Gut microbiota: Implications in pathogenesis and therapy to cardiovascular disease (Review).

The gut microbiota refers to the diverse bacterial community residing in the gastrointestinal tract. Recent data indicate a strong correlation between alterations in the gut microbiota composition and the onset of various diseases, notably cardiovascular disorders. Evidence suggests the gut-cardiovascular axis signaling molecules released by the gut microbiota play a pivotal role in regulation. This review systematically delineates the association between dysbiosis of the gut microbiota and prevalent cardiovascular diseases, including atherosclerosis, hypertension, myocardial infarction and heart failure. Furthermore, it provides an overview of the putative pathogenic mechanisms by which dysbiosis in the gut microbiota contributes to the progression of cardiovascular ailments. The potential modulation of gut microbiota as a preventive strategy against cardiovascular diseases through dietary interventions, antibiotic therapies and probiotic supplementation is also explored and discussed within the present study.

Dynamic changes in carbohydrate components and the bacterial community during the ensiling of wilted and unwilted sweet sorghum.

Sweet sorghum can be used to produce a substantial quantity of biofuel due to its high biological yield and high carbohydrate content. In this study, we investigated the dynamic changes in fermentation characteristics, carbohydrate components, and the bacterial community during the ensiling of wilted and unwilted sweet sorghum. The results revealed a rapid fermentation pattern and high-quality fermentation quality in wilted and unwilted sweet sorghum, wherein lactic acid, and acetic acid accumulated and stabilized during the initial 9 days of ensiling, with the pH values less than 4.2, until 60 days of ensiling. We found that the ensiling of sweet sorghum involved the degradation (5% ~ 10%) of neutral detergent fiber (NDF) and hemicellulose and that the degradation of NDF fit a first-order exponential decay model. A shift in dominance from Lactococcus to Lactobacillus occurred before the first 9 days of ensiling, and the abundance of Lactobacillus (r = -0.68, p < 0.001) was negatively correlated with the NDF content. The relative abundances of Lactobacillus in wilted and unwilted sweet sorghum after ensiling for 60 days were 76.30 and 93.49%, respectively, and relatively high fermentation quality was obtained. In summary, ensiling is proposed as a biological pretreatment for sweet sorghum for subsequent biofuel production, and unlike other materials, sweet sorghum quickly achieves good fermentation quality and has great potential for bioresource production.

TESMIN is a Prognostic Biomarker Associated with Immunosuppression and Activated Cell Cycle in Lung Adenocarcinoma.

BACKGROUND: The Testis Expressed Metallothionein Like Protein (TESMIN) gene encodes highly conserved, cysteine-rich, low-molecular proteins that are activated by and have an affinity for heavy metal ions. Previous literature has shown its association with cancer. Nevertheless, no thorough bioinformatics analysis of TESMIN has been done yet in lung adenocarcinoma (LUAD). METHODS: Differential expression of TESMIN between cancer and normal tissues was confirmed by analyzing databases and immunohistochemistry staining. Enrichment analysis was adopted to explore biological functions. The relationship of TESMIN with immune infiltration was evaluated by ssGSVA, with immunotherapy response predicted by TCIA and TIDE tools, with mutational traits analyzed by R software. Drug sensitivity analysis was implemented via GSCA tool, pRRophetic algorithms, and CellMiner database. RESULTS: The results demonstrated that TESMIN expression was upregulated in tumor tissue and related to Ki67. TESMIN was associated with poor survival and significantly related to age, gender, N stage, M stage, pathological stage, and survival status. TESMIN- related genes (TRGs) were primarily involved in cell division and cancer-related enrichment pathways. TESMIN was associated with high frequencies of somatic mutations and an immunosuppressive tumor microenvironment. Interestingly, patients with elevated levels of TESMIN expression benefited more from commonly used chemotherapy drugs such as cisplatin, paclitaxel, vinorelbine, and docetaxel, whereas those with low levels of TESMIN expression showed favorable clinical responses to immunotherapy. CONCLUSION: As a prognostic biomarker associated with the cell cycle and immune infiltration, TESMIN may serve as an effective target for predicting the sensitivity to immunotherapy and chemotherapy.

Ultra-high-resolution mapping of myelin and g-ratio in a panel of Mbp enhancer-edited mouse strains using microstructural MRI.

Non-invasive myelin water fraction (MWF) and g-ratio mapping using microstructural MRI have the potential to offer critical insights into brain microstructure and our overall understanding of neuroplasticity and neuroinflammation. By leveraging a unique panel of variably hypomyelinating mouse strains, we validated a high-resolution, model-free image reconstruction method for whole-brain MWF mapping. Further, by employing a bipolar gradient echo MRI sequence, we achieved high spatial resolution and robust mapping of MWF and g-ratio across the whole mouse brain. Our regional white matter-tract specific analyses demonstrated a graded decrease in MWF in white matter tracts which correlated strongly with myelin basic protein gene (Mbp) mRNA levels. Using these measures, we derived the first sensitive calibrations between MWF and Mbp mRNA in the mouse. Minimal changes in axonal density supported our hypothesis that observed MWF alterations stem from hypomyelination. Overall, our work strongly emphasizes the potential of non-invasive, MRI-derived MWF and g-ratio modeling for both preclinical model validation and ultimately translation to humans.

A simple, robust, cost-effective, and low-input ChIP-seq method for profiling histone modifications and Pol II in plants.

Chromatin immunoprecipitation and sequencing (vs ChIP-seq) is an essential tool for epigenetic and molecular genetic studies. Although being routinely used, ChIP-seq is expensive, requires grams of plant materials, and is challenging for samples that enrich fatty acids such as seeds. Here, we developed an Ultrasensitive Plant ChIP-seq (UP-ChIP) method based on native ChIP-seq combined with Tn5 tagmentation-based library construction strategy. UP-ChIP is generally applicable for profiling both histone modification and Pol II in a wide range of plant samples, such as a single Arabidopsis seedling, a few Arabidopsis seeds, and sorted nuclei. Compared with conventional ChIP-seq, UP-ChIP is much less labor intensive and only consumes 1 µg of antibody and 10 µl of Protein-A/G conjugated beads for each IP and can work effectively with the amount of starting material down to a few milligrams. By performing UP-ChIP in various conditions and genotypes, we showed that UP-ChIP is highly reliable, sensitive, and quantitative for studying histone modifications. Detailed UP-ChIP protocol is provided. We recommend UP-ChIP as an alternative to traditional ChIP-seq for profiling histone modifications and Pol II, offering the advantages of reduced labor intensity, decreased costs, and low-sample input.

Fat mass and obesity-mediated m6A modification modulates neuroinflammatory responses after traumatic brain injury.

The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury. The post-transcriptional modification of N6-methyladenosine (m6A) is ubiquitous in the immune response of the central nervous system. The fat mass and obesity (FTO)-related protein catalyzes the demethylation of m6A modifications on mRNA and is widely expressed in various tissues, participating in the regulation of multiple diseases' biological processes. However, the role of FTO in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear. In this study, we found that the expression of FTO was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model. After FTO interference, BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b+/CD86+ cells and the secretion of pro-inflammatory cytokines. FTO-mediated m6A demethylation accelerated the degradation of ADAM17 mRNA, while silencing of FTO enhanced the stability of ADAM17 mRNA. Therefore, down-regulation of FTO expression leads to the abnormally high expression of ADAM17 in microglia. These results indicate that the activation of microglia and neuroinflammatory response regulated by FTO-related m6A modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.

Peptide-Mediated Small Molecule Lysosome-Targeting Chimeras for Targeted Degradation of Membrane and Intracellular Proteins.

Targeted protein degradation through the lysosomal pathway has attracted increasing attention and expanded the scope of degradable proteins. However, the endogenous lysosomal degradation strategies are mainly based on antibodies or nanobodies. Effective small molecule lysosomal degraders are still rather rare. Herein, a new lysosomal degradation approach, termed peptide-mediated small molecule lysosome-targeting chimeras (PSMLTACs), was developed by the incorporation of small molecule ligands with a lysosome-sorting NPGY motif containing the cell-penetrating peptide. PSMLTACs were successfully applied to degrade both membrane and intracellular targets. In particular, the PSMLTAC strategy demonstrated higher degradation efficiency on membrane target PD-L1 and intracellular target PDEδ than corresponding PROTAC degraders. Taken together, this proof-of-concept provides a convenient and effective strategy for targeted protein degradation.

Cerastecin Inhibition of the Lipooligosaccharide Transporter MsbA to Combat Acinetobacter baumannii: From Screening Impurity to In Vivo Efficacy.

Acinetobacter baumannii, a commonly multidrug-resistant Gram-negative bacterium responsible for large numbers of bloodstream and lung infections worldwide, is increasingly difficult to treat and constitutes a growing threat to human health. Structurally novel antibacterial chemical matter that can evade existing resistance mechanisms is essential for addressing this critical medical need. Herein, we describe our efforts to inhibit the essential A. baumannii lipooligosaccharide (LOS) ATP-binding cassette (ABC) transporter MsbA. An unexpected impurity from a phenotypic screening was optimized as a series of dimeric compounds, culminating with 1 (cerastecin D), which exhibited antibacterial activity in the presence of human serum and a pharmacokinetic profile sufficient to achieve efficacy against A. baumannii in murine septicemia and lung infection models.

Structure and Function of Somatostatin and its Receptors in Endocrinology.

Somatostatin analogs, such as octreotide (OCT), lanreotide, and pasireotide, which function as somatostatin receptor ligands (SRLs), are the main drugs used for the treatment of acromegaly. These ligands are also used as important molecules for radiation therapy and imaging of neuroendocrine tumors (NETs). Somatostatin receptors (SSTRs) are canonical G protein-coupled proteins (GPCRs) that play a role in metabolism, growth, and pathological conditions such as hormone disorders, neurological diseases, and cancers. Cryogenic electron microscopy (cryo-EM) combined with the protein structure prediction platform AlphaFold has been used to determine the three-dimensional structures of many proteins. Recently, several groups published a series of papers illustrating the three-dimensional structure of SSTR2, including that of the inactive/activated SSTR2-G protein complex bound to different ligands. The results revealed the residues that contribute to the ligand binding pocket and demonstrated that Trp8-Lys9 (the W-K motif) in somatostatin analogs is the key motif in stabilizing the bottom part of the binding pocket. In this review, we discuss the recent findings related to the structural analysis of SSTRs and SRLs, the relationships between the structural data and clinical findings, and the future development of novel structure-based therapies.

A comparison of respiratory oscillometry and spirometry in idiopathic pulmonary fibrosis: performance time, symptom burden and test-retest reliability.

Study question: In large multinational patient surveys, spirometry (which requires repeated, reproducible maximal efforts) can be associated with cough, breathlessness and tiredness, particularly in those with idiopathic pulmonary fibrosis (IPF). Oscillometry is an effort-independent test of airways resistance and reactance. We hypothesised that oscillometry would take less time to perform and would be associated with reduced symptom burden than spirometry. Patients and methods: Spirometry and oscillometry were performed in 66 participants with IPF and repeated 2 weeks later. We compared time taken to perform tests, symptom burden and test-retest reliability with Bland-Altman plots and intraclass correlation coefficients (ICCs). Results: Oscillometry took significantly less time to perform than spirometry (mean -4.5 (99% CI -6.0 to -3.0) min) and was associated with lower symptom burden scores for cough (-1.3, 99% CI -1.7 to -0.8), breathlessness (-1.0, 99% CI -1.4 to -0.5), and tiredness (-0.5, 99% CI -0.9 to -0.2). On Bland-Altman analysis, all measures showed good agreement, with narrow limits of agreement and the mean bias lying close to 0 in all cases. The ICCs for forced expiratory volume in 1 s and forced vital capacity were 0.94 and 0.89, respectively, and ranged between 0.70 and 0.90 for oscillometry measures. Conclusion: Oscillometry is quicker to perform and provokes less symptoms than spirometry in patients with IPF.

Hepatotoxicity of oral exposure to 2-methyl-4-nitroaniline: toxicity prediction and in vivo evaluation.

2-Methyl-4-nitroaniline (MNA), an intermediate in the synthesis of azo dyes, is widely distributed in various environmental media and organisms. Although there is speculation regarding MNA's potential to be hepatotoxic, the underlying mechanisms of its hepatotoxicity and its definitive diagnostic process remain largely unexplored. In this research. In the present study, we initially predicted the toxicity and possible toxic effect pathways of MNA using ProTox-II, and found that MNA binds to the PPARγ receptor (binding energy －6.118 kcal/mol) with a potential PPARγ agonist effect. Subsequently, in vivo exposure evaluation was conducted on Wistar rats to assess the impact of MNA after a 90-day exposure period, by detecting serum biochemical indexes, hematological indexes, urinary indexes, inflammatory factors, liver histopathological observations and liver tissue PPARγ mRNA expression. The results showed that MNA causes liver function abnormalities, liver histopathological changes and inflammatory response, along with a pronounced increase in PPARγ mRNA levels. This study suggests that the hepatotoxic mechanism of MNA may be related to its possible upregulation of PPARγ expression, increased liver dysfunction and inflammatory responses. Based on these results, the benchmark dose lower limit (BMDL) of 1.503 mg/kg for male Wistar rats was also established, providing a vital benchmark for determining the safety threshold of MNA. Our data highlight the hepatotoxic mechanism of MNA and contribute to a better understanding of its potential etiological diagnosis.

Targeting HTR2B suppresses non-functioning pituitary adenoma growth and sensitizes cabergoline treatment via inhibiting Gαq/PLC/PKCγ/STAT3 axis.

BACKGROUND: Managing non-functioning pituitary adenomas (NFPAs) is difficult due to limited drug treatments. Cabergoline's (CAB) effectiveness for NFPAs is debated. This study explores the role of HTR2B in NFPAs and its therapeutic potential. METHODS: We conducted screening of bulk RNA-sequencing data to analyze HTR2B expression levels in NFPA samples. In vitro and in vivo experiments were performed to evaluate the effects of HTR2B modulation on tumor growth and cell cycle regulation. Mechanistic insights into the HTR2B-mediated signaling pathway were elucidated using pharmacological inhibitors and molecular interaction assays. RESULTS: Elevated HTR2B expression was detected in NFPA samples, which was associated with increased tumor survival. Inhibition of HTR2B activity resulted in the suppression of tumor growth through modulation of the G2M cell cycle. The inhibition of HTR2B with PRX-08066 was found to block STAT3 phosphorylation and nuclear translocation by interfering with the Gαq/PLC/PKC pathway. A direct interaction between PKC-γ and STAT3 was critical for STAT3 activation. CAB was shown to activate pSTAT3 via HTR2B, reducing its therapeutic potential. However, the combination of an HTR2B antagonist with CAB significantly inhibited tumor cell proliferation in HTR2B-expressing pituitary tumor cell lines, a xenografted pituitary tumor model, and patient-derived samples. Analysis of patient-derived data indicated that a distinct molecular pattern characterized by upregulated HTR2B/PKC-γ and downregulated BTG2/GADD45A may benefit from combination treatment with CAB and PRX-08066. CONCLUSIONS: HTR2B is a potential therapeutic target for NFPAs, and its inhibition could improve CAB efficacy. A dual therapy approach may be beneficial for NFPA patients with high HTR2B expression.

CT Quantitation and Prediction of the Risk of Type 2 Diabetes Mellitus in Non-Obese Patients with Pancreatic Fatty Infiltration.

Purpose: To examine the risk of type 2 diabetes mellitus in non-obese patients with pancreatic fatty infiltration through abdominal computed tomography (CT) quantitation. Patients and Methods: We carried out a retrospective analysis of abdominal CT and inpatient medical records of 238 inpatients from July 2019 to April 2021. The patients were divided into a normal non-obese group (BMI < 25, n = 135) and diabetic non-obese group (BMI < 25, n = 103). Abdominal CT-related parameters included body width; mean CT values of the pancreas, liver, and spleen; difference between pancreas and spleen CT values (P-S); pancreas-to-spleen attenuation ratio (P/S); and liver-to-spleen attenuation ratio (L/S). Logistic regression was used to estimate the risk factors for comorbid diabetes in a non-obese population. Results: The P-values of the pancreas CT value, P-S, P/S, body width, and L/S were all <0.05 and correlated to comorbid diabetes in non-obese patients. Worsening pancreatic fatty infiltration increased the risk of developing diabetes. Using a P/S of 1.0 as reference, every successive decrease in this ratio by 0.1 increases patient risk by 3.981, 4.452, 6.037, and 12.937 times. Conclusion: The risk of developing type 2 diabetes mellitus in non-obese patients increases with the degree of pancreatic fatty infiltration as assessed by CT.

Mechanism research progress of acupuncture for regulating axon regeneration after stroke. / é’ˆåˆºè°ƒæŽ§è„‘å’ä¸­åŽè½´çªå†ç”Ÿçš„æœºåˆ¶ç ”ç©¶è¿›å±•.

Stroke brings the pathological changes of brain tissues such as hematoma formation or ischemia and hypoxia, which leads to neuronal death and axon degeneration. Axon regeneration after its injury is mainly dependent on the surrounding microenvironment and the related proteins, including glial scar, myelin associated inhibitory factors, axon guidance molecules, and neurotrophic factors. All of them affect axon growth by regulating the morphology and orientation of growth cones, the synaptic stability, and the proliferation and differentiation of neural stem cells. This article summarizes the mechanism of acupuncture in regulating axon regeneration after stroke. Acupuncture inhibits glial scar formation, alleviates the inhibitory effects of its physical and chemical barriers on axon growth, reverses the inhibitory effects of myelin-related inhibitory factors on axon growth, and adjusts the level of axon guidance molecules to promote the proliferation and differentiation of neural stem cells and the regeneration of injured axons, and up-regulates neurotrophic factors. Eventually, post-stroke nerve injury can be ameliorated.

Analysis of Bending Deformation and Stress of 6063-T5 Aluminum Alloy Multi-Cavity Tube Filled with Liquid.

The production of aluminum alloy multi-lumen tubes primarily involves hot bending formation, a process where controlling thermal deformation quality is difficult. Specifically, the inner cavity wall of the tube is prone to bending instability defects under the bending stress field. To address these challenges in the bending deformation of aluminum alloy multi-lumen tubes, a multi-lumen liquid-filled bypass forming method is proposed in this paper. This study focuses on the 6063-T5 aluminum alloy double-lumen tube as the research object. The liquid-filled bending deformation behavior of the aluminum alloy double-lumen tube was investigated, and the deformation theory of the aluminum alloy double-lumen tube was studied. Through experimental and numerical simulation methods, the influence of support internal pressure, bending radius, and tube wall thickness on the liquid-filled bending deformation behavior of the double-lumen tube was examined. The results indicate that when the value of internal pressure was 7.5 MPa, the straightening of the outer wall was improved by 2.51%, the thinning rate of wall thickness was minimized, and the internal concave defect was effectively suppressed. The liquid-filled bending method provides a promising new approach for the integrated bending and forming of multi-lumen tubes.

Mechanical rheological model on the assessment of elasticity and viscosity in tissue inflammation: A systematic review.

Understanding the extent of inflammation is crucial for early disease detection, monitoring disease progression, and evaluating treatment responses. Over the past decade, researchers have demonstrated the need to understand the extent of inflammation through qualitative or quantitative characterization of tissue viscoelasticity using different techniques. In this scientific review, an examination of research on the association between elasticity and Viscosity in diseases, particularly as tissue inflammation progresses, is conducted. A review of utilizing mechanical rheological models to characterize quantitative viscoelastic parameters of normal and inflamed tissues is also undertaken. Based on inclusion and exclusion criteria, we identified 14 full-text studies suitable for review out of 290 articles published from January 2000 to January 2024. We used PRISMA guidelines for the systematic review. In the review, three studies demonstrated the criterion used by the researchers in identifying the best rheological model. Eleven studies showed the clinical application of the rheological model in quantifying the viscoelastic properties of normal and pathological tissue. The review quantified viscoelastic parameters for normal and pathological tissue across various soft tissues. It evaluated the effectiveness of each viscoelastic property in distinguishing between normal and pathological tissue stiffness. Furthermore, the review outlined additional viscoelastic-related parameters for researchers to consider in future stiffness classification studies.

Blood-based inflammatory protein biomarker panel for the prediction of relapse and severity in patients with neuromyelitis optica spectrum disorder: A prospective cohort study.

BACKGROUND: To date, most existing models for predicting neuromyelitis optica spectrum disorder (NMOSD) are based primarily on clinical characteristics. Blood-based NMOSD severity and prognostic predictive immune- and inflammation-related biomarkers are needed. We aimed to investigate the associations between plasma inflammatory biomarkers and relapse and attack severity in NMOSD. METHODS: This two-step, single-center prospective cohort study included discovery and validation cohorts. We quantified 92 plasma inflammatory proteins by using Olink's proximity extension assay and identified differentially expressed proteins in the relapse group (relapse within 1 year of follow-up) and severe attack group. To define a new molecular prognostic model, we calculated the risk score of each patient based on the key protein signatures and validated the results in the validation cohort. RESULTS: The relapse prediction model, including FGF-23, DNER, GDNF, and SLAMF1, predicted the 1-year relapse risk. The severe attack prediction model, including PD-L1 and MCP-2, predicted the severe clinical attack risk. Both the relapse and severe attack prediction models demonstrated good discriminative ability and high accuracy in the validation cohort. CONCLUSIONS: Our discovered biomarker signature and prediction models may complement current clinical risk stratification approaches. These inflammatory biomarkers could contribute to the discovery of therapeutic interventions and prevent NMOSD progression.

Efficacy of acupuncture in experimental intracerebral hemorrhage: a systematic review and meta-analysis.

Objective: There is currently a lack of evidence in evidence-based medicine regarding acupuncture treatment for experimental intracerebral hemorrhage (ICH). The aim of this study was to systematically evaluate the efficacy of acupuncture treatment for experimental ICH based on neurological function scores and brain water content (BWC). Methods: Eight mainstream Chinese and English databases were searched. Outcome measures included neurological function scores and BWC, and subgroup analysis was conducted based on study characteristics. Results: A total of 32 studies were included. Meta-analysis results indicated that compared to the control group, the acupuncture group showed significant reductions in mNSS (MD = -3.16, p < 0.00001), Bederson score (MD = -0.99, p < 0.00001), Longa score (MD = -0.54, p < 0.0001), and brain water content (MD = -5.39, p < 0.00001). Subgroup analysis revealed that for mNSS, the autologous blood model (MD = -3.36) yielded better results than the collagenase model (MD = -0.92, p < 0.00001), and simple fixation (MD = -3.38) or no fixation (MD = -3.39) was superior to sham acupuncture (MD = -0.92, p < 0.00001). For BWC, the autologous blood model (MD = -7.73) outperformed the collagenase model (MD = -2.76, p < 0.00001), and GV20-GB7 (MD = -7.27) was more effective than other acupuncture points (MD = -2.92, p = 0.0006). Conclusion: Acupuncture significantly improves neurological deficits and brain edema in experimental ICH. Acupuncture at GV20 - GB7 is more effective than at other points. These findings support further studies to translate acupuncture into clinical treatment for human ICH. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023435584.

Proximal termination generates a transcriptional state that determines the rate of establishment of Polycomb silencing.

The mechanisms and timescales controlling de novo establishment of chromatin-mediated transcriptional silencing by Polycomb repressive complex 2 (PRC2) are unclear. Here, we investigate PRC2 silencing at Arabidopsis FLOWERING LOCUS C (FLC), known to involve co-transcriptional RNA processing, histone demethylation activity, and PRC2 function, but so far not mechanistically connected. We develop and test a computational model describing proximal polyadenylation/termination mediated by the RNA-binding protein FCA that induces H3K4me1 removal by the histone demethylase FLD. H3K4me1 removal feeds back to reduce RNA polymerase II (RNA Pol II) processivity and thus enhance early termination, thereby repressing productive transcription. The model predicts that this transcription-coupled repression controls the level of transcriptional antagonism to PRC2 action. Thus, the effectiveness of this repression dictates the timescale for establishment of PRC2/H3K27me3 silencing. We experimentally validate these mechanistic model predictions, revealing that co-transcriptional processing sets the level of productive transcription at the locus, which then determines the rate of the ON-to-OFF switch to PRC2 silencing.

Disulfiram mediated anti-tumour effect in pituitary neuroendocrine tumours by inducing cuproptosis.

CONTEXT: Medical treatment plays a critical role in pituitary neuroendocrine tumour (PitNET) treatment. Dopamine agonists and somatostatin receptor agonists are the only known drugs for effectively treating PitNET. Thus, the identification of potential therapeutic targets and drugs is urgently needed. OBJECTIVE: To discover potential drugs that can suppress PitNET growth and to further investigate the underlying mechanism involved. METHODS: High-throughput drug screening of primary cultures of 17 patient-derived PitNETs was performed to identify potential therapeutic compounds. Cell viability assays, Western blot analysis and flow cytometry were used to investigate pituitary neuroendocrine tumour cell lines and patient-derived PitNET cultures in vitro. In vivo drug efficacy was examined in a mouse xenograft model. RESULTS: Seventeen primary PitNET samples were collected for high-throughput drug screening, and a class of copper ionophores that can effectively inhibit cell growth, such as zinc pyrithione, elesclomol, and disulfiram (DSF), was identified. Subsequent experiments initially validated the dose-dependent cell growth-suppressing effect of these copper ionophores on AtT20, GH3, and MMQ cells and several primary PitNET cell lines. Moreover, we confirmed that the cytotoxic effect of DSF depends on the presence of copper. Additionally, we determined that cell death occurs via cuproptosis, with events such as Fe-S cluster protein loss, dihydrolipoyl transacetylase oligomerization and heat shock protein 70 upregulation. Finally, we verified the cytotoxic effects of DSF in vivo. CONCLUSION: The present study revealed copper ionophores as a potential class of drugs for PitNET treatment. DSF induced PitNET cell death via cuproptosis and might be a promising option for PitNET therapy.