👤 Jiayu Ye

In recent years, there has been a steady increase in professionals engaged in radioactive work. The biological impacts of long-term exposure to low dose-rate radiation remain elusive, as there is a dearth of systematic research in this field. BEAS-2B cells were used to establish a cell model with continuous passaging after radiation exposure, which was subsequently subjected to in vivo tumorigenesis assays and in vitro malignant phenotype experiments. By scRNA-seq, we conducted copy number variation analysis, cell trajectory analysis, and cell communication analysis. Furthermore, we used FACS, molecular docking, multiplex immunohistochemistry, qRT-PCR, and co-immunoprecipitation to validate and further explore the molecular mechanisms driving tumor evolution. Long-term low dose-rate exposure is associated with a higher degree of malignancy, as evidenced by the induction of more CNV and EMT events, as well as the delayed activation of DNA repair pathways, which trigger increased genomic instability. The long-term low dose-rate specific ligand-receptor pair, ANGPTL4-SDC4, enhances cell malignancy by promoting angiogenesis in newly formed lung tumor cells. This study not only provides the first evidence and mechanistic explanation that long-term low dose-rate radiation leads to increased cellular malignancy but also offers valuable theoretical insights into the dynamic processes of early tumor evolution in lung cancer within the realm of tumor biology. Show less

This study aims to establish a hypoxia-immune-related gene signature within the tumor microenvironment (TME) to reliably predict prognosis in non-small cell lung cancer (NSCLC). Transcriptomic profiles and clinical data of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases (GSE74777, GSE68465). Hypoxia- and immune-related genes were curated from MSigDB, ImmPort, and INATDB. Prognostic genes were identified via Cox and LASSO regression analyses, and a risk model was constructed. Model validity was assessed through Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves, and external validation. An eight-gene prognostic signature (AKAP12, MT2A, SERPINE1, CD1E, CD79A, CXCL13, XCL2, ANGPTL4) was established. The model demonstrated significant predictive accuracy for NSCLC survival (AUC: 0.643/0.649/0.620 at 1/3/5 years in TCGA cohort). Patients with high immune activity exhibited superior survival outcomes compared to those with low-immune counterparts (log-rank P < 0.001). Multivariate Cox regression confirmed the risk score as an independent prognostic factor (HR = 1.82, 95% CI: 1.44-2.30, P < 0.001). The hypoxia-immune microenvironment signature serves as a robust prognostic classifier for NSCLC, providing a quantitative framework for personalized risk stratification and clinical decision support. Show less

Emerging evidence suggests that ApoB outperforms LDL-C in predicting cardiovascular risk, especially in cases of discordance with the two. However, the specific type and composition of lipoprotein particles in this situation remain unclear. 375,544 individuals were enrolled from the UK Biobank without baseline cardiovascular disease, not on lipid-lowering therapy, and with available lipid nuclear magnetic resonance (NMR) data. Based on whether the absolute difference in baseline percentile of LDL-C and ApoB level was over 10 units, participants were categorized into concordant, discordantly high ApoB, and discordantly low ApoB group. The primary endpoint was major adverse cardiovascular events (MACE). Cox regression analysis showed the risk of MACE was increased in the discordantly high ApoB group (HR, 1.11; 95% CI, 1.06-1.15) and reduced in the discordantly low ApoB group (HR, 0.87; 95% CI, 0.83-0.93). Similar trends were observed in the NMR data. Compared to the other two groups, the discordantly high ApoB group exhibited the highest concentrations of VLDL-C, VLDL-CE, and VLDL particles. However, the CE content per LDL, IDL, and VLDL particle was lower in this group. Mediation analysis showed that VLDL particles and triglycerides mediated 25.5% and 26.6% of the MACE risk, respectively, in the discordantly high ApoB group (both P < 0.001). ApoB is a more comprehensive marker of cardiovascular risk than LDL-C. The higher cardiovascular risk in discordantly high ApoB individuals was partly mediated by VLDL; however, no conclusive evidence indicated that VLDL provides additional prognostic value beyond triglyceride measurements alone. Show less

Gout is a chronic inflammatory condition increasingly recognized as a risk factor for cardiovascular events (CVE). Early identification of high-risk individuals is crucial for targeted prevention and management. However, conventional risk stratification approaches often fall short in accuracy and clinical utility. This study aimed to develop and validate a robust, interpretable machine learning (ML)-based model for predicting CVE in patients with gout. This retrospective cohort study included 686 hospitalized gout patients at Xiyuan Hospital (Beijing, China) between January 1, 2013, and December 31, 2023. We applied Synthetic Minority Oversampling Technique (SMOTE) combined with random undersampling of the majority class. Then, patients were randomly divided into training (70%) and testing (30%) sets. A comprehensive set of clinical and biochemical variables (n = 39) was collected. Feature selection was performed using Boruta algorithms and Lasso to identify the most predictive variables. Multiple ML algorithms-including Decision Tree Learner, LightGBM Learner, K Nearest Neighbors Learner, CatBoost Learner, Gradient Boosting Desicion Tree Learner-were implemented to construct predictive models. SHAP values were used to assess model interpretability, and robustness was evaluated through 10-fold bootstrap resampling with enhanced standard error estimation. Of the 686 patients, 263 experienced cardiovascular events during follow-up (incidence rate: 38.3%). A logistic regression model was constructed based on eight variables selected using the Boruta feature selection algorithm: sex, age, PLT, EOS, LYM, CO2, GLU and APO-B. Among the five models evaluated, the CatBoost classifier achieved the best performance, with the highest area under the ROC curve (AUC) of 0.976 and the recall of 0.971. Furthermore, SHAP (SHapley Additive exPlanations) values were employed to provide both global and individual-level interpretability of the CatBoost model. To assess the model's generalization performance, bootstrap resampling was performed 10 times. Based on these results, the standard error was improved using machine learning-based enhancement methods, thereby optimizing the model's robustness and predictive stability. The logistic regression analysis revealed that age (OR=1.351, p<0.001), CO2 (OR=0.603, p=0.004), eosinophil count (OR=2.128, p=0.001), and platelet count (OR=0.961, p<0.001) were significantly associated with the outcome, indicating their potential roles as independent predictors. Notably, while APO_B (p=0.138) and sex (p=0.132) showed no significant association, glucose levels (OR=2.1, p=0.066) exhibited a marginal trend toward significance, warranting further investigation. This tool may support clinicians in identifying high-risk individuals, enabling early interventions and optimized management strategies. This study has several limitations. First, the analysis was based on a single-center dataset, which may limit the generalizability of the findings. External validation in multi-center and prospective cohorts, along with an expanded sample size, is warranted to confirm these results. Second, key confounding factors such as medication use, lifestyle habits, and gout flare frequency were not included in the analysis; future studies should incorporate these variables to provide a more comprehensive assessment. Show less

Emerging lipid-modifying agents show potential but lack evidence for the management of uric acid and gout. We aimed to explore the causal effects of lipid traits, lipid-modifying drugs on uric acid levels and risk of gout. Two-sample MR analyses were performed to investigate the associations of genetically predicted lipid traits (LDL-C, HDL-C and TG) and lipid-modifying drug targets (PCSK9, HMGCR, NPC1L1, CETP, ABCG5/G8, APOB, LDLR, LPL, ANGPTL3, and APOC3) with uric acid levels and gout risk. Validation analyses were performed using the independent cohort of the UK Biobank. Summary-data-based MR was further conducted to estimate the associations of the expression of drug target genes with the outcomes. Genetically predicted lower HDL-C and higher TG were significantly associated with elevated uric acid levels ( The online version contains supplementary material available at 10.1007/s43657-024-00212-7. Show less

To assess the value of preoperative peripheral blood inflammatory and nutritional parameters in distinguishing between benign and malignant parotid gland tumors. A retrospective analysis was conducted on 79 patients with malignant parotid gland tumors and 79 patients with benign parotid gland tumors who were treated at the Second Hospital of Dalian Medical University from January 2015 to December 2024. Preoperative levels of total protein (TP), prealbumin (PA), albumin (Alb), albumin-to-globulin ratio (AGR), apolipoprotein A1-to-apolipoprotein B ratio (ApoA1/ApoB), and platelet-to-lymphocyte ratio (PLR) were compared between the malignant and benign tumor groups. The diagnostic value of these parameters in differentiating between benign and malignant parotid tumors was evaluated. The ApoA1/ApoB ratio and PLR were significantly higher in the malignant tumor group compared to the benign tumor group (P < .05). Conversely, TP, Alb, PA, and AGR were significantly lower in the malignant tumor group than in the benign tumor group (P < .05). Binary logistic regression analysis identified TP, PA, AGR, and ApoA1/ApoB as independent risk factors for parotid malignancy (P < .05). The optimal cut-off values for diagnosing parotid malignancy were 65.75 for TP, 248.46 for PA, 1.55 for AGR, and 1.45 for ApoA1/ApoB. Preoperative peripheral blood inflammatory and nutritional markers may serve as valuable indicators for differentiating between benign and malignant parotid gland tumors, providing a potential adjunctive diagnostic tool. However, further large-scale studies are required to validate these findings. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a prevalent liver condition in children and teenagers with obesity. Unfortunately, there is no standardized treatment. To examine the connection between apolipoprotein B (apoB), apolipoprotein A1 (apoA1), and the apoB/apoA1 ratio with the occurrence of MASLD in this population. A retrospective study was made on children and adolescents with obesity in a children's hospital between the period 2020 and 2022. Anthropometric data, ultrasound results, and blood biochemistry were analysed to assess the connection between apoB, apoA1, and the presence of MASLD. Of the 916 participants included, 313 were diagnosed with MASLD. The level of serum apoB reflected a substantial dose-response correlation with the odds of having MASLD. When apoB levels exceeded the 50th percentile, the risk increased significantly, and at the 95th percentile, the odds were 4.83 times higher than at the 50th percentile (95% CI: 2.02-11.56). The ratio of apoB/apoA1 at the 95th percentile was connected to a 2.41-fold higher prevalence compared to the 50th percentile (95% CI: 1.33-4.37). No significant correlation was found between the levels of apoA1 and MASLD prevalence. Elevated levels of apoB and the apoB/apoA1 ratio have been strongly connected to increased MASLD prevalence in children and adolescents with obesity; hence, signifying their potential usefulness as biomarkers for early detection and intervention. Show less

Currently, understanding of the nonlinear relationship between age and hepatocellular carcinoma (HCC) prognosis is insufficient. Thus, this study aimed to analyze the relationship between age at HCC diagnosis and overall survival (OS) and identify possible influencing mechanisms. Clinical data from the TCGA public database were analyzed. Restricted cubic spline and segmented logistic regression were employed to explore the nonlinear relationship between age at diagnosis and mortality risk following hepatectomy. Furthermore, bioinformatics methods were employed to understand the possible mechanisms of this nonlinear relationship at the genetic level. The results indicated a nonlinear relationship between age at diagnosis and OS, with the age of 60 years identified as a critical point. Segmented regression showed that age ≥60 years is an unfavorable prognostic factor. The "DNA mismatch repair" pathway was considerably enriched in patients aged <60 years. However, the gene mutation rate of "APOB," "MUC16," "ALB," and "PCLO" and the median tumor mutation burden were relatively more evident in patients aged ≥60 years. MGEA12 was more highly expressed in tumor tissues than in normal ones, particularly in patients aged ≥60 years. The survival rate of the high-expression group was lower than that of the low-expression group. At the mRNA level, the MGEA12 expression in Huh-7 and SUN449 was higher than that in the HSC-LX2 cell line. A nonlinear relationship was found between age at HCC diagnosis and OS, with the age of 60 years being the critical point. MGEA12 may affect the prognosis of elderly people. Show less

Despite the well-established association between the apolipoprotein B/apolipoprotein A1 (apoB/apoA1) ratio and ischemic stroke, its specific relationship with the underlying vascular pathologies contributing to stroke remains poorly understood. This study aims to investigate the association between the apoB/apoA1 ratio and intracranial or extracranial atherosclerosis. We enrolled 408 patients with acute ischemic stroke who had never been treated with statins or fibrates. Based on the images from computed tomography angiography (CTA), the patients were categorized into four groups: intracranial atherosclerosis stenosis (ICAS, n = 136), extracranial carotid atherosclerosis stenosis (ECAS, n = 45), combined intracranial and extracranial atherosclerosis stenosis (COAS, n = 73), and non-cerebral atherosclerosis stenosis (NCAS, n = 154). Demographic characteristics, clinical factors, and serum lipid levels were collected and then compared across groups. The apoB/apoA1 ratio was significantly higher in patients with ICAS, ECAS and COAS compared to those in the NCAS group. Multivariable logistic regression analysis demonstrated that the ApoB/ApoA1 ratio was independently associated with ICAS, but not with ECAS. ROC curve analysis showed that the ApoB/ApoA1 ratio had a good diagnostic ability for ICAS, with an area under the curve (AUC) of 0.764, an optimal cut-off value of 0.8122, a sensitivity of 81.3%, and a specificity of 59.8%. An higher apoB/apoA1 ratio is associated with ICAS in ischemic stroke patients. Show less

This study aims to evaluate the relationship between apolipoproteins (ApoA1, ApoB, and the ApoB/A1 ratio) and the incidence of major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) and impaired kidney function, assessing their potential role in secondary prevention. A prospective cohort of 1,640 patients with impaired kidney function who underwent percutaneous coronary intervention in China was analyzed. Patients were categorized based on the measurements of ApoA1, ApoB, and ApoB/A1 ratio. MACE, defined as a composite of all-cause mortality, cardiovascular death, nonfatal myocardial infarctions, strokes, and unplanned revascularizations, was tracked post-procedure, with statistical analyses including Kaplan-Meier survival curves and Cox regression models to identify associations with apolipoproteins. Subgroup analyses according to kidney function were conducted. During a median follow-up of 3.1 years, 324 MACE events were observed. Multivariable Cox regression analyses illustrated higher levels of ApoB and the ApoB/A1 ratio were significantly associated with increased MACE incidence (adjusted HR [95%CI] 1.668[1.044-2.666]; adjusted HR [95%CI] 2.231[1.409-3.533], respectively), while lower ApoA1 levels correlated with a higher risk (adjusted HR [95%CI] 0.505[0.326-0.782]). ROC curve analyses indicated comparable predictive performances to traditional risk factors like LDL cholesterol. Subgroup analysis revealed that the above association was not statistically significant in the moderate-to-severe renal impairment CAD patients (eGFR < 45 mL/min/1.73 m Our findings illustrate that apolipoproteins, specifically ApoA1 and ApoB, along with their ratio, are significant predictors of major adverse cardiovascular events in CAD patients with impaired kidney function. These results emphasize the need for incorporating apolipoprotein measurements in secondary prevention strategies for this high-risk population. Show less

This study investigates the relationship between serum homocysteine, blood lipids, and perinatal outcomes in patients with diet-controlled gestational diabetes mellitus (GDM) and those with normal glucose tolerance (NGT). A prospective cohort of 150 diet-controlled GDM patients and 150 pregnant women with NGT, all delivering at our hospital, were selected based on predefined criteria. Data on demographics, physical parameters, and perinatal outcomes were compiled. Blood samples for fasting plasma glucose (FPG), homocysteine (Hcy), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB), and apolipoprotein A1 (apoA1) were collected before delivery. GDM patients exhibited higher levels of FPG, Hcy, and the apoB/apoA1 ratio, but lower HDL-C and apoA1 levels compared to the NGT group. Adverse outcomes such as macrosomia, premature rupture of membranes, and postpartum hemorrhage were more prevalent in the GDM group. In GDM patients, neonatal birth weight positively correlated with FPG and TG levels. Stratified Hcy analysis in GDM showed no significant differences in perinatal outcomes. However, the third quartile of the apoB/apoA1 ratio had a lower incidence of macrosomia compared to the first quartile, and the second quartile showed a higher incidence of birth asphyxia. GDM patients demonstrated increased levels of Hcy, FPG, and the apoB/apoA1 ratio, correlating with more adverse perinatal outcomes than healthy pregnant individuals. The relationships between Hcy, lipids, and these outcomes remain inconclusive, highlighting the need for further research. Show less

In view of the favorable effect of hormone replacement therapy (HRT) on the lipid profile in postmenopausal women, and the discrepancies that exist on the effect of medroxyprogesterone acetate (MPA) on lipoprotein concentrations and cardiovascular disease (CVD) risk, we conducted this meta-analysis of randomized controlled trials (RCT) to assess the efficacy of MPA on apolipoprotein and lipoprotein(a) concentrations in healthy postmenopausal women. A systematic search was conducted across multiple databases, including for English-language papers published up to September 2023 comparing the effect of MPA on ApoA-I, Apo-AII, and Lp(a) levels with those of a control group. A meta-analysis was conducted using a random-effects model, reporting the results as the weighted mean difference (WMD) with a 95 % confidence interval (CI). The current meta-analysis included 11 publications. the comprehensive findings indicated a noteworthy reduction in ApoA-I (WMD:-8.70 mg/dL,95 %CI: -12.80, -4.59,P<0.001), a significant increase in Lp(a) concentrations (WMD: 1.36 mg/dL, 95 % CI: 0.10, 2.63, P=0.033), and a non-significant increase in ApoB concentrations (WMD: 0.57 mg/dL, 95 %CI: -1.25, 2.40, P=0.539) after the administration of MPA in postmenopausal women. In addition, a significant reduction in ApoB levels was identified in studies with a mean participant BMI ≥25 kg/m2 (WMD: -4.94 mg/dL, 95 %CI: -5.71 to -4.18,P< 0.001) and a greater impact on ApoA-1 and Lp(a) levels was observed in trials with doses of 5 mg/day compared with 2.5 mg/day. MPA administration resulted in a significant increase in Lp(a) and decrease in ApoA-I levels and a non-significant increase in ApoB levels in healthy postmenopausal women. Show less

Temozolomide (TMZ) is a first-class clinical drug for patients with pancreatic neuroendocrine tumors (pNETs). However, the therapeutic effects of TMZ are limited because of the chemoresistance of pNET cells, which has not been fully elucidated. Here, we demonstrate that the reprogramming of lipid metabolism regulates TMZ resistance in patients with pNETs. Via integrated multiomics sequencing, apolipoprotein E (APOE), which is a critical lipid carrier, was identified to be highly increased in the tissue and blood plasma of patients in the TMZ treatment group compared with those in the control group. Further mechanistic studies revealed that TMZ treatment promotes the expression and secretion of APOE, which binds to its surface receptor known as scavenger receptor class B member 1 (SCARB1), thus leading to increased uptake of exogenous lipids to remodel cellular lipid metabolism and activation of the homologous recombination repair (HRR) pathway to repair DNA damage via the β-catenin-BRCA1/2 axis. The interruption of APOE-mediated lipid uptake via a SCARB1 inhibitor named as block lipid transport-1 (BLT-1), suppressed TMZ-induced HRR activation and sensitized tumor cells to TMZ treatment in preclinical models, including PDCs, PDOs, and PDXs. In addition, APOE expression levels were shown to be positively correlated with BRCA1/2 expression in clinical specimens and online databases. This study reveals a new functional role of APOE that leads to chemoresistance in patient treatment. Our findings suggest the potential of combined administration of BLT-1 to overcome TMZ chemoresistance and improve treatments for patients with pNETs. Show less

Alzheimer's disease (AD) is a neurodegenerative disease characterized by abnormal accumulation of β-amyloid (Aβ) and hyperphosphorylation of the Tau protein. Currently, there is a lack of effective and safe therapeutic approaches. In Traditional Chinese medicine (TCM), Gandou Decoction has shown significant efficacy in improving cognitive decline and dementia-related symptoms, but its specific mechanism remains unclear. This study systematically analyzed the active components and anti-AD mechanism of Modified Gandou Decoction (MGD) by integrating network pharmacology, machine learning, molecular docking, molecular dynamics (MD) simulation, and A total of 21 potential active molecules of MGD and 68 intersection targets were screened out. Among them, 8 core targets (EIF2AK2, PPARG, BACE1, ESR1, GSK3B, ACE, CASP3, MAPK14) were confirmed to be significantly associated with AD pathology by gene expression difference analysis (P ≤ 0.05). KEGG enrichment analysis showed that MGD mainly intervenes in the amyloid production pathway, the MAPK pathway, and the IL-17 pathway. Molecular docking demonstrated that the majority of the 21 potential active compounds exhibited strong binding affinities to the 8 core targets. Moreover, some potential active molecules exhibited better binding energy and similar binding modes compared with known inhibitors when binding to the corresponding target proteins. Molecular dynamics simulation showed that Alisol B, a potential active component of MGD, could stably bind to BACE1, EIF2AK2, and CASP3. MGD exerts its anti-AD effect through its potential active component Alisol B, which binds to target proteins BACE1, EIF2AK2, and CASP3, and synergistically inhibits Aβ production, Tau phosphorylation, and neuroinflammatory processes through multiple pathways. This study provides a foundation for developing MGD-derived natural products for AD treatment, although the precise mechanisms require further experimental validation. Show less

Homologous recombination repair (HRR) is crucial for maintaining genomic stability by repairing DNA damage. Despite its importance, HRR's role in cancer progression is not fully elucidated. Here, this work shows that nuclear-localized branched-chain α-ketoacid dehydrogenase kinase (BCKDK) acts as a modulator of HRR, promoting cell resistance against DNA damage-inducing therapy in breast cancer. Mechanistically, this work demonstrates that BCKDK is localized in the nucleus and phosphorylates RNF8 at Ser157, preventing the ubiquitin-mediated degradation of RAD51, thereby facilitating HRR-mediated DNA repair under replication stress. Notably, aberrant expression of the BCKDK/p-RNF8/RAD51 axis correlates with breast cancer progression and poor patient survival. Furthermore, this work identifies a small molecule inhibitor of BCKDK, GSK180736A, that disrupts its HRR function and exhibits strong tumor suppression when combined with DNA damage-inducing drugs. Collectively, this study reveals a new role of BCKDK in regulating HRR, independent of its metabolic function, presenting it as a potential therapeutic target and predictive biomarker in breast cancer. Show less

Diabetes mellitus (DM) and tuberculosis (TB) are two global health challenges that significantly impact population health, with DM increasing susceptibility to TB infections. However, early risk prediction methods for DM patients complicated with TB (DM-TB) are lacking. This study mined transcriptome data of DM-TB patients from the GEO database (GSE181143 and GSE114192) and used differential analysis, weighted gene co-expression network analysis (WGCNA), intersecting immune databases, combined with ten machine learning algorithms, to identify immune biomarkers associated with DM-TB. An early alert model for DM-TB was constructed based on the identified core differentially expressed genes (DEGs) and validated through a prospective cohort study and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) for gene expression levels. Furthermore, we performed a detailed immune status analysis of DM-TB patients using the CIBERSORT algorithm. We identified 1090 DEGs associated with DM-TB and further pinpointed CETP (cholesteryl ester transfer protein) (AUC = 0.804, CI: 0.744-0.864), TYROBP (TYRO protein tyrosine kinase binding protein) (AUC = 0.810, CI: 0.752-0.867), and SECTM1 (secreted and transmembrane protein 1) (AUC = 0.811, CI: 0.757-0.864) as immune-related biomarkers for DM-TB patients. An early alert model was developed based on these three genes (AUC = 0.86, CI: 0.813-0.907), with a sensitivity of 0.80829 and a specificity of 0.75758 at a Youden index of 0.56587. External validation using the GSE114192 dataset showed an AUC of 0.901 (CI: 0.847-0.955). Population cohort research and RT-qPCR verified the expression levels of these three genes, demonstrating consistency with trends seen in the training set. KEGG enrichment analysis revealed that NF-κB and MAPK signaling pathways play crucial roles in the DM-TB pathogenic mechanism, and immune infiltration analysis showed significant suppression of certain adaptive immune cells and activation of inflammatory cells in DM-TB patients. This study identified three potential immune-related biomarkers for DM-TB, and the constructed risk assessment model demonstrated significant predictive efficiency, providing an early screening strategy for DM-TB. Show less

Ochratoxin A (OTA) is a core environmental toxin that induces kidney injury by interfering with glomerular filtration, antioxidant defense, and tubular transport functions. Alginate oligosaccharides (AOS), as active substances from marine, carry natural antioxidant, anti-inflammatory and other biological activities. The purpose of this study is to explore the molecular network of AOS against nephrotoxicity caused by OTA. A total of 36 5-week male mice were randomly divided into three groups: the CON group, the OTA group (250 μg/kg B.W. OTA) and the AOS + OTA group (400 mg/kg B.W. AOS +250 μg/kg B.W. OTA). The treatment was continued for 21 d. OTA induced renal injury in mice, manifested by glomerular capsule blurring, lymphocytic infiltration, and mitochondrial damage in tubular epithelial cells. Treatment with AOS significantly alleviated these pathological changes. Multi‑omics analysis revealed that AOS activated the PPAR signaling pathway, upregulating key genes (Aldehyde Dehydrogenase 1 Family Member A3 ( This study reveal that AOS antagonizes OTA-induced nephrotoxicity in mice through PPAR signaling axis, thus providing new insight into the renal protection mechanism of marine active substances. Show less

Tumorigenesis is typically accompanied by cellular dedifferentiation and the acquisition of stem cell-like attributes. However, few studies have comprehensively evaluated the putative relationships between these characteristics and various cancers. Here, we integrated gene expression and DNA methylation quantitative trait loci (cis-eQTL and cis-mQTL) data from the blood to perform multi-omics Mendelian randomization analysis. Our analyses revealed 967 stem cell-associated genes (P < 0.05) and 11,262 methylation sites (P < 0.01) significantly related to 12 cancers. SMAD7 (cg14321542) in colon cancer, IGF2 (cg13508136) in prostate cancer, and FADS1 (cg07005513) in rectal cancer were prioritized as candidate causal genes and regulatory elements. Notably, using cis-eQTL data from the corresponding tissue sites, we detected 16 stem cell-associated genes dramatically causally associated with six cancers (FDR<0.2). The gene THBS3 was particularly common in both blood and stomach tissues and exhibited prognostic significance. Furthermore, it was markedly associated with one microbial metabolic pathway and four immunophenotypes. Functional validation using the ECC12 gastric cancer cell line revealed that the inhibition of its expression could accelerate oxidative phosphorylation and reactive oxygen species production, reduce clonal proliferation ability, and promote the apoptosis of stomach tumor cells. Additionally, based on spatial transcriptomic data from gastrointestinal cancers, the results demonstrated the clusters enriched with the most stem cell-associated genes exhibited significantly enhanced tumor-promoting potency, and the THBS3-expressing cells displayed suppressed oxidative phosphorylation. Overall, this study enhances our understanding of tumorigenic mechanisms and aids in the identification of therapeutic targets. Show less

Fish oil supplements (FOS) are known to alter circulating levels of polyunsaturated fatty acids (PUFAs) but in a heterogeneous manner across individuals. These varied responses may result from unidentified gene-FOS interactions. To identify genetic factors that interact with FOS to alter the circulating levels of PUFAs, we performed a multi-level genome-wide interaction study (GWIS) of FOS on 14 plasma measurements in 200,060 unrelated European-ancestry individuals from the UK Biobank. From our single-variant tests, we identified genome-wide significant interacting SNPs (p < 5 × 10 Show less

Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide association study approaches on homeostatic model assessment for insulin resistance, insulin resistance index, fasting insulin, and ratio of triglycerides to high-density lipoprotein cholesterol from MAGIC and UK Biobank to develop a comprehensive phenotype ('mvIR'), and identify 217 independent loci, including 24 novel loci. The mvIR is causally associated with higher risks of 17 cardiometabolic diseases and five aging phenotypes, independent of adiposity and sarcopenia. We outline 21 of 2644 druggable genes for insulin resistance by Mendelian randomization and colocalization, where six genes (AKT1, ERBB3, FCGR1A, FGFR1, LPL, NR1H3) encode targets for approved drugs with consistent directions in alleviating insulin resistance, with no significant side effects revealed by phenome-wide association study. This study uncovers novel loci and therapeutic targets to inform strategies promoting insulin resistance-centered cardiometabolic health and longevity. Show less

Drug resistance severely hinders the clinical application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of non-small cell lung cancer (NSCLC). Notably, resistance caused by rare target mutations (with a mutation incidence rate below 5 %) accounts for approximately 15 % of total resistance cases in NSCLC. Due to the diversity and complexity of these mutations, targeted therapies against them are currently very limited. To address the challenge of multi-driver resistance in NSCLC, this study aimed to explore a novel therapeutic strategy that can simultaneously inhibit multiple resistance drivers and enhance drug resensitization to EGFR-TKIs, overcoming the limitations of conventional single-protein inhibitors. Established gefitinib-resistant HCC827 cell models driven by rare co-activation of two EGFR-independent membrane proteins. Developed a strategy targeting lipid raft cholesterol to destabilize raft integrity, leveraging the cholesterol-modulating properties of ginsenosides. Evaluated the synergistic effect of co-administering ginsenoside Rg3 with gefitinib in both in vitro and in vivo models. Explored the mechanism of Rg3 action, including its binding to lipid raft cholesterol, disruption of membrane anchoring of resistance-associated receptor tyrosine kinases, and acceleration of their endocytic degradation. Co-administration of ginsenoside Rg3 with gefitinib synergistically restored antitumor efficacy in both in vitro and in vivo models, outperforming conventional single-protein inhibitors. Mechanistically, Rg3 specifically binds to lipid raft cholesterol, disrupting the membrane anchoring of resistance-associated receptor tyrosine kinases (e.g., FGFR1 and VEGFR2) and accelerating their endocytic degradation. Structural-activity relationship analyses revealed that the cholesterol-binding capacity of ginsenosides-critical for resistance reversal-is modulated by the stereochemical configuration of sugar moieties at C3, C6, and C20 positions. This study elucidates a novel membrane-centric paradigm for overcoming multi-driver resistance in NSCLC, where pharmacological perturbation of cholesterol-lipid raft interactions by natural compounds like Rg3 enables broad-spectrum suppression of coexisting resistance mechanisms. It not only provides novel insights into the mechanisms underlying resistance in NSCLC but also presents a promising clinical strategy that could significantly improve treatment outcomes for patients. Show less

Fibroblast growth factor receptors (FGFRs) are well-established oncology targets, with aberrant FGFR2 and FGFR3 activation implicated in multiple tumor types, including cholangiocarcinoma and urothelial carcinoma. Currently approved FGFR2/3-targeted therapies rely on pan-FGFR small-molecule kinase inhibitors, which often lead to off-target toxicities due to unintended inhibition of FGFR1 and FGFR4, as well as acquired resistance driven by gatekeeper mutations. Herein, we report the discovery of INCB126503, a highly potent, orally bioavailable FGFR2/3 inhibitor with excellent isoform selectivity and equipotent activity against gatekeeper mutants. INCB126503 effectively suppresses FGFR signaling in vivo without inducing hyperphosphatemia and demonstrates significant antitumor efficacy in xenograft models harboring FGFR3 genetic alterations. Show less

FGFR1 amplification and FGFR1/2 activating mutations have been associated with antiestrogen resistance in estrogen receptor-positive (ER+) breast cancer. However, there are no approved FGFR1-targeted therapies for breast cancers harboring these alterations. In this study, we investigated the selective degradation of FGFR1/2 using the proteolysis-targeting chimera (PROTAC) DGY-09-192 as a novel therapeutic strategy in ER + breast cancers harboring FGFR1/2 somatic alterations. Treatment of ER+/FGFR1-amplified breast cancer cells and patient-derived xenografts with DGY-09-192 resulted in sustained degradation of FGFR1 in a proteasome-dependent manner and suppressed downstream signal transduction. The combination of DGY-09-192 and the ERα degrader fulvestrant resulted in complete cell growth arrest and tumor regression of ER+/FGFR1-amplified patients-derived xenografts. In addition, we tested the effect of DGY-09-192 on breast cancer cells expressing FGFR1 Show less

Liver diseases, ranging from chronic liver disease (CLD) to acute liver injury (ALI), pose significant global health challenges. Metabolic dysfunction and inflammatory disorders are key to the progression of both CLD and ALI, suggesting that dual-targeting of metabolism and immune response may lead to better clinical performance for patients with liver disease. Interleukin-27 (IL-27) is a classic cytokine known for its immune-modulating role, with many ongoing clinical trials in the context of anti-tumoral therapy and inflammatory bowel disease. Our previous studies have revealed an unexpected role of IL-27 in promoting adipocyte thermogenesis and ameliorating role in systemic metabolism. This review outlines the involvement of the IL-27/IL-27R signaling pathway in hepatic metabolism and immunity, highlighting its potential as a therapeutic target for both CLD and ALI. Meanwhile, when serum IL-27 displays a disease-specific change in dynamic liver diseases, a summary and elaboration on its diagnostic potential are also carried out. Show less

B cells express many protein ligands, yet their regulatory functions are incompletely understood. We profiled ligand expression across murine B sublineage cells, including those activated by defined receptor signals, and assessed their regulatory capacities and specificities through in silico analysis of ligand-receptor interactions. Consequently, we identified a B cell subset that expressed cytokine interleukin-27 (IL-27) and chemokine CXCL10. Through the IL-27-IL-27 receptor interaction, these IL-27/CXCL10-producing B cells targeted CD40-activated B cells in vitro and, upon induction by immunization and viral infection, optimized antibody responses and antiviral immunity in vivo. Also present in breast cancer tumors and retained there through CXCL10-CXCR3 interaction-mediated self-targeting, these cells promoted B cell PD-L1 expression and immune evasion. Mechanistically, Show less

Our aim was to explore the IL-27 effect in sepsis (SP)-related acute hepatic injury (AHI) as well as its possible mechanism. Herein, we utilized both wild-type (WT) and IL-27 receptor (WSX-1)-deficient (IL-27R The results revealed that IL-27 exacerbated systemic inflammation and liver damage in AHI mice by promoting M1 macrophage polarization, thereby increasing pro-inflammatory phenotype macrophages (M1). This further exacerbated the inflammatory response and pyroptosis in vivo and in vitro. Additionally, IL-27 down-regulated p-AMPK and SIRT1 protein expression while overexpressing macrophage inflammatory mediators including IL-1β/6 and TNFα. Furthermore, IL-27 promoted increased RAGE and caspase-11 protein expression, aggravating macrophage pyroptosis. Employing CC to block the AMPK pathway further aggravated M1 macrophage polarization and pyroptosis in vitro and in vivo, ultimately worsening liver injury. Here, IL-27 aggravates AHI by promoting macrophage M1 polarization to induce caspase-11-mediated pyroptosis in vitro and in vivo, which may be linked to the AMPK/SIRT1 signaling pathway. Show less