strategy for immune modulation in BC therapy.
研究领域:
癌症生物学
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免疫学
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生物化学
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糖生物学
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分子生物学
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CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Haiyang Wang,Hao Zhuang,Chunyan Wu,Bangting Wang,Shijie Zhang,Yao Wang,Li Liu,Lianzhen Yu,Lei Zhang,Su Jing,Zhining Fan
The limited treatment options for colorectal cancer (CRC) and its adverse effects of chemotherapy underscore the urgent need for innovative therapeutic strategies. Focusing on early cellular glycosylation, particularly through the targeting of O-GlcNAcylation with small-molecule inhibitors, emerges as a promising direction. In this study, we developed artificial cell-like nanovesicles with a bilayer membrane structure to encapsulate OSMI-1, a specific inhibitor of O-GlcNAc transferase, aimed at inhibiting CRC progression. To enhance the effectiveness and specificity of the treatment, these self-targeted nanovesicles (T–Se–Lip–OSMI) were reinforced using internal diselenide bridges enabling redox-responsive release within the tumor microenvironment. In vitro assays revealed that T–Se–Lip–OSMI substantially diminished CRC cell proliferation, migration, and invasion. This was further validated using patient-derived organoid models, which highlighted the superior therapeutic efficacy of T–Se–Lip–OSMI over nanovesicles without the diselenide bridge. Subsequent in vivo studies confirmed its targeted delivery and pronounced suppression of tumor growth. Further mechanistic analysis illustrated that the therapeutic effect was mediated through the inhibition of O-GlcNAcylation of the Yes-associated protein (YAP), ultimately preventing the nuclear translocation of YAP and the activation of oncogenic downstream targets. This study leverages the unique properties of the diselenide bridge to enhance stability and functionality of the nanovesicles, offering a novel avenue for targeted CRC treatment.
研究领域:
癌症生物学
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药学
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分子生物学
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纳米技术
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细胞生物学
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ENVIRONMENTAL POLLUTION
·
2025
·
IF 7.3
Ziyuan Li,Pu Chen,Yongfeng Lin,Jingxu Zhang,Jian Ding,Rifat Zubair Ahmed,Xiaoting Jin,Yuxin Zheng
Tris (2-chloroethyl) phosphate (TCEP), recognized as an emerging pollutant, has been frequently detected in human blood. Maintenance of blood homeostasis is indispensable for regulating various physiological states and overall health, yet hematological toxicology of TCEP has not been extensively investigated. Platelets, a vital component of blood, are fundamental in the processes of hemostasis and thrombosis through their activation; thus, this study was designed to elucidate the effects and underlying mechanisms of TCEP on platelet activation. Utilizing an in vivo model, we conducted a proteomic analysis of platelets and found that TCEP exposure inhibited platelet activation. An ex vivo platelet evaluation system was employed to further dissect the processes of platelet activation, revealing that TCEP predominantly suppressed platelet aggregation, degranulation and clot retraction. These processes were highly dependent on energy metabolism, and TCEP was found to decrease ATP levels, primarily by impairing glycolysis and pentose phosphate pathways. Subsequent investigation into the molecular mechanisms revealed that TCEP decreased the activity of phosphofructokinase platelet (PFKP) by enhancing O-linked N-acetylglucosamine (O-GlcNAc) transferase interaction with PFKP. This study is the first to uncover the disruptive effects of TCEP on platelet activation process, providing valuable insights into the assessment of hematologic health risks associated with TCEP-like emerging pollutants exposure.
研究领域:
血液学
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毒理学
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分子生物学
·
生物化学
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