👤 Yimeng Lyu

Disruption of metabolic interactions between astrocytes and neurons, in particular of the lactate shuttle, may contribute to neurodevelopmental and psychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia. The enzyme glycine decarboxylase (GLDC), predominantly expressed in astrocytes, degrades glycine and plays a critical role in regulating NMDA receptor function and cellular metabolism. Here, we investigated whether administration of lactate would reverse schizophrenia-like phenotypes in a mouse model for psychosis with 4 copies of the Gldc gene (4cG mice). Adult male and female 4cG and wildtype mice were subjected to acute L-lactate intraperitoneal administration one hour before behavioral testing and brain collection for biochemical assays. Y-maze spontaneous alternation test, prepulse inhibition of acoustic startle test, and the three-chamber social interaction test were performed for behavioral analysis, and Western blots for protein estimations. In 4cG mice, acute lactate administration one hour before assessment rescued short-term memory deficits, acoustic startle habituation deficits, and normalized deficits in social preference behavior. Furthermore, lactate treatment restored the expression of PGC1α, a master regulator of mitochondrial biogenesis, and brain-derived neurotrophic factor (BDNF), a protein essential for synaptic plasticity. The results suggest a role for astrocytic metabolism in modulating neuronal function, and potential molecular mechanisms underlying the reversal of behavioral phenotypes. The results indicate that exogenous lactate may reverse key pathophysiological and behavioral deficits in a mouse model for schizophrenia and that lactate supplementation may be useful as a therapeutic strategy for schizophrenia and related disorders. Show less

Women face a heightened risk of Alzheimer's disease (AD), partly attributed to post-menopausal estrogen loss. Given that ERβ activation avoids the oncogenic risks of ERα and GPR40 plays a pivotal role in neuronal function, the ERβ/GPR40 axis show a promising therapeutic target for anti-AD drug discovery. To inspect the role of this axis, we employed Vincamine (Vin), a monoterpenoid indole alkaloid from Madagascar periwinkle that we previously identified as a GPR40 agonist. To elucidate the role of ERβ/GPR40 axis in AD pathogenesis and to investigate the therapeutic potential of Vin in ameliorating AD-related deficits. We combined analyses of clinical data from female AD patients (GSE33000) with the research in 3×Tg-AD mice to examine the differences in ERβ/GPR40 expression. The binding of ERβ and GPR40 was detected by CUT&Tag assay, protein-DNA docking simulation and molecular dynamics simulation assays. Vin was used to evaluate the therapeutic potential of ERβ/GPR40 axis activation for AD. The underlying mechanisms were investigated by assay against the adeno-associated virus (AAV)-CMV-PHP.eB-KD-GPR40 injected 3×Tg-AD female mice. ERβ and GPR40 are both downregulated in brains of female AD patients and 3×Tg-AD mice, and ERβ directly binds to GPR40 promoter. Brain-specific GPR40 knockdown caused cognitive impairment in female wild type (WT) mice. Vin as a GPR40 agonist but not an ERβ ligand ameliorated AD-like pathology in 3×Tg-AD female mice. Specifically, Vin suppressed neuroinflammation via GPR40/NF-κB/NLRP3 pathway, inhibited neuronal tau hyperphosphorylation via GPR40/GSK3β/CaMKII pathway, while promoted synaptic plasticity via GPR40/PKA/CREB/BDNF pathway. To our knowledge, our study provides the first identification of the specific ERβ-binding regions and key residues within the GPR40 promoter, offering novel mechanistic insight into their transcriptional regulation. Furthermore, our work establishes ERβ/GPR40 axis as a potentially therapeutic strategy for female AD and highlight the medication interest of Vin in treating this disease. Show less

Residual cardiovascular risk persists in type 2 diabetes mellitus (T2DM) despite intensive risk-factor management. Apolipoprotein B (apoB) and excess apoB are potentially promising biomarkers for identifying residual cardiovascular risk. We assessed apoB and excess apoB in T2DM for incremental prediction of atherosclerotic cardiovascular disease (ASCVD) risk. This prospective cohort included 11,918 UK Biobank participants (mean age 59.7 ± 6.6 years; 61% male) with T2DM and no ASCVD at baseline. Excess apoB was defined as the observed minus predicted apoB, where the predicted value was derived using a linear regression model of apoB on low-density lipoprotein cholesterol (LDL-C) fitted in a statin-naïve reference subset with triglycerides ≤ 1.0 mmol/L. The primary endpoint was incident ASCVD. Secondary endpoints included major adverse cardiovascular events (MACE) and all-cause mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox models. Nonlinearity was assessed using restricted cubic splines. Incremental improvements were quantified using the C-index, net reclassification improvement (NRI). During a median 185.3-month follow-up, 2,548 ASCVD and 1,205 MACE events occurred. ApoB was linearly related to ASCVD and MACE, while excess apoB showed J-shaped associations with a nadir near - 7.5 mg/dL for ASCVD. Both apoB and excess apoB showed positive associations with ASCVD across ascending percentile categories. Versus < 50th percentile, HRs (95% CIs) for ASCVD in higher apoB categories (50-<75th, 75-<90th, ≥ 90th) were 1.31 (1.16-1.49), 1.51 (1.25-1.81), and 1.47 (1.10-1.95); corresponding HRs (95% CIs) for excess apoB were 1.50 (1.36-1.66), 1.45 (1.29-1.63), and 1.53 (1.33-1.76), respectively. Similar but weaker risk gradients were observed for MACE. Neither apoB nor excess apoB was associated with all-cause mortality. Excess apoB yielded greater prediction improvement than apoB (ΔC-index: 0.009 vs. 0.002; NRI: 0.270 vs. 0.101) and better stratified risk in statin users and those with LDL-C ≤ 100 mg/dL (P for interaction < 0.05). In T2DM, apoB is independently associated with ASCVD but adds limited discrimination over conventional lipids. Excess apoB yielded improved discrimination and reclassification, and may serve as a complementary ASCVD risk marker, particularly in statin-treated settings. However, its clinical application requires external validation and standardization. Show less

Vascular smooth muscle cell (VSMC)-derived foam cells critically drive atherosclerotic plaque progression, yet their regulatory mechanisms remain incompletely understood. This study aimed to elucidate the pathophysiological role of the VSMC-enriched factor axin interactor, dorsalization-associated (AIDA) in this process and evaluate its therapeutic potential. We utilized VSMC-specific AIDA knockout in male ApoE Show less

Accumulating evidence suggested that bile acids play a significant role in modulating metabolic and inflammatory diseases. In this study, we investigated the roles of the farnesoid X receptor (FXR) and its endogenous antagonist hyodeoxycholic acid (HDCA) in the development of atherosclerosis (AS). We found that serum HDCA was significantly reduced in patients with AS, and systemic HDCA therapy attenuated plaque burden in vivo. Adoptive transfer of HDCA-treated Foxp3+ Tregs into ApoE-deficient recipients reduced lesion growth, whereas FXR-deficient Tregs failed to confer benefit. HDCA enhanced Treg migration and accumulation within plaques and reprogrammed Treg metabolism by antagonizing FXR and modulating PD-1/mTORC1 signaling. This shift relieved CPT1a-driven fatty acid oxidation bias, increased glycolysis and ATP production, and improved migratory capacity and effector function. We further identify ZNF671 as a transcriptional inhibitor of Treg migration that is mitigated by HDCA-dependent metabolic switching. Collectively, HDCA reduced FXR-mediated metabolic constraints while activating glycolytic and migratory programs in Tregs, thereby improving lipid handling and immune regulation within the plaque microenvironment. These findings position the HDCA-FXR-PD-1/mTORC1 axis as a novel immunometabolic target for AS. Show less

Cancer-associated fibroblasts (CAF) are abundant stromal cells in the tumor microenvironment (TME) that play a vital role in promoting tumor progression and drug resistance. The mechanisms regulating heterogeneity of CAFs in renal cell carcinoma (RCC) could represent potential targets for reprogramming the TME. In this study, we conducted single-cell RNA sequence and flow cytometry analyses that identified a CAF subset overexpressing apolipoprotein E (ApoE), which was correlated with poor survival in patients with RCC. Mechanistically, NRF1 activation in CAFs induced formation of ApoEhigh CAFs and secretion of NRG1. ApoEhigh CAFs potentiated stemness properties in the surrounding RCC cells by secreting NRG1 and subsequently activating the HER2/NF-κB pathway. Interfering with NRG1 expression or inhibiting NF-κB signaling reduced ApoEhigh CAF-induced stemness of RCC cells. Furthermore, neutralizing NRG1 enhanced the efficacy of sunitinib in RCC models in vivo. Together, these findings highlight targeting the tumor-promoting functions of ApoEhigh CAFs as a promising approach for treating advanced RCC. NRF1 drives formation of ApoEhigh cancer-associated fibroblasts that secrete NRG1 to stimulate stemness of renal cell carcinoma, revealing a stromal-mediated mechanism that can be inhibited to improve treatment of advanced kidney cancer. Show less

Atherosclerosis is a chronic inflammatory disease marked by lipid accumulation and immune cell infiltration in arterial walls. Macrophages contribute by internalizing oxidized low-density lipoprotein, forming foam cells, and driving inflammation. The ubiquitin-proteasome system regulates immune and inflammatory responses in atherosclerosis. This study investigated the protective role of TRIM31 (tripartite motif-containing 31), an E3 ubiquitin ligase, in macrophage lipid metabolism and inflammation through selective regulation of LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1). Transcriptomic profiling, macrophage-specific TRIM31 was selectively upregulated in macrophages under oxidized low-density lipoprotein stimulation and in atherosclerosis plaques. Trim31 deficiency exacerbated plaque burden, foam cell formation, and inflammatory signaling (n=8 per group). Single-cell analysis revealed enrichment of lipid transport and inflammatory pathways in Trim31-deficient plaques. LOX-1 was identified as a key TRIM31 substrate. TRIM31 promoted K48-linked ubiquitination of LOX-1 at lysine 12, facilitating its degradation. The atheroprotective effects of Trim31 were abolished in TRIM31, an inducible, macrophage-enriched protective factor in atherosclerosis, restricts foam cell formation and inflammation by targeting LOX-1 for proteasomal degradation. These findings position TRIM31 as a promising therapeutic target for macrophage-driven atherogenesis. Show less

Chronic hepatitis B virus (HBV) infection is a major risk factor of hepatocellular carcinoma (HCC), and hepatocyte-derived host factors play important roles in HBV-associated tumor progression. Alpha-1B glycoprotein (A1BG) is a plasma glycoprotein reported to be dysregulated in multiple cancers. In this study, we investigated the functional role of A1BG in HBV-associated HCC progression. Both the HepG2 and HBV-transfected HepG2 cell lines were used to examine the biological effects of A1BG. A1BG expression was modulated using siRNA and a plasmid vector. A series of functional assays were conducted to assess cell proliferation, apoptosis, stemness, migration, and invasion. RNA microarray analysis and gene set enrichment analysis (GSEA) were performed to identify A1BG-regulated pathways. Functionally, A1BG overexpression suppressed cell proliferation, stemness, migration, invasion, and HBV products while promoting apoptosis in both HepG2 and HBV-transfected HepG2 cells. In contrast, opposite effects were shown in the event of A1BG knockdown. Moreover, A1BG expression was reduced in HBV-associated HCC tissues and correlated with advanced pathological stage and poor prognosis. RNA microarray analysis and GSEA revealed the activation of anti-HBV-related genes and suppression of FGFR1 signaling and the matrix metalloproteinase pathway in A1BG-overexpressing cells. This study provides evidence that A1BG may be a novel host factor associated with the in vitro suppression of HBV replication and HCC progression by modulating pathways related to enhanced antiviral effects, reduced proliferative capacity and stemness, and suppression of EMT. These findings suggest that A1BG is a potential therapeutic target in HBV-related HCC. Show less

With the widespread use of smartphones among adolescents, smartphone addiction has become a growing mental health concern. Adolescents' limited self-regulation makes them particularly vulnerable to using smartphones to escape real-life stress, heightening addiction risk. However, the heterogeneity of addictive behaviors and the dynamic role of experiential avoidance have been underexplored. This 6-month longitudinal study surveyed 547 Chinese primary and secondary students using the Smartphone Addiction Scale (SAS) and the Acceptance and Action Questionnaire-II (AAQ-II). Latent profile analysis (LPA) and latent transition analysis (LTA) were applied to identify subgroups and examine transitions between these subgroups. Cross-lagged panel network analysis (CLPN) revealed key symptom interactions between experiential avoidance and addiction. The study identified two addiction subgroups: a stable "low-risk group" (84.9 percent) and a "high-risk group," 51.4 percent of whom transitioned to low risk over time. Logistic regression showed that experiential avoidance significantly predicted high-risk membership (odds ratios [OR] = 1.083-1.102) and deterioration within the low-risk group (OR = 1.036). The CLPN identified "online intimacy" (SPA-3) and "hesitation and overcautious" (EA-7) as driver nodes, with "withdrawal symptoms" (SPA-2) serving as a central node. These findings emphasize the crucial role of experiential avoidance in adolescent smartphone addiction and suggest symptom-level targets for early intervention. The results support acceptance and commitment therapy (ACT) as a promising approach for reducing smartphone addiction among youth. Show less

Improving Internet addiction among nursing students is of great significance to the future development of the nursing industry. Previous studies have proved that childhood trauma is closely related to Internet addiction. However, the direct relationship between alexithymia and childhood trauma and Internet addiction has not been fully explored. The aim of this study is to identify different subgroups of nursing students based on their childhood trauma and to examine the mediating role of alexithymia between childhood trauma and Internet addiction. From April to May 2025, 3,697 nursing students were recruited as samples from Shandong, Hubei, Hunan, and Henan provinces in China by convenient sampling. This survey collected social demographic data. Including The Childhood Trauma Questionnaire - Short Form (CTQ-SF), the Toronto Alexithymia Scale (TAS-26), and the Internet addiction Scale. Potential profile analysis was used to determine the potential categories of childhood trauma characteristics of nursing students, and Pearson correlation analysis, Bayesian factor robustness analysis and mediation analysis were used to determine the potential relationships among variables. LPA identified three distinct groups based on their dominant usage: low (77.4%), medium (19.5%), and high (3.1%). In the relationship between childhood trauma and Internet addiction based on potential profile analysis, alexithymia has a significant mediating effect (SE = 0.442,95%CI = 0.095, 1.824; SE = 0.219, 95%CI = 0.093, 0.962). There is heterogeneity in childhood trauma among nursing students. Alexithymia plays an important mediating role in the relationship between childhood trauma and Internet addiction. It is suggested that nursing educators pay attention to the differences in childhood trauma among nursing students, provide corresponding psychological counseling for different students, improve them, thereby alleviating Internet addiction among nursing students and promoting their mental health. Show less

Extensive research has documented a high comorbidity prevalence between depression and Internet gaming disorder (IGD). However, the distinct comorbidity patterns in adolescents have not been thoroughly investigated. Additionally, the longitudinal dynamics of these comorbidity patterns over time and the specific factors that may drive these transitions remain poorly understood. A total of 3,296 adolescents (1,501 boys; age baseline: 15.17 [1.44] years) were included in the current study. Latent profile analysis (LPA) was used to identify optimal comorbidity patterns of depression and IGD, while random intercept latent transition analysis (RI-LTA) was conducted to assess transitions in the comorbidity patterns over one and a half years and to identify factors influencing these transitions. Three patterns of comorbidity between depression and IGD symptoms were identified: no symptoms, low depression-high IGD symptoms, and high depression-low IGD symptoms. Results indicate that 72 % of individuals exhibited a stable symptom pattern trajectory. From Time 1 to Time 2, the probabilities of remaining in the three patterns were 78.3 %, 31.5 %, and 51.5 %, respectively. Findings also showed that sex, grade levels, boarding status, father's occupation as well as educational attainment, intra-week and weekend screen time, parent-child relationship, and perceived social support influenced the probabilities of transitions between comorbidity patterns in adolescents over time. Adopting targeted interventions for different comorbidity patterns and transitions, while considering specific influencing factors, provides insights into adolescent mental health dynamics and inform more effective prevention and support strategies. Show less

Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine implicated in fat metabolism regulation. Its genetic inactivation has been associated with improved glucose homeostasis, while elevated plasma ANGPTL4 levels are observed in diabetic and obese individuals. However, the potential link between ANGPTL4 and diabetes- or obesity-related complications remains uncertain. This study aimed to explore whether plasma ANGPTL4 level could serve as a predictor of cancer mortality, cardiovascular mortality, and all-cause mortality in a community-based cohort. A community-based cohort study was conducted, where fasting plasma ANGPTL4 concentrations were measured at baseline, and vital status was ascertained through linkage with the National Health Insurance Research Database in Taiwan. During a 10.46-year follow-up period, 29 (2.49%) of the 1163 participants died. Subjects within the highest tertile of plasma ANGPTL4 levels exhibited the lowest survival rate. In unadjusted models, plasma ANGPTL4 significantly predicted all-cause mortality, cancer mortality, and cardiovascular or cancer-related mortality. Upon adjustment for confounders including age, sex, smoking, body mass index (BMI), hypertension, diabetes mellitus (DM), and renal function, each standard deviation increase in plasma ANGPTL4 was associated with HRs of 1.35 (95% CI: 1.01-1.80, Plasma ANGPTL4 emerges as a promising biomarker capable of predicting 10-year mortality and enhancing risk prediction beyond established risk factors. Show less

Fibrotic remodeling of nucleus pulposus (NP) leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration, leading to low back pain incidence and disability. Emergence of fibroblastic cells in disc degeneration has been reported, yet their nature and origin remain elusive. In this study, we performed an integrative analysis of multiple single-cell RNA sequencing datasets to interrogate the cellular heterogeneity and fibroblast-like entities in degenerative human NP specimens. We found that disc degeneration severity is associated with an enrichment of fibrocyte phenotype, characterized by CD45 and collagen I dual positivity, and expression of myofibroblast marker α-smooth muscle actin. Refined clustering and classification distinguished the fibrocyte-like populations as subtypes in the NP cells - and immunocytes-clusters, expressing disc degeneration markers HTRA1 and ANGPTL4 and genes related to response to TGF-β. In injury-induced mouse disc degeneration model, fibrocytes were found recruited into the NP undergoing fibrosis and adopted a myofibroblast phenotype. Depleting the fibrocytes in CD11b-DTR mice in which myeloid-derived lineages were ablated by diphtheria toxin could markedly attenuate fibrous modeling and myofibroblast formation in the NP of the degenerative discs, and prevent disc height loss and histomorphological abnormalities. Marker analysis supports that disc degeneration progression is dependent on a function of CD45 Show less

The early detection of high-risk individuals is crucial to delay and reduce the incidence of type 2 diabetes. In this study, we aimed to explore the performance of a novel subgroup-specific biomarker strategy in the prediction of incident diabetes. In the Taiwan Lifestyle Cohort Study, adult subjects without diabetes were included and followed for the incidence of diabetes in 2006-2019. The biomarkers measured included blood secretogranin III (SCG3), vascular adhesion protein-1 (VAP-1), fibrinogen-like protein 1 (FGL1), angiopoietin-like protein 6 (ANGPTL6), and angiopoietin-like protein 4 (ANGPTL4). Among the 1,287 subjects, 12.2% developed diabetes during a 6 year follow-up. Blood VAP-1 was significantly associated with incident diabetes in the overall population (HR = 0.724, P < 0.05), participants under 65 years old (HR = 0.685, P < 0.05), those with a BMI of ≥24 kg/m Gender- and BMI-specific biomarker strategy can improve the prediction of incident diabetes. A subgroup-specific biomarker strategy is a novel approach in the prediction of incident diabetes. Show less

Atherosclerosis underlies most coronary artery disease (CAD). It involves a significant autoimmune component against apolipoprotein B (APOB). In this study, we used short activation-induced marker (AIM) assays to characterize APOB-reactive CD4 Show less

To explore the mechanism of astragaloside Ⅳ in regulating energy metabolic reprogramming, alleviating endothelial-to-mesenchymal transition(EndMT), and preventing atherosclerosis(AS) in ApoE~(-/-) AS mice, ApoE~(-/-) AS mouse models were established by high-fat feeding and randomly divided into three groups: model group, astragaloside Ⅳ group, and blank control group. The mice in the astragaloside Ⅳ group were administered astragaloside Ⅳ via gavage at a dose of 40 mg·kg~(-1)·d~(-1), while mice in the blank control group and model group received an equal volume of normal saline via gavage for four consecutive weeks. The blood lipid levels of mice in each group were measured using an automatic biochemical analyzer. Hematoxylin-eosin(HE) staining was used to observe the pathomorphological changes in the mouse aorta. The degree of EndMT was detected by immunofluorescence, and the protein expression levels of α-smooth muscle actin(α-SMA) and vascular endothelial cadherin(VE-cadherin) in the aorta were detected by Western blot. Targeted energy metabolomics technology was used to qualitatively and quantitatively analyze the spectrum of serum energy metabolites in mice, followed by KEGG pathway enrichment analysis of differential metabolites. The expression of glycolysis-related genes was detected using RT-PCR. The results showed that astragaloside Ⅳ significantly reduced the levels of serum total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-C) while increasing high-density lipoprotein cholesterol(HDL-C) levels. It reduced atherosclerotic plaque formation, decreased the number of α-SMA and VE-cadherin double staining positive cells, downregulated the protein expression of mesenchymal cell surface antigen α-SMA, and upregulated the protein expression of endothelial cell surface antigen VE-cadherin. Targeted energy metabolomics analysis shows that astragaloside Ⅳ restored nine altered energy metabolites in the serum. The pathway enrichment analysis indicated that serum differential metabolites were mainly enriched in glycolytic pathways. RT-PCR detection revealed that astragaloside Ⅳ significantly downregulated the mRNA expression of key glycolytic enzymes, including hexokinase-Ⅱ(HK-Ⅱ), phosphofructokinase(PFKM), and pyruvate kinase M2(PKM2). These results suggest that astragaloside Ⅳ may ameliorate AS by inhibiting the excessive activation of glycolysis, modulating energy metabolic reprogramming, and alleviating EndMT. Show less

The activation of blood monocytes and the infiltration of monocyte-derived macrophages into the vessel walls are the central part of atherosclerosis. However, the mechanisms underlying the processes remain unclear. Here, we report that G-protein signaling modulator 1 (GPSM1) plays a critical role in atherogenesis. We found that GPSM1 expression in lesional macrophages was increased during atherosclerosis development both in mice and humans. Myeloid-specific GPSM1 ablation protects mice against atherosclerosis and reduces aortic inflammation in both Show less

Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain. Therefore, systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines, which may play critical roles in the pathogenesis of sepsis. This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes. First, a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and sepsis. A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetically proxied lipid-modifying therapies on the risk of sepsis, sepsis-related critical care admission, and sepsis-related death. The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines. Finally, enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response. Genetically proxied cholesteryl ester transfer protein (CETP) inhibitors were significantly associated with sepsis-related critical care admission ( This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death. These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines, influencing the inflammatory response pathway. Show less

G-quadruplexes (G4s) are prevalent DNA structures that regulate transcription but also threaten genome stability. How G4 dynamics are controlled remains poorly understood. Here, we report that RNA transcripts govern G4 landscapes through coordinated G-loop assembly and disassembly. G-loop assembly involves activation of the ATM and ATR kinases, followed by homology-directed invasion of RNA opposite the G4 strand mediated by BRCA2 and RAD51. Disassembly of the G-loop resolves the G4 structure through DHX36-FANCJ-mediated G4 unwinding, which triggers nucleolytic incision and subsequent hybrid strand renewal by DNA synthesis. Inhibition of G-loop disassembly causes global G4 and R-loop accumulation, leading to transcriptome dysregulation, replication stress, and genome instability. These findings establish an intricate G-loop assembly-disassembly mechanism that controls G4 landscapes and is essential for cellular homeostasis and survival. Show less

Fibroblast growth factor receptor (FGFR) alterations are established therapeutic targets in cholangiocarcinoma and urothelial carcinoma but remain understudied in colorectal cancer (CRC). This study investigates the prevalence, clinicopathological correlates, and prognostic impact of FGFR alterations in CRC. We analyzed 608 stage I-IV CRC samples (2014-2024) through next-generation sequencing (NGS) and immunohistochemistry (IHC). FGFR genomic status was correlated with survival outcomes using Kaplan-Meier and Cox regression analyses. External validation of FGFR genomic alterations was carried out using the 19 datasets (n = 6998) with prognostic impact validated through The Cancer Genome Atlas Colon and Rectum Adenocarcinoma (COREAD) dataset (Firehose Legacy, n = 640), both accessed via cBioPortal database. Large-scale genomic profiling of CRC [n = 7606 (608 in-house + 6998 public cohorts)] identified FGFR1 amplification (3.8% prevalence) as the predominant FGFR alteration subtype. Multivariable analysis confirmed FGFR alterations as independent predictors of poor disease-free survival [DFS; hazard ratio (HR) 2.58, P = 0.0002] and progression-free survival (PFS; HR 2.17, P = 0.0011), with FGFR1 amplification showing strongest prognostic impact (DFS HR 2.91, PFS HR 2.52, P < 0.01). Notably, the prognostic magnitude of FGFR alterations was comparable to KRAS/BRAF mutations in both localized and metastatic CRC. In addition, we established a semiquantitative immunoreactive score (IRS) system achieving 95.2% concordance with NGS (κ = 0.901), enabling reliable FGFR1 screening in routine pathology workflows. This study provides the first comprehensive characterization of FGFR genomic alterations in CRC through large-scale profiling (n = 7606), establishing FGFR1 amplification as the predominant alteration. Unlike FGFR2/3-driven malignancies, FGFR1-amplified CRC exhibited aggressive clinical behavior and inferior survival outcomes across disease stages. To address the diagnostic challenges in routine practice, we further developed a validated immunohistochemical scoring system (IRS), establishing a cost-effective and clinically feasible alternative to molecular assays for identifying FGFR1-driven CRC subsets. Show less

Obesity is turning into a more critical problem for public health. Vitamin D The study aims to examine the influence of VD Firstly, a small sample population study was conducted to compare the disparities in serum 25(OH)D A correlation was identified between serum 25(OH)D The study shows that VD Show less

We conducted a systematic review on cardiac metabolomic alterations in type 2 diabetes and the interplay with lipoprotein lipase (LPL). To synthesize evidence on LPL activity, cardiac metabolomics, and cardiovascular outcomes in type 2 diabetes. EMBASE, PsycINFO, AMED, LILACS, and Web of Science were searched from January 2000 to August 2025; last searches: EMBASE [22 August 2025], PsycINFO [22 August 2025], AMED [22 August 2025], LILACS [22 August 2025], Web of Science [22 August 2025]. Original human studies in type 2 diabetes reporting cardiac metabolomics and LPL activity; no language restrictions. Two reviewers independently screened records/reports and extracted data; risk of bias was assessed with RoB 2 (randomized trials), ROBINS-I (nonrandomized studies), and the Newcastle-Ottawa Scale (observational). We planned random-effects meta-analyses using mean difference/standardized mean difference or risk ratio, quantified heterogeneity with I2 and τ2, examined small-study effects with funnel plots/Egger's test, and rated certainty with GRADE. We included 11 studies ( Show less

The tumor microenvironment (TME) is integral to tumor progression. However, its prognostic implications and underlying mechanisms in clear cell renal cell carcinoma (ccRCC) are not yet fully elucidated. This study aims to examine the prognostic significance of genes associated with immune-stromal scores and to explore their underlying mechanisms in ccRCC. Data from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) were subjected to analysis to compute immune and stromal scores utilizing the ESTIMATE algorithm. The weighted gene co-expression network analysis (WGCNA) was employed to identify gene modules associated with these scores. Differentially expressed genes were assessed using the limma package. Prognostic biomarkers were subsequently identified through univariate, LASSO, and multivariate Cox regression analyses, culminating in the development of a risk score model. Gene expression was confirmed in ccRCC cell lines (786-O, Caki-1) and tumor tissues. Functional assays, such as wound healing and Transwell assays, were employed to evaluate tumor invasion and migration. The prognostic accuracy was assessed through ROC curve analysis, and a nomogram integrating risk scores with clinical variables was constructed. Analyses of immune infiltration, human leukocyte antigen (HLA) expression, immune checkpoint expression, immunophenoscore (IPS), tumor immune dysfunction and exclusion (TIDE) scores, and responses to six targeted therapies were conducted across different risk groups. Twelve critical prognostic markers, including CAPRIN1, CXCR3, FERMT3, HAPLN3, HBP1, MACF1, MPEG1, OSCAR, STAT1, UBA7, VAMP1, and VSIG4, were identified. The risk score model exhibited a high degree of predictive accuracy for survival outcomes in ccRCC. Immune profiling revealed significant differences in the TME between risk groups, with high-risk patients displaying elevated expression of HLA and immune checkpoints. Drug sensitivity analyses suggested that high-risk patients had a better response to erlotinib, temsirolimus, axitinib, and sunitinib, whereas low-risk patients demonstrated greater sensitivity to pazopanib. Variability in immunotherapy responsiveness between groups was observed based on IPS and TIDE analyses. This study highlights the prognostic value and TME-related mechanisms of immune-stromal score signatures in ccRCC, developing a risk score model and nomogram for predicting patient prognosis. Show less

The KIT/c-KIT proto-oncogene is frequently over-expressed in Merkel cell carcinoma (MCC), an aggressive skin cancer commonly caused by Merkel cell polyomavirus (MCPyV). Here, we demonstrated that truncated MCPyV-encoded large T-antigen (LT) suppressed macroautophagy/autophagy by stabilizing and sequestering KIT in the paranuclear compartment via binding VPS39. KIT engaged with phosphorylated BECN1, thereby enhancing its association with BCL2 while diminishing its interaction with the PIK3C3 complex. This process ultimately resulted in the suppression of autophagy. Depletion of KIT triggered both autophagy and apoptosis, and decreased LT expression. Conversely, blocking autophagy in KIT-depleted cells restored LT levels and rescued apoptosis. Additionally, stimulating autophagy efficiently increased cell death and inhibited tumor growth of MCC xenografts in mice. These insights into the interplay between MCPyV LT and autophagy regulation reveal important mechanisms by which viral oncoproteins are essential for MCC cell viability. Thus, autophagy-inducing agents represent a therapeutic strategy in advanced MCPyV-associated MCC. Show less

Gastroesophageal reflux disease (GERD) and asthma are commonly co-occurring conditions, with shared genetic factors identified. However, the specific loci and the influence of common genetic architecture remain undefined. We obtained genome-wide association study (GWAS) summary statistics for GERD (71 522 cases and 261 079 controls) and asthma (56 167 cases and 352 255 controls). Using linkage disequilibrium score regression (LDSC), we assessed genetic correlations between GERD and asthma. Bidirectional Mendelian randomization (MR) was performed to investigate potential causal relationships, followed by cross-trait GWAS meta-analysis and colocalization analysis to identify shared risk loci. Additionally, summary-data-based MR and transcriptome-wide association study were conducted to pinpoint common functional genes. Finally, we analyzed gene expression profiles in both healthy individuals and GERD patients using esophageal single-cell RNA sequencing (scRNA-seq) data. We identified a significant genetic correlation between GERD and asthma ( rg  = 0.37, P = 6.19 × 10 -38 ) and a significant causal effect of GERD on asthma [odds ratio (OR) = 1.22, P = 1.54 × 10 -5 ]. Cross-trait meta-analyses revealed 56 shared risk loci between GERD and asthma, including 51 loci that were newly identified. Three loci (rs61937247, rs7960225, and rs769670) exhibited evidence of colocalization. Gene-level analyses pinpointed three novel shared genes ( RBM6, SUOX , and MPHOSPH9 ) between GERD and asthma. scRNA-seq analysis uncovered heightened expression of these genes in immune cells of patients diagnosed with GERD. Our study has discovered novel shared genetic loci and candidate genes between GERD and asthma, providing further insights into the genetic susceptibility of comorbidity and potential mechanisms of the two diseases. Show less

Recent development of immune checkpoint inhibitors has revolutionized cancer immunotherapy. Although these drugs show dramatic effects on a subset of cancer patients, many other tumors are non-responsive and the pathological mechanism of the resistance is largely unknown. To identify genes underlying anti-PD-1 immunotherapy resistance using a systematic approach, we performed an in vivo genome wide CRISPR screening in lung cancer cells. We integrated our results with multi-omics clinical data and performed both in vitro and in vivo assays to evaluate the role of the top candidate in regulating cytotoxic T cell killing. We identified TUBB3 as a potential target to overcome the resistance and enhance the efficacy of anti-PD-1 immunotherapy. TUBB3 expression is upregulated in lung cancer patients, and its higher expression correlates with poorer patients' survival. We found that TUBB3 expression was significantly elevated in the non-responders compared to responders in our patient cohort that received immunotherapies. Importantly, the results of our preclinical experiments showed that inhibition of TUBB3 with a small molecule inhibitor synergized with anti-PD-1 treatment and enhanced tumor cell killing by cytotoxic T cells. Consistently, anti-PD-1 resistant cells showed significantly higher expression of TUBB3; however, TUBB3 inhibition rendered the resistant cells more susceptible to T cell killing. Mechanistic studies revealed that blocking TUBB3 suppressed the expression of PD-L1 through the EMT-related SNAI1 gene. Our results provide a rationale for a novel combination therapy consisting of the TUBB3 inhibition and anti-PD-1 immunotherapy for lung cancer. Show less

The vertebrate genome is spatially organized into topologically associating domains (TADs), primarily via cohesin-mediated loop extrusion which typically halts at convergent CTCF binding sites to establish domain boundaries. However, despite the essential roles of CTCF and cohesin in establishing TADs, a long-standing paradox persists: CTCF and cohesin binding sites dramatically outnumber observed TAD boundaries, suggesting the existence of undiscovered architectural factors. To identify such missing factors, we conducted high-resolution Show less

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone secreted by K cells in the small intestine and is considered an obesity-promoting factor. In this study, we systematically investigated the anti-obesity effects of intragastric safflower yellow (SY)/hydroxysafflor yellow A (HSYA) and the underlying mechanism for the first time. Our results showed that intragastric SY/HSYA, rather than an intraperitoneal injection, notably decreased serum GIP levels and GIP staining in the small intestine in diet-induced obese (DIO) mice. Moreover, intragastric SY/HSYA was also first found to significantly suppress GIP receptor (GIPR) signaling in both the hypothalamus and subcutaneous White adipose tissue. Our study is the first to show that intragastric SY/HSYA obviously reduced food intake and body weight gain in leptin sensitivity experiments and decreased serum leptin levels in DIO mice. Further experiments demonstrated that SY treatment also significantly reduced leptin levels, whereas the inhibitory effect of SY on leptin levels was reversed by activating GIPR in 3 T3-L1 adipocytes. In addition, intragastric SY/HSYA had already significantly reduced serum GIP levels and GIPR expression before the serum leptin levels were notably changed in high-fat-diet-fed mice. These findings suggested that intragastric SY/HSYA may alleviate diet-induced obesity in mice by ameliorating hyperleptinemia via dual inhibition of the GIP-GIPR axis. Show less

Melanocortin-4 receptor (MC4R) functions as a crucial neuroendocrine G protein-coupled receptor (GPCR) in the central nervous system of mammals, displaying agonist-independent constitutive activity that is mainly determined by its N-terminal domain. We previously reported that zebrafish MC4R exhibited a much higher basal cAMP level in comparison to mammalian MC4Rs. However, the functional evolution of constitutive activities in chordate MC4Rs remains to be elucidated. Here we cloned and compared the constitutive activities of MC4Rs from nine vertebrate species and showed that the additive action of the N-terminus with the extracellular region or transmembrane domain exhibited a combined pharmacological effect on the MC4R constitutive activity. In addition, we demonstrated that four residues of F149, Q156, V163, and K164 of the second intracellular loop played a vital role in determining MC4R constitutive activity. This study provided novel insights into functional evolution and identified a key motif essential for constitutive modulation of MC4R signaling. Show less

This investigation aimed to evaluate the efficacy and safety of rosuvastatin in treating moderate to severe metabolic associated fatty liver disease (MAFLD). This prospective, open-label, randomized study included non-diabetic participants with metabolic syndrome and intrahepatocellular lipid (IHCL) levels >10 %, as determined by proton magnetic resonance spectroscopy ( Thirty-two participants completed the study. Rosuvastatin resulted in a significant absolute (△IHCL: 7.61 ± 4.51 vs. 1.54 ± 5.33, p = 0.002) and relative reduction in IHCL (△IHCL%: -42.28 ± 24.90 % vs. -8.91 ± 31.93 %, p = 0.003) compared to the control. Reduction in IHCL correlated significantly with decreases in low-density lipoprotein cholesterol (LDL-C) (r = 0.574, p < 0.01), apolipoprotein B (ApoB) (r = 0.660, p < 0.001), and free fatty acids (FFA) (r = 0.563, p = 0.005). No significant safety differences were observed between groups. Rosuvastatin significantly reduced hepatic steatosis in individuals with moderate to severe MAFLD and metabolic syndrome over 52 weeks, while maintaining a favorable safety profile. Show less