Ganoderic Acid A prevents bone loss in lipopolysaccharide-treated male rats by reducing oxidative stress and inflammatory.

Ganoderic Acid A (GAA) has demonstrated beneficial effects in anti-inflammatory and anti-oxidative stress studies. However, it remains unknown whether GAA exerts positive impacts on bone loss induced by lipopolysaccharide (LPS). This study aims to investigate the influence of GAA on bone loss in LPS-treated rats. The study assesses changes in the viability and osteogenic potential of MC3T3-E1 cells, as well as osteoclast differentiation in RAW264.7 cells in the presence of LPS using CCK-8, ALP staining, AR staining, and Tartrate-resistant acid phosphatase (TRAP) staining. In vitro experiments indicate that LPS-induced inhibition of osteoclasts (OC) and Superoxide Dismutase 2 (SOD2) correlates with heightened levels of inflammation and oxidative stress. Furthermore, GAA has displayed the ability to alleviate oxidative stress and inflammation, enhance osteogenic differentiation, and suppress osteoclast differentiation. Animal experiment also proves that GAA notably upregulates SOD2 expression and downregulates TNF-α expression, leading to the restoration of impaired bone metabolism, improved bone strength, and increased bone mineral density. The collective experimental findings strongly suggest that GAA can enhance osteogenic activity in the presence of LPS by reducing inflammation and oxidative stress, hindering osteoclast differentiation, and mitigating bone loss in LPS-treated rat models.

Non-Classical Swine Leukocyte Antigens SLA-6, -7, and -8, Are Xenoantigens for Some Waitlisted Patients.

Attack of donor tissues by pre-formed anti-pig antibodies is well known to cause graft failure in xenotransplantation. Genetic engineering of porcine donors to eliminate targets of these pre-formed antibodies coupled with advances in immunosuppressive medicines have now made it possible to achieve extended survival in the pre-clinical pig-to-non-human primate model. Despite these improvements, antibodies remain a risk over the lifetime of the transplant, and many patients continue to have pre-formed donor-specific antibodies even to highly engineered pigs. While therapeutics exist that can help mitigate the detrimental effects of antibodies, they act broadly potentially dampening beneficial immunity. Identifying additional xenoantigens may enable more targeted approaches, such as gene editing, to overcome these challenges by further eliminating antibody targets on donor tissue. Because we have found that classical class I swine leukocyte antigens are targets of human antibodies, we now examine whether related pig proteins may also be targeted by human antibodies. We show here that non-classical class I swine leukocyte proteins (SLA-6, -7, -8) can be expressed at the surface of mammalian cells and act as antibody targets.

Constructing 3D Zincophilic Skeleton in Nitrogen-Doped Carbon Hybrid Fibers for Dendrite-Free Zn Anodes.

The Zn dendrite growth and side reactions are two major issues for the practical use of Zn metal anodes (ZMAs). Herein, an N-doped carbon-based hybrid fiber with the 3D porous skeleton and the zincophilic Cu nanoparticles (denoted as Cu@HLCF) is developed for stable ZMAs. The zincophilic Cu particles in the skeleton work as the active sites to facilitate uniform Zn nucleation. Meanwhile, the abundant pores in the framework of the hybrid fibers provide a large space to relieve the structural stress and suppress the dendrite growth. Moreover, the good mechanical characteristics of the hybrid fiber ensure its high potential applications for flexible electronics. Theoretical analysis results disclose the strong interaction between Zn and Cu sites, and experimental results demonstrate the low voltage hysteresis, high reversibility, and dendrite-free behavior of the Cu@HLCF host for Zn plating/stripping. Moreover, the solid-state Zn-ion battery (ZIB) assembled with a Cu@HLCF/Zn anode shows the prominent flexibility, impressively reliability, and outstanding cycling capability. Therefore, this work not only provides a novel design for the efficient and stable Zn metal anode but also promotes the development of flexible power sources for flexible electronics.

Integrating Experimental and Computational Analyses for Mechanical Characterization of Titanium Carbide/Aluminum Metal Matrix Composites.

This study investigates the mechanical properties of titanium carbide/aluminum metal matrix composites (AMMCs) using both experimental and computational methods. Through accumulative roll bonding (ARB) and cryorolling (CR) processes, AA1050 alloy surfaces were reinforced with TiCp particles to create the Al-TiCp composite. The experimental analysis shows significant improvements in tensile strength, yield strength, elastic modulus, and hardness. The finite element analysis (FEA) simulations, particularly the microstructural modeling of RVE-1 (the experimental case model), align closely with the experimental results observed through scanning electron microscopy (SEM). This validation underscores the accuracy of the computational models in predicting the mechanical behavior under identical experimental conditions. The simulated elastic modulus deviates by 5.49% from the experimental value, while the tensile strength shows a 6.81% difference. Additionally, the simulated yield strength indicates a 2.85% deviation. The simulation data provide insights into the microstructural behavior, stress distribution, and particle-matrix interactions, facilitating the design optimization for enhanced performance. The study also explores the influence of particle shapes and sizes through Representative Volume Element (RVE) models, highlighting nuanced effects on stress-strain behavior. The microstructural evolution is examined via transmission electron microscopy (TEM), revealing insights regarding grain refinement. These findings demonstrate the potential of Al-TiCp composites for lightweight applications.

Bacillus amyloliquefaciens attenuates the intestinal permeability, oxidative stress and endoplasmic reticulum stress: transcriptome and microbiome analyses in weaned piglets.

Endoplasmic reticulum (ER) stress is related to oxidative stress (OS) and leads to intestinal injury. Bacillus amyloliquefaciens SC06 (SC06) can regulate OS, but its roles in intestinal ER stress remains unclear. Using a 2 × 2 factorial design, 32 weaned piglets were treated by two SC06 levels (0 or 1 × 108 CFU/g), either with or without diquat (DQ) injection. We found that SC06 increased growth performance, decreased ileal permeability, OS and ER stress in DQ-treated piglets. Transcriptome showed that differentially expressed genes (DEGs) induced by DQ were enriched in NF-κB signaling pathway. DEGs between DQ- and SC06 + DQ-treated piglets were enriched in glutathione metabolism pathway. Ileal microbiome revealed that the SC06 + DQ treatment decreased Clostridium and increased Actinobacillus. Correlations were found between microbiota and ER stress genes. In conclusion, dietary SC06 supplementation increased the performance, decreased the permeability, OS and ER stress in weaned piglets by regulating ileal genes and microbiota.

Microstructure and Mechanical Properties of AA1050/AA6061 Laminated Composites Fabricated through Three-Cycle Accumulative Roll Bonding and Subsequent Cryorolling.

In this study, AA1050/AA6061 laminated composites were prepared by three-cycle accumulative roll bonding (ARB) and subsequent rolling. The effects of the rolling process on the microstructure evolution and mechanical properties of AA1050/AA6061 laminated composites were systematically investigated. The results indicate that the mechanical properties of the laminated composites can be effectively improved by cryorolling compared with room-temperature rolling. The microstructure analysis reveals that cryorolling can suppress the necking of the hard layer to obtain a flat lamellar structure. Moreover, the microstructure characterized by transmission electron microscopy shows that cryorolling can inhibit the dynamic recovery and significantly refine the grain size of the constituent layers. Meanwhile, the tensile fracture surface illustrates that AA1050/AA6061 laminated composites have the optimal interfacial bonding quality after cryorolling. Therefore, the laminated composites obtain excellent mechanical properties with the contribution of these factors.

A comparative study of stereo-dependent SSVEP targets and their impact on VR-BCI performance.

Steady-state visual evoked potential brain-computer interfaces (SSVEP-BCI) have attracted significant attention due to their ease of deployment and high performance in terms of information transfer rate (ITR) and accuracy, making them a promising candidate for integration with consumer electronics devices. However, as SSVEP characteristics are directly associated with visual stimulus attributes, the influence of stereoscopic vision on SSVEP as a critical visual attribute has yet to be fully explored. Meanwhile, the promising combination of virtual reality (VR) devices and BCI applications is hampered by the significant disparity between VR environments and traditional 2D displays. This is not only due to the fact that screen-based SSVEP generally operates under static, stable conditions with simple and unvaried visual stimuli but also because conventional luminance-modulated stimuli can quickly induce visual fatigue. This study attempts to address these research gaps by designing SSVEP paradigms with stereo-related attributes and conducting a comparative analysis with the traditional 2D planar paradigm under the same VR environment. This study proposed two new paradigms: the 3D paradigm and the 3D-Blink paradigm. The 3D paradigm induces SSVEP by modulating the luminance of spherical targets, while the 3D-Blink paradigm employs modulation of the spheres' opacity instead. The results of offline 4-object selection experiments showed that the accuracy of 3D and 2D paradigm was 85.67 and 86.17% with canonical correlation analysis (CCA) and 86.17 and 91.73% with filter bank canonical correlation analysis (FBCCA), which is consistent with the reduction in the signal-to-noise ratio (SNR) of SSVEP harmonics for the 3D paradigm observed in the frequency-domain analysis. The 3D-Blink paradigm achieved 75.00% of detection accuracy and 27.02 bits/min of ITR with 0.8 seconds of stimulus time and task-related component analysis (TRCA) algorithm, demonstrating its effectiveness. These findings demonstrate that the 3D and 3D-Blink paradigms supported by VR can achieve improved user comfort and satisfactory performance, while further algorithmic optimization and feature analysis are required for the stereo-related paradigms. In conclusion, this study contributes to a deeper understanding of the impact of binocular stereoscopic vision mechanisms on SSVEP paradigms and promotes the application of SSVEP-BCI in diverse VR environments.

Mi-2ß promotes immune evasion in melanoma by activating EZH2 methylation.

Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitive will provide a significant improvement in patient outcome. Here we identify Mi-2ß as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Studies in genetically engineered mouse melanoma models indicate that loss of Mi-2ß rescues the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq analysis shows that Mi-2ß controls the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2ß binds to EZH2 and promotes K510 methylation of EZH2, subsequently activating the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2ß-targeted inhibitor, Z36-MP5, which reduces Mi-2ß ATPase activity and reactivates ISG transcription. Consequently, Z36-MP5 induces a response to immune checkpoint inhibitors in otherwise resistant melanoma models. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones.

Optimization of the morphological, structural, and physicochemical properties of maize starch using straw returning and nitrogen fertilization in Northeast China.

The combination of straw returning and nitrogen (N) fertilization is a popular tillage mode and essential strategy for achieving stable yield and high quality. However, the optimal combination strategy and the influence of tillage mode on the morphological, crystalline, and molecular structures of maize starch remain unclear. We conducted a long-term field experiment over 7 years in Northeast China using two tillage modes, rotary tillage with straw returning (RTS) and plow tillage with straw returning (PTS), and four N application rates. The relative crystallinity, 1045/1022 cm-1 value, and B2 and B3 chains of maize starch were higher under RTS than under PTS, resulting in increased stability of starch and improvements in gelatinization enthalpy and temperature. The surface of the starch granules induced by N fertilizer was smoother than that under the N0 (0 kg N ha-1) treatment. The proportion of amylose content, solubility, swelling power, and light transmittance increased under N2 (262 kg N ha-1) treatment, along with improvement in starch pasting properties. These results suggest that RTS combined with N2 treatment can regulate the morphological, structural, and physicochemical characteristics of maize starch, providing an essential reference for improving the quality of maize starch from an agronomic point of view.

Incidence and predictors of restenosis following successful recanalization of non-acute internal carotid artery occlusion in 252 cases.

BACKGROUND: Data concerning restenosis following successful recanalization of non-acute internal carotid artery occlusion (ICAO) are scarce. This study was conducted to identify the incidence and predictors of restenosis following successful recanalization of non-acute ICAO. METHODS: We reviewed the incidence of restenosis (defined as >70% restenosis or reocclusion) among 252 consecutive patients with successful recanalization of non-acute ICAO. Baseline, imaging, and surgery-related characteristics were analyzed to assess their association with restenosis. A scoring system was developed to identify high-risk patients for restenosis. RESULTS: During a median follow-up of 12.6 months, restenosis occurred in 56 patients (22.2%), including 39 with reocclusion and 17 with >70% restenosis. The cumulative restenosis rate was 18.0% at 12 months and 24.1% at 24 months. The incidence of stroke was higher in patients with restenosis (25.0% vs 1.5%, P<0.01). Multivariate analysis showed occlusion length (5-10 cm vs <5 cm (hazard ratio (HR) 3.15, 95% confidence interval (95% CI) 1.07 to 9.29); ≥ 10 cm vs <5 cm (HR 5.01, 95% CI 1.73 to 14.49)), residual stenosis ≥30% (HR 3.08, 95% CI 1.79 to 5.30), and internal carotid artery (ICA) wall collapse (HR 1.96, 95% CI 1.12 to 3.44) as independent predictors of restenosis. Point scores proportional to model coefficients were assigned, with scores ranging from 0 to 6. Patients scoring 3-6 had a 4.00 times higher chance of developing restenosis (95% CI 2.35 to 6.79) compared with those scoring 0-2. CONCLUSIONS: Nearly one in five patients experienced restenosis following successful recanalization of non-acute ICAO. Occlusion length, residual stenosis ≥30%, and ICA wall collapse were independently associated with restenosis.

General Control Non-derepressible 2 Alleviates Cartilage Degeneration and Inhibits NLRP3 Inflammasome Activation in Osteoarthritis.

This study aimed to evaluate the effects of general control non-derepressible 2 (GCN2) on osteoarthritis (OA) in vivo and in vitro. First, anterior cruciate ligament transection (ACLT)-induced rat model and interleukin (IL)-1ß-induced ATDC5 chondrocyte were established. Hematoxylin and eosin staining and safranin O/fast green staining were employed for analyzing the histological changes in the rat cartilage. In addition, immunohistochemistry, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, western blot, and immunofluorescence staining were employed for examining cartilage degeneration-, inflammation-, autophagy-, and NLR family pyrin domain containing 3 (NLRP3) inflammasome-associated genes expression. Moreover, 2,7-dichlorodihydrofluorescein acetoacetic acid probe was utilized for examining the intracellular reactive oxygen species. In addition, 5-ethynyl-2'-deoxyuridine assay and flow cytometry were applied for detecting chondrocyte proliferation and apoptosis IL-1ß-treated ATDC5 chondrocytes. GCN2 overexpression ameliorated articular cartilage degeneration and inflammation but promoted chondrocyte autophagy in ACLT-induced OA rats. Similarly, we demonstrated that the upregulation of GCN2 could promote chondrocyte proliferation, suppress chondrocyte apoptosis, attenuate chondrocyte inflammation and extracellular matrix degradation, and promote chondrocyte autophagy. Moreover, GCN2 overexpression could inhibit the activation of NLRP3 inflammasome in IL-1ß-induced ATDC5 chondrocyte. Furthermore, 3-methyladenine neutralized the protective and autophagy-promoting effects of GCN2 overexpression on ATDC5 chondrocytes. GCN2 could attenuate inflammation and cartilage degeneration, promote chondrocyte autophagy, and inhibit NLRP3 inflammasome activation in OA.

The clinical outcome of emergency superficial temporal artery-to-middle cerebral artery bypass in acute ischemic stroke with large vessel occlusion.

The role of superficial temporal artery-to-middle cerebral artery (STA-MCA) bypass in acute ischemic stroke (AIS) is contentious, with no evidence in patients with AIS and large vessel occlusion (AIS-LVO). We conducted a cohort study to assess emergency STA-MCA outcomes in AIS-LVO and a meta-analysis to evaluate STA-MCA outcomes in early AIS treatment. From January 2018 to March 2021, we consecutively recruited newly diagnosed AIS-LVO patients, dividing them into STA-MCA and non-STA-MCA groups. To evaluate the neurological status and outcomes, we employed the National Institutes of Health Stroke Scale (NIHSS) during the acute phase and the modified Rankin Scale (mRS) during the follow-up period. Additionally, we conducted a meta-analysis encompassing all available clinical studies to assess the impact of STA-MCA on patients with AIS. In the cohort study (56 patients), we observed more significant neurological improvement in the STA-MCA group at two weeks (p = 0.030). However, there was no difference in the clinical outcomes between the two groups. Multivariable logistic regression identified the NIHSS at two weeks (OR: 0.840; 95% CI: 0.754-0.936, p = 0.002) as the most critical predictor of a good outcome. Our meta-analysis of seven studies indicated a 67% rate for achieving a good outcome (mRS < 3) at follow-up points (95% CI: 57%-77%, I2 = 44.1%). In summary, while the meta-analysis suggested the potential role of STA-MCA bypass in mild to moderate AIS, our single-center cohort study indicated that STA-MCA bypass does not seem to improve the prognosis of patients who suffer from AIS-LVO.

Segmenting tourists' motivations via online reviews: An exploration of the service strategies for enhancing tourist satisfaction.

Tourism motivation and satisfaction are classic themes in tourism research. This study combines latent Dirichlet allocation (LDA) and the Censydiam motivation model to analyze online reviews of tourism in Qinghai, China. The aim of this research is to explore tourist motivation through online reviews and provide innovative service suggestions to improve tourist satisfaction. The LDA model initially extracts six main topics from online comments. Then, using the fuzzy analytic hierarchy process (FAHP), it maps the relationship between topics and tourism motivations to propose strategies for enhancing tourists' enjoyment, conviviality, and other motivating factors. Furthermore, we employ the Kano model to evaluate tourists' satisfaction levels regarding these strategies, demonstrating their positive evaluations. Hence, this study provides tourism industry professionals and service designers with an innovative method for understanding tourists' motivations through online reviews, enabling them to design specific services that enhance tourism experiences.

Revisiting Aurora Kinase B: A promising therapeutic target for cancer therapy.

Cancer continues to be a major health concern globally, although the advent of targeted therapy has revolutionized treatment options. Aurora Kinase B is a serine-threonine kinase that has been explored as an oncology therapeutic target for more than two decades. Aurora Kinase B inhibitors show promising biological results in in-vitro and in-vivo experiments. However, there are no inhibitors approved yet for clinical use, primarily because of the side effects associated with Aurora B inhibitors. Several studies demonstrate that Aurora B inhibitors show excellent synergy with various chemotherapeutic agents, radiation therapy, and targeted therapies. This makes it an excellent choice as an adjuvant therapy to first-line therapies, which greatly improves the therapeutic window and side effect profile. Recent studies indicate the role of Aurora B in some deadly cancers with limited therapeutic options, like triple-negative breast cancer and glioblastoma. Herein, we review the latest developments in Aurora Kinase B targeted research, with emphasis on its potential as an adjuvant therapy and its role in some of the most difficult-to-treat cancers.

Development and validation of a prognostic score to identify the optimal candidate for preemptive TIPS in patients with cirrhosis and acute variceal bleeding.

BACKGROUND AND AIM: Baveno VII workshop recommends the use of preemptive TIPS (p-TIPS) in patients with cirrhosis and acute variceal bleeding (AVB) at high- risk of treatment failure. However, the criteria defining "high-risk" have low clinical accessibility or include subjective variables. We aimed to develop and externally validate a model for better identification of p-TIPS candidates. APPROACH AND RESULTS: The derivation cohort included 1554 patients with cirrhosis and AVB who were treated with endoscopy plus drug (n = 1264) or p-TIPS (n = 290) from 12 hospitals in China between 2010 and 2017. We first used competing risk regression to develop a score for predicting 6-week and 1-year mortality in patients treated with endoscopy plus drugs, which included age, albumin, bilirubin, international normalized ratio, white blood cell, creatinine, and sodium. The score was internally validated with the bootstrap method, which showed good discrimination (6 wk/1 y concordance-index: 0.766/0.740) and calibration, and outperformed other currently available models. In the second stage, the developed score was combined with treatment and their interaction term to predicate the treatment effect of p-TIPS (mortality risk difference between treatment groups) in the whole derivation cohort. The estimated treatment effect of p-TIPS varied substantially among patients. The prediction model had good discriminative ability (6 wk/1 y c -for-benefit: 0.696/0.665) and was well calibrated. These results were confirmed in the validation dataset of 445 patients with cirrhosis with AVB from 6 hospitals in China between 2017 and 2019 (6-wk/1-y c-for-benefit: 0.675/0.672). CONCLUSIONS: We developed and validated a clinical prediction model that can help to identify individuals who will benefit from p-TIPS, which may guide clinical decision-making.

The extraction and anti-inflammatory screening of Onosma glomeratum Y. L. Liu.

"Zicao" has a long medicinal history and has a variety of pharmacological activities. As the main resource of "zicao" in Tibet, Onosma glomeratum Y. L. Liu (tuan hua dian zi cao), usually used for treating pneumonia in Tibet, has not been reported deeply. In order to determine the main anti-inflammatory active ingredients of Onosma glomeratum Y. L. Liu, in this study, the extracts enriched in naphthoquinones and polysaccharides were optimized prepared form Onosma glomeratum Y. L. Liu by ultrasonic extraction, and reflux extraction, respectively, with Box-Behnken design effect surface method. And their anti-inflammatory abilities were screened on LPS induced A549 cells model, for figuring out the anti-inflammatory active ingredients from Onosma glomeratum Y. L. Liu.The extract enriched naphthoquinone was obtained under following condition: extract with 85% ethanol in a liquid to material ratio of 1:40 g/mL at 30 °C for 30 minutes using ultrasound, leading to the extraction rate of total naphthoquinone as 0.98 ± 0.017%; the extract enriched polysaccharides was prepared as follows: extract 82 minutes at 100 °C with distilled water in a liquid to material ratio of 1:50 g/mL, with extraction rate of polysaccharide as 7.07 ± 0.02%.On the LPS-induced A549 cell model, the polysaccharide extract from Onosma glomeratum Y. L. Liu showed better anti-inflammatory effects than the naphthoquinone extract, indicating the extract enriched in polysaccharides is the anti-inflammatory extract of Onosma glomeratum Y. L. Liu, which could serve as a potential anti-inflammatory extract in medical and food industries in the future.

Mechanical compression management of the right middle cerebral artery inferior trunk using a stent during coil embolization of middle cerebral artery aneurysms: A case report and literature review.

Endovascular coil embolization is a minimally invasive, rapid, and effective method for the treatment of intracranial aneurysms. However, complications associated with coil embolization, such as intraoperative aneurysm rupture or arterial occlusion, should be promptly managed during the procedure to avoid catastrophic consequences. This study presents a case of mechanical compression management of the right middle cerebral artery (MCA) inferior trunk during coil embolization for bilateral MCA aneurysms. The inferior trunk of the right MCA was abruptly occluded due to mechanical compression during coil embolization of the right MCA bifurcation aneurysm. A Solitaire AB stent (4 â€‹× â€‹20 mm, Covidien/Medtronic, Dublin, Ireland) was implanted in the inferior trunk of the right MCA after tirofiban was injected via a microcatheter, and the right inferior trunk was recanalized. The patient also underwent coil embolization of the left MCA bifurcation aneurysm, without any complications. It is crucial to recognize compressive occlusion of adjacent aneurysm branches to avoid severe complications during intracranial aneurysm embolization. Stent placement is a rescue treatment option for recanalization of an occluded artery.

Patients on the Transplant Waiting List Have Anti-Swine Leukocyte Antigen Class I Antibodies.

Organ supply remains inadequate to meet the needs of many patients who could benefit from allotransplantation. Xenotransplantation, the use of animals as organ donors, provides an opportunity to alleviate this challenge. Pigs are widely accepted as the ideal organ donor, but humans and nonhuman primates have strong humoral immune responses to porcine tissue. Although carbohydrate xenoantigens have been studied intensively, the primate Ab response also targets class I and class II swine leukocyte Ags (SLAs). Human Abs that recognize HLAs can cross-react with SLA molecules because epitopes can be shared across species. However, ∼15% of people may also exhibit Abs toward class II SLAs despite lacking Abs that also recognize class II HLAs. Here, we extend these studies to better understand human Ab responses toward class I SLAs. When tested against a panel of 18 unique class I SLA proteins, 14 of 52 sera samples collected from patients in need of an organ transplant contained Abs that bound class I SLAs. Class I SLA-reactive sera may contain IgM only, IgG, only, or IgM and IgG capable of recognizing the pig proteins. The presence of class I HLA-reactive Abs was not essential to generating anti-class I SLA Ig. Last, anti-class I SLA reactivity varied by serum; some recognized a single SLA allele, whereas others recognized multiple class I SLA proteins.

NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance.

Glucose metabolism is known to orchestrate oncogenesis. Whether glucose serves as a signaling molecule directly regulating oncoprotein activity for tumorigenesis remains elusive. Here, we report that glucose is a cofactor binding to methyltransferase NSUN2 at amino acid 1-28 to promote NSUN2 oligomerization and activation. NSUN2 activation maintains global m5C RNA methylation, including TREX2, and stabilizes TREX2 to restrict cytosolic dsDNA accumulation and cGAS/STING activation for promoting tumorigenesis and anti-PD-L1 immunotherapy resistance. An NSUN2 mutant defective in glucose binding or disrupting glucose/NSUN2 interaction abolishes NSUN2 activity and TREX2 induction leading to cGAS/STING activation for oncogenic suppression. Strikingly, genetic deletion of the glucose/NSUN2/TREX2 axis suppresses tumorigenesis and overcomes anti-PD-L1 immunotherapy resistance in those cold tumors through cGAS/STING activation to facilitate apoptosis and CD8+ T cell infiltration. Our study identifies NSUN2 as a direct glucose sensor whose activation by glucose drives tumorigenesis and immunotherapy resistance by maintaining TREX2 expression for cGAS/STING inactivation.