👤 Bobo Yuan

Abnormal lipid accumulation is an important cause of metabolic dysfunction-associated fatty liver disease (MAFLD) progression and can induce several stress responses within cells. This study is the first to explore the role and molecular mechanism of stress granules (SGs) in MAFLD. A gene knock-down model of G3BP1, a core SG molecule in mice and HepG2 cells, was constructed to explore the role of SGs in MAFLD induced in vivo by a high-fat diet or in vitro by palmitic acid (PA). Methods included metabolic phenotyping; western blotting; qPCR; and immunofluorescence, haematoxylin/eosin and masson staining. The downstream molecules of G3BP1 and its specific molecular mechanism were screened using RNA sequencing (RNA-seq). G3BP1 and TIA1 expression were upregulated in high-fat diet-fed mouse liver tissues and PA-induced HepG2 cells, and the two molecules showed significantly increased colocalisation. G3BP1 knock-down slightly increased TIA1 expression in the livers of obese mice but not in lean mice. G3BP1 deficiency aggravated liver lipid deposition and insulin resistance in obese mice, and this phenotype was confirmed in vitro in PA-induced hepatocytes. RNA-seq demonstrated that G3BP1 slowed down MAFLD progression by inhibiting APOC3, possibly through a mechanistic suppression of APOC3 entry into the nucleus. This study reveals for the first time a protective role for SGs in MAFLD. Specifically, knocking down the core G3BP1 molecule in SGs aggravated the progression of fatty acid-induced MAFLD through a mechanism that may involve the nuclear entry of APOC3. These findings provide a new therapeutic direction for MAFLD. Show less

Clustered regularly interspaced short palindromic repeats-Cas13 effectors are used for RNA editing but the adeno-associated virus (AAV) packaging limitations because of their big sizes hinder their therapeutic application. Here we report the identification of the Cas13j family, with LepCas13j (529 aa) and ChiCas13j (424 aa) being the smallest and most highly efficient variants for RNA interference. The miniaturized Cas13j proteins enable the development of compact RNA base editors. Chi-RESCUE-S, by fusing dChiCas13j with hADAR2dd, demonstrates high efficiency and specificity in A-to-G and C-to-U conversions. Importantly, this system is compatible with single-AAV packaging without the need for protein sequence truncation. It successfully corrected pathogenic mutations, such as APOC3 Show less

In the microenvironment of atherosclerosis (AS), low-density lipoprotein (LDL) accumulates in injured endothelial areas and undergoes oxidation, thereby generating oxidized LDL (ox-LDL). The formation of ox-LDL, in turn, not only amplifies endothelial cell (EC) dysfunction but also triggers macrophage polarization into the pro-inflammatory M1 phenotype. This cascade results in increased inflammatory cytokine secretion and exacerbated lipid accumulation. Therefore, a dual-targeting strategy aimed at both ECs and macrophages to inhibit the vicious circle between inflammation and lipids is a promising avenue for AS treatment. Simvastatin (SIM)-loaded nanomicelles (PLA-PEG/SIM) were prepared using the thin-film hydration method. Then, platelet membrane (PM) was coated the nanomicelles via sonication to obtain PM@PLA-PEG/SIM dual-targeting biomimetic nanoparticles. The morphological features of the nanoparticles were assessed by transmission electron microscopy (TEM). Cytotoxicity was evaluated using the CCK-8 assay and live/dead cell staining. Their targeting ability toward ECs and macrophages was assessed by flow cytometry and confocal laser scanning microscopy (CLSM). The biosafety, targeting ability, and therapeutic efficacy of PM@PLA-PEG/SIM against AS were further validated in ApoE PM@PLA-PEG/SIM effectively reduced the drug toxicity of SIM, exhibiting good biocompatibility. In vitro, cell experiment results showed that the nanoparticles inhibited foam cell formation, decreased interleukin-6 (IL-6) expression, and increased interleukin-4 (IL-4) and interleukin-10 (IL-10) expression by promoting macrophage repolarization. In vivo, results indicated that the formulation demonstrated excellent plaque-targeting ability. More importantly, the plaque area and lipid levels in the PM@PLA-PEG/SIM group were lowest, and plaques were most stable, showing its best therapeutic efficiency. PM@PLA-PEG/SIM alleviated progression of AS by co-targeting ECs and macrophages to inhibit the vicious cycle between inflammation and lipids. Our study provides a new strategy for the treatment of the disease by the co-targeting biomimetic nanoparticle. Show less

Bladder cancer (BCa) is a lethal cancer, but early-detection offers an opportunity to improve prognosis. Our objective was to develop a urine-based multi-marker panel for BCa detection across multiple longitudinal cohort studies in a nested case-control study. Longitudinal cohorts included healthy participants enrolled in the Southern Community Cohort Study (SCCS), Singapore Chinese Health Study (SCHS), Shanghai Women/Men Health Study (SWMHS), and Multiethnic Cohort (MEC). We measured the levels of 10 protein biomarkers (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1, and VEGF) in spot-voided urine samples using the multiplex immunoassay Oncuria. Single urine specimens collected from 274 participants who would go on to develop BCa in the ensuing 3‒60 months (i.e., cases) were age/sex-matched to 274 cancer-free controls. We used generalized estimating equation models, logistic regression analysis, and random forest algorithms to analyze the data. Differences in the individual biomarker levels between cases and controls were noted for ANG at 12 months ( Additional testing is needed; however preliminary results demonstrate that a multiplex immunoassay may be able to facilitate the early detection of BCa in at-risk patients. Identification of BCa at an early stage may lead to improved patient outcomes. Using large multinational patient populations, we tested the performance of the Oncuria multiplex assay to accurately predict the risk of developing bladder cancer by simultaneously analyzing the concentrations of 10 protein biomarkers in urine samples. The online version contains supplementary material available at 10.1186/s12967-025-07511-1. Show less

Phenotypic switching of vascular smooth muscle cells (VSMCs) from a contractile toward a synthetic phenotype plays a critical role in atherosclerosis. Although the redox-sensitive sentrin/Small Ubiquitin-like Modifier (SUMO)-specific protease 3 (SENP3), which preferentially deconjugates SUMO2/3, has been linked to oxidative stress, its role in atherosclerosis remains poorly defined. In this study, we demonstrate that SENP3 is significantly upregulated in human and mouse atherosclerotic lesions and in VSMCs exposed to pro-atherogenic stimuli. Using smooth muscle-specific Senp3 knockout mice (ApoE Show less

Age-related retinal degeneration, such as diabetic retinopathy and age-related macular degeneration, are major causes of blindness in modern society. Recent studies suggest that dysbiosis and intraocular translocation of bacteria from the blood circulation are critically involved in retinal degeneration. We hypothesise that the blood-retinal barrier (BRB) cells can protect the neuroretina from blood-borne pathogens by producing antimicrobial peptides (AMPs). The antimicrobial activity may decline during ageing, putting the retina at risk of low-degree chronic inflammation and degeneration. Here, we found that the retinal pigment epithelial (RPE) cells, which form the outer BRB, express a variety of AMPs/AMP precursors, including APP, RARRES2, FAM3A, HAMP, CAMP, GNLY, and PI3. Senescent RPE cells expressed lower levels of APP and RARRES2 mRNA, accompanied by increased intracellular retention of E. coli in a bactericidal assay. Silencing APP, not RARRES2, with shRNA reduced the antibacterial activity of RPE cells. Senescent RPE cells had lower levels of α-secretase and higher levels of β-secretase (BACE1) and γ-secretase (PS1), accompanied by reduced soluble APPα and increased amyloid beta (Aβ) production, particularly the Aβ42 isoform. Eyes from aged donors showed a higher Aβ accumulation within RPE cells. Our results suggest that while RPE cells possess antimicrobial activity, this ability declines with age and is impaired in senescent cells. The impaired antimicrobial activity and augmented Aβ deposition in senescent RPE cells may contribute to age-related retinal para-inflammation and neurodegeneration. Show less

Hyperglycemia accelerates Alzheimer's disease (AD) progression, yet the role of monosaccharides remains unclear. Here, it is demonstrated that mannose, a hexose, closely correlates with the pathological characteristics of AD, as confirmed by measuring mannose levels in the brains and serum of AD mice, as well as in the serum of AD patients. AD mice are given mannose by intra-cerebroventricular injection (ICV) or in drinking water to investigate the effects of mannose on cognition and AD pathological progression. Chronic mannose overload increases β-amyloid (Aβ) burdens and exacerbates cognitive impairments, which are reversed by a mannose-free diet or mannose transporter antagonists. Mechanistically, single-cell RNA sequencing and metabolomics suggested that mannose-mediated N-glycosylation of BACE1 and Nicastrin enhances their protein stability, promoting Aβ production. Additionally, reduced mannose intake decreased BACE1 and Nicastrin stability, ultimately lowering Aβ production and mitigating AD pathology. this results highlight that high-dose mannose consumption may exacerbate AD pathogenesis. Restricting dietary mannose may have therapeutic benefits. Show less

Pericytes regulate cerebral blood flow (CBF) and excess amyloid in the brain. Pericyte dysfunction may contribute to the pathology of Alzheimer's disease (AD). Acorus tatarinowii (AT), a Chinese medicine commonly used to treat AD, protects the central nervous system. However, whether AT can regulate pericyte function and ameliorate cognitive dysfunction remains unclear. We employed a novel target recognition assay, quantitative measurement of CBF, hematoxylin and eosin staining, immunofluorescence staining, and Western blot to investigate the role of AT in improving cognitive function in patients with AD. Additionally, we investigated the therapeutic potential of β-Asarone, the primary active compound in AT, for treating AD by modulating pericyte function using transmission electron microscopy, silver staining, electrical impedance, and other methodologies. The results revealed that administration of AT effectively alleviated the cognitive impairments induced by D-galactose in mice, as evidenced by enhanced CBF, improved histological characteristics of damaged brain tissue cells, increased expression of platelet-derived growth factor-β (PDGF-β), decreased Aβ accumulation via enhanced lipoprotein receptor-related protein 1 (LRP1), and reduced beta-site APP-cleaving enzyme 1 (BACE1). β-Asarone treatment mitigated ROS release and BACE1 expression while elevating the cell index in Aβ1-40 injured mouse brain vascular pericytes (MBVP). These findings suggest that AT has the potential to enhance CBF and mitigate pericellular dysfunction, thereby ameliorating Aβ deposition in the brain and improving cognitive impairment in patients with AD. Show less

Osteosarcoma, an aggressive bone malignancy predominantly affecting children and adolescents, is characterized by a poor prognosis and high mortality rates. The development of reliable prognostic tools is critical for advancing personalized treatment strategies. However, identifying robust gene signatures to predict osteosarcoma outcomes remains a significant challenge. In this study, we analyzed gene expression data from 138 osteosarcoma samples across two multicenter cohorts and identified 14 consensus prognosis-associated genes via univariate Cox regression analysis. Using 66 combinations of 10 machine learning (ML) algorithms, we developed a machine learning-derived prognostic signature (MLDPS) optimized by the average C-index across TARGET, GSE21257, and merged cohorts. The MLDPS effectively stratified osteosarcoma patients into high- and low-risk score groups, achieving strong predictive performance for 1-, 3-, and 5-year overall survival (AUC range: 0.852 - 0.963). The MLDPS, comprising seven genes (CTNNBIP1, CORT, DLX2, TERT, BBS4, SLC7A1, NKX2-3), exhibited superior predictive accuracy compared to 10 established gene signatures. The findings of the MLDPS carry significant clinical implications for osteosarcoma treatment. Patients with a high-risk score demonstrated worse prognosis, increased metastasis risk, reduced immune infiltrations, and greater sensitivity to immunotherapy. Conversely, low-risk patients exhibited prolonged survival and distinct drug sensitivities. These findings underscore the potential of MLDPS to guide risk stratification, inform personalized therapeutic strategies, and improve clinical management in osteosarcoma. Show less

Xylaria nigripes, is a rare medicinal fungus known as Wulingshen in China. It has a neutral and sweet nature and belongs to the heart and kidney meridians. Rich in a variety of bioactive ingredients, it serves as a nutrient-dense food and a therapeutic agent for disease prevention. Wuling powder, a fermented form of X. nigripes, leverages biotechnology to harness the fungus's health benefits, showing significant therapeutic efficacy clinically, offering patients a safer and more effective treatment option. This article reviews the recent progress in the biological characteristics, chemical constituents, and pharmacological effects of X. nigripes. Additionally, it evaluates the modern clinical applications of Wuling powder and the current state of product development, aiming to provide insights for its further development and utilization. Research materials were collected from databases including SciFinder, PubMed, and Web of Science, encompassing over 20 years of academic literature, including books, doctoral dissertations, and master's theses from 2004 to October 2024. The literature search integrated keywords related to "X. nigripes", "Wulingshen", "Leizhenzi", "Wuling powder", "biological characteristics", "pharmacological profile", "chemical constituents", and "clinical applications", used in both English and Chinese. This review highlights the chemical diversity and bioactivities of 82 compounds identified from X. nigripes between 2004 and October 2024. Among these, 26 compounds exhibit diverse pharmacological properties, including antioxidant, anti-inflammatory, neuroprotective, anti-tumor, and cholesteryl ester transfer protein (CETP) inhibitory activities. Both aqueous and ethanol extracts of X. nigripes demonstrate comparable bioactivities. Clinical studies have further validated the efficacy of Wuling powder (dried mycelium product of X. nigripes) in regulating mental health, alleviating insomnia, and treating related disorders. The review also explores the product development status and potential of X. nigripes, analyzing its market prospects. Furthermore, it addresses advancements in artificial cultivation and industrial production, emphasizing the importance of sustainable supply chains for ongoing research and commercial applications. X. nigripes, with its elusive specific ingredients, is recognized for its potential health benefits and has been extensively researched. Due to its notable bioactive effects on human health, X. nigripes and its application, Wuling powder, have garnered considerable attention and have undergone extensive research. Recent multidimensional and interdisciplinary research approaches have achieved a deeper understanding of the biochemical nature and pharmacological effects of X. nigripes. This has led to the accumulation of substantial practical experience in the clinical application of Wuling powder-based medicines. Concurrently, the development of health products, deep fermentation technology, artificial cultivation and deep fermentation technology of X. nigripes have been successfully achieved. It is anticipated that X. nigripes holds the potential to emerge as a pivotal resource for the development of novel pharmaceuticals and therapeutic strategies targeting various human ailments. Show less

An association has been observed between alcohol and cheese intake and the onset of inflammatory bowel disease (IBD), necessitating further exploration from a genetic structural perspective. The present analysis was focused on the intake of alcohol and cheese in conjunction with IBD genome-wide association study (GWAS) data, with the objective of exploring genetic correlations and identifying common loci. Initially, overall genetic correlations were assessed employing two methodologies: linkage disequilibrium score regression (LDSC) and genetic covariance analyzer (GNOVA). Subsequently, local correlations were examined through the SUPERGNOVA method. A genetic overlap analysis between various traits was then conducted based on the statistical theory of conditional/conjunctional false discovery rate (cond/conjFDR). Ultimately, shared loci between the two traits were identified via conjFDR analysis and multi-trait analysis of GWAS (MTAG). Substantial overall correlations were noted at the genome-wide level between alcohol and cheese intake and both IBD and Crohn's disease (CD), whereas the association with ulcerative colitis (UC) was of lesser significance. In the local genetic analysis, chromosome 16 emerged as a key region implicated in the relationship between alcohol and cheese intake and IBD (including both CD and UC). The conjFDR analysis confirmed the genetic overlap between the two diseases. Furthermore, both conjFDR and MTAG analyses identified multiple shared genetic loci, with nine genes ( The present study provides genetic evidence supporting the comorbidity of alcohol and cheese intake with IBD, offering novel insights into potential strategies for the prevention and treatment of IBD through the modulation of alcohol and cheese consumption. Show less

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer. Previous studies have highlighted the critical roles of complement and coagulation cascades in tumor development, maintenance, and therapeutic response. However, the overall impact of complement and coagulation cascade-related (CCCR) genes on LUAD progression and their role in the tumor microenvironment (TME) remain insufficiently explored. Therefore, we screened CCCR genes with important roles in LUAD using RNA sequencing data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Subsequently, a prognostic model, based on 8 hub genes (IGFBP1, TUBB, PLEK2, CNTNAP2, CPS1, EREG, CENPE, HBEGF) identified using the Lasso-Cox algorithm, was developed to stratify LUAD patients into high- and low-risk groups. This model demonstrated strong predictive capability and calibration, with an AUC of 0.816 in the external validation cohort. Multiomics clustering revealed that 2 cancer subtypes (CSs) are associated with prognosis, with CS2 demonstrating the most favorable prognostic outcome and validating the validity of the prognostic model. Additionally, we analyzed the immune infiltration, tumor mutation burden (TMB) and immunophenoscore (IPS) of the riskscore in the models. Through this analysis, we have identified for the first time CCCR genes are highly associated with clinical characteristics, immune cell infiltration patterns, and immune therapeutic responses of LUAD. This prognostic model constructed based on CCCR genes represents a valid tool for the prognosis of LUAD patients. Our findings provide valuable insights into the prognostic and immunological relevance of CCCR genes in LUAD, offering a robust foundation for personalized treatment strategies and future research. Show less

Heat stress (HS) severely significantly reduces milk yield and causes substantial economic losses of dairy cows. TMT-based proteomes and an untargeted metabolomics approach were used to conduct the proteomics and metabolomics in heat-stressed (HS, Show less

The potential causal effects of perinatal exposure to polyunsaturated fatty acids (PUFAs) on child neurodevelopment remains controversial. To infer causation, we assessed the association of perinatal PUFA patterns and child neurodevelopment by using conventional regression analyses and 1-sample Mendelian randomization (MR). Among 1096 mother-child pairs from the French Etude des Déterminants Pré- et Postnatals du Développement de la Santé de L'enfant cohort, patterns of perinatal exposure to PUFAs were previously identified combining PUFA levels from maternal and cord erythrocytes, and colostrum. Child verbal, performance, and full-scale intelligence quotients (IQs) were assessed at ages 5-6 y. Among maternal fatty acid desaturase (FADS) variants genotyped, 2 candidates, rs174546 (FADS1) and rs174634 (FADS3), were selected, as instrumental variables, for the MR analysis. The association of PUFA patterns with child IQ was examined by conventional multivariable linear regression and 2-stage least-squares MR regression. In the conventional approach, the first pattern "high omega-3 long-chain PUFAs (LC-PUFAs), low omega-6 LC-PUFAs" was positively associated with verbal IQ [β (95% confidence interval) = 1.24 (0.27, 2.21) points per 1 standard deviation (SD) increase in pattern] and full-scale IQ [1.11 (0.18, 2.05)]. This pattern was independent of FADS variants, rendering MR analysis inapplicable. The third pattern, "colostrum LC-PUFAs," was positively associated with verbal [1.11 (0.19, 2.02)], performance [1.01 (0.09, 1.93)], and full-scale IQ [1.13 (0.25, 2.01)]. The MR approach, based on genetic instruments strongly associated with the third pattern, supported the beneficial effect on performance IQ [2.93 (0.05, 5.81) points per 1 SD increase in genetically predicted pattern]. The MR also suggested a deleterious effect of the fourth pattern "linoleic acid (LA) and dihomo-gamma-linolenic acid (DGLA)" on performance IQ [-1.66 (-3.22, -0.09)]. These findings supported the potential beneficial effects of perinatal exposure to LC-PUFAs on child neurodevelopment while highlighting possible adverse effects associated with exposure to LA and DGLA. Show less

Gut microbiota dysbiosis has been linked to the progression of age-related macular degeneration, though the underlying molecular mechanisms remain unclear. This study is the first to systematically link gutMGene-derived genes to AMD pathogenesis using a multi-algorithm machine learning approach. Using the gutMGene database, we identified gut microbiota-related genes and analyzed the GSE29801 dataset for differential expression. Our enrichment analysis revealed unique insights into the involvement of gut microbiota-related genes in inflammatory, immune response, and metabolic pathways in age-related macular degeneration. Machine learning algorithms (LASSO, Random Forest, XGBoost) identified five consistent biomarker genes: CXCL10, FADS3, GHRL, APOE, and VEGFA. A nomogram was developed to predict AMD risk, showing moderate-to-high predictive accuracy with area under the curve of 0.719 (GSE29801) and 0.933 (GSE99248). Gene set variation analysis indicated upregulation of inflammatory and immune pathways and downregulation of lipid metabolism pathways in age-related macular degeneration. Single-gene set enrichment analysis further underscored the roles of diagnostic genes in immune response and metabolic regulation. This study contributes novel evidence that gut microbiota dysbiosis influences AMD progression through systemic inflammatory and metabolic pathways, and highlights potential therapeutic targets. Show less

Hair follicle stem cells (HFSCs) are resident stem cells within hair follicles (HFs) that possess self-renewal and differentiation capacities, serving as a critical model for regenerative medicine research. Their dynamic interaction with dermal papilla cells (DPCs) plays a decisive role in HF development and cycling. Show less

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane glycoprotein that differentially regulates tissue homeostasis and disease pathogenesis. In physiological contexts, it maintains melanosome biogenesis, osteogenesis, and neuroprotection through domain-specific interactions. Pathologically, tumors exploit GPNMB's dual mechanisms: membrane-bound isoforms mediate T cell exclusion via DC-HIL/Syndecan-4, while soluble GPNMB(sGPNMB) promote metabolic reprogramming through CD44/NF-κB. Clinically, GPNMB overexpression correlates with poor outcomes, notably demonstrating 40% versus 8% ADC response in high- versus low-expressing TNBC (p < 0.001). Emerging data reveal its crosstalk with HER2/FGFR1 pathways and identify K48-ubiquitination as a therapeutic resistance mechanism. These findings position domain-selective GPNMB targeting as a promising precision oncology strategy. Show less

The limited response rate to immune checkpoint inhibitors (ICIs) remains a significant challenge in the treatment of lung adenocarcinoma (LUAD). In our study, we identified a lactate-based chemical barrier surrounding FAP Show less

Triple-negative breast cancer (TNBC) is a highly aggressive subtype with a poor prognosis and lacks effective targeted therapies. Six-transmembrane epithelial antigen of prostate 3(STEAP3) is specifically overexpressed in TNBC, but its precise role and molecular mechanisms remain unclear. Here, we show that STEAP3 is positively correlated with proliferation markers in TNBC, but not in non-TNBC. Further assays revealed that STEAP3 significantly enhances TNBC cell proliferation, invasion, and metastasis Show less

SANET-ep (NCT02588170) and SANET-p (NCT02589821) demonstrated the efficacy and safety of surufatinib versus placebo in patients with advanced extra-pancreatic and pancreatic neuroendocrine tumours (NETs). Here, we present a pooled analysis of final overall survival (OS) from two randomised phase 3 studies. The SANET studies were randomised, placebo-controlled, double-blind, phase 3 studies in China, comparing the efficacy and safety of oral 300-mg surufatinib (n = 265) versus placebo (n = 133) in patients with unresectable/metastatic, well-differentiated NETs (grade 1/2). After progression of disease or study unblinding, patients receiving placebo crossed over/switched to open-label surufatinib. By pooling the data from the two studies, OS analysis was completed using Kaplan-Meier methodology and a Cox proportional hazards model in the intention-to-treat population. Exploratory analyses were performed using different models to correct the confounding effect introduced by crossover. Long-term safety was assessed. At study termination, 69 % of the placebo group had crossed over/switched to surufatinib. Median OS was 50.1 versus 46.8 months for patients initially on surufatinib versus those initially on placebo (stratified hazard ratio [HR] 0.935, 95 % confidence interval [CI] 0.684-1.278; p = 0.6727). After correcting the confounding effect introduced by crossover/switching, the HR ranged from 0.558 to 0.825. Commonly (≥10 %) reported treatment-related adverse events (grade 3/4) included hypertension and proteinuria. OS of patients initially on surufatinib was not significantly longer versus patients initially on placebo, likely due to the high amount of crossover from placebo to surufatinib. No new safety signals were observed. SANET-ep (NCT02588170) and SANET-p (NCT02589821). Show less

Lipolysis in white adipose tissue (WAT) provides fatty acids as energy substrates for thermogenesis to increase energy expenditure. Syndecan-4 (Sdc4) is a transmembrane proteoglycan bearing heparan sulfate chains. Although single nucleotide polymorphisms (SNPs) of the Sdc4 gene have been identified linking to metabolic syndromes, its specific function in adipose tissue remains obscure. Here, we show that Sdc4 serves as a regulator of lipid metabolism and adaptive thermogenesis. Sdc4 expression and shedding are elevated in the white adipose tissue (WAT) of diet-induced obese mice. Adipocyte-specific deletion of Sdc4 promotes lipolysis and WAT browning, thereby raising whole-body energy expenditure to protect against diet-induced obesity. Mechanistically, fibroblast growth factor 2 (FGF2) is a paracrine factor that maintains energy homeostasis. Elevated shed Sdc4 concentrates and delivers FGF2 to fibroblast growth factor receptor 1 (FGFR1) on adipocytes, which in turn suppresses lipolysis by reducing hormone-sensitive lipase (HSL) activity, thus exaggerating adipose tissue dysfunction upon high-fat diet induction. Sdc4-deficient adipocytes show higher lipolytic and thermogenic capacity by enhancing HSL phosphorylation and UCP1 expression. Overall, our study reveals that adipocyte-derived shed Sdc4 is a novel suppressor of lipolysis, contributing to decreased energy expenditure, thus exaggerating obesity. Targeting shed Sdc4 is a potential therapeutic strategy for obesity. Show less

Deep brain stimulation (DBS) has emerged as a prospective treatment for psychiatric disorders; for example, DBS targeting the nucleus accumbens (NAc) abolishes addictive behaviors. However, neither the core pathway nor the cellular mechanisms underlying these therapeutic effects are known. Here, morphine-induced conditioned place preference (CPP) in mice as an addiction model and NAc-DBS combined with adeno-associated virus gene delivery for activity-dependent tagging, transgenic and chemogenetic manipulation of recruited neuronal networks are used. It is reported that a cortical-accumbal pathway and local fibroblast growth factor 1 (FGF1) signaling in the medial prefrontal cortex (mPFC) are critical for NAc-DBS to be effective in altering morphine CPP. It is shown that NAc-DBS retrogradely activates mPFC neurons projecting to the NAc, and chemogenetic activation/inhibition of these DBS-activated neuron ensembles in the mPFC reproduces the NAc-DBS effects on CPP. Sustained therapeutic effects accompany reductions in local FGF1 binding to fibroblast growth factor receptor 1 (FGFR1) in these neurons. Additionally, overexpressing FGF1 in the mPFC-NAc pathway abolishes the therapeutic effects of NAc-DBS. These results demonstrate that the mPFC-NAc pathway forms a top-down motif to regulate the therapeutic effects of subcortical DBS on addiction. These results support the potential for addiction treatments involving FGF1 signaling and highlight the mPFC as a target for noninvasive brain stimulation. Show less

This study aimed to compare the diagnostic value of [ A prospective study was conducted between March 2023 and July 2023. Patients with high clinical suspicion of lung cancer were recruited. Each participant underwent PET/CT scanning using [ A total of 101 participants were included (mean age 63.267 ± 9.344 [range 39-86 years]). In benign lung lesions, [ [ Show less

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia and insulin resistance, Migraine is a common chronic neurological disease caused by increased excitability of the central nervous system, both exerting substantial health burdens. However, the shared genetic basis and underlying molecular mechanisms remain largely unexplored. This study integrates single-cell data and Mendelian randomization (MR) analysis to identify comorbidity-associated genes and elucidate potential mechanistic links between these two conditions. Single-cell datasets from T2DM and migraine were analyzed to identify differentially expressed genes (DEGs). MR analysis was employed to prioritize key causal genes, followed by network-based functional characterization, disease-drug association analysis, cell annotation, and pseudo-time trajectory modeling. Analysis of single-cell data identified 2,128 migraine-associated and 3,833 T2DM-associated genes, with 714 genes shared between the two diseases. MR analysis highlighted AP4E1 and HSD17B12 as key regulators implicated in both conditions. Network analysis further linked these genes to lipid metabolism and vesicle transport pathways. Computational predictions revealed common comorbidities, including metabolic dysregulation and chemical-induced liver injury, as well as potential therapeutic agents such as valproic acid and bisphenol A. Single-cell annotation identified six major immune cell types in T2DM (T cells, NK cells, B cells, CD14 monocytes, CD16 monocytes, and dendritic cells), with T cells emerging as central players. In migraine, five immune cell types were identified (CD4 T cells, CD8 T cells, B cells, NK cells, and monocytes), with monocytes being the predominant cell type. Pseudo-time analysis delineated seven subpopulations of T cells and four subpopulations of monocytes, suggesting distinct functional trajectories in disease pathogenesis. However, due to the use of peripheral blood-derived single-cell data, genes primarily expressed in the central nervous system, such as CALCA and RAMP1, could not be detected, limiting the identification of certain migraine-specific pathways. This single-cell data and MR analysis investigation identifies AP4E1 and HSD17B12 as pivotal genetic determinants in T2DM-migraine comorbidity, shedding light on their molecular interplay and potential therapeutic relevance. Show less

Regulatory B cells (Bregs) contribute to immune homeostasis via IL-10-dependent and independent pathways. To dissect additional mediators, we investigated splenic derived GM-CSF/IL-15 fusokine (GIFT15)-induced Bregs in experimental autoimmune encephalomyelitis (EAE) using transcriptomics and functional validation. Bulk RNA-seq of splenic Bregs revealed upregulation of Ccl3, GzmB, and Il27 subunits compared to resting B cells. Functional studies showed that CCL3-deficient Bregs failed to suppress disease, whereas GzmB-deficient Bregs retained efficacy, and IL-27 receptor signaling in recipients was dispensable. Flow cytometry demonstrated that CCL3 expression correlated with FoxP3⁺ Treg and Tr1 expansion, along with CD206⁺ macrophage polarization. In the CNS, transient, tissue-dependent increases in oligodendroglial markers O4 and GalC were detected. Collectively, these findings identify CCL3 as a non-redundant effector of Breg-mediated protection, acting primarily through peripheral T-cell and myeloid remodeling, with secondary CNS impacts. These results highlight the translational potential of CCL3-competent, spleen-derived GIFT15 Bregs for therapeutic modulation of autoimmune demyelination. Show less

Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, has emerged as a leading cause of mortality in ICU patients. Macrophages, crucial effector cells in innate immunity, play pivotal regulatory roles in sepsis pathogenesis. While Programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule, is traditionally believed to exert immunosuppressive effects through membrane anchoring, its involvement in macrophage polarization during sepsis remains unclear. This study investigated the spatial distribution of PD-L1 in macrophages and its regulatory effects on inflammatory responses during sepsis. This study investigated PD-L1’s regulatory role in macrophage polarization through RNA sequencing, Immunoprecipitation-mass spectrometry, molecular docking, and site-directed mutagenesis, with preliminary validation in C57BL/6 mice. Using GEO database analysis combined with qRT-PCR and Western blotting, we confirmed elevated PD-L1 expression in sepsis and M1-polarized macrophages. Laser scanning confocal microscopy demonstrated dual localization of PD-L1, appearing both on the plasma membrane and intracellularly within M1 macrophages. RNA sequencing revealed PD-L1’s promotion of M1 polarization through enhanced AIM2 expression in the NOD-like receptor pathway. Integrated analyses employing mass spectrometry, molecular docking, site-directed mutagenesis, and Western blotting demonstrated PD-L1 binding to AIM2, which augmented expression of downstream effector molecules (IL-18 and IFN-γ) and potentiated STAT1 activation. Silencing AIM2 by siRNA or IL-18 antagonism reversed PD-L1-induced M1 markers (IL-27, IL-6, iNOS/NO). PD-L1 was further shown to exacerbate pathological progression in septic mouse models. Our study demonstrated that sepsis-induced PD-L1 overexpression in macrophages exacerbates pathological progression by upregulating AIM2 expression, binding to AIM2 to enhance IL-18 production, which activates STAT1 to drive M1 polarization. The online version contains supplementary material available at 10.1186/s12964-025-02578-1. Show less

Hyperactivation of cutaneous macrophages promotes the development of chronic pain. Stimulation of nociceptive regions promotes neuroplasticity, which affects pain perception and related physiological responses. However, the specific mechanisms by which cutaneous macrophages sense and elicit nociceptive responses are unknown. Here, we exacerbated the reduction of systemic pain threshold after chronic heart failure (CHF) by silencing follistatin-like 1 (FSTL1), especially the abnormal cutaneous nociceptive sensation at PC6 acupoint, the site associated with cardiac involvement pain. The upregulation of P2Y6 and interleukin-27 expression is intimately linked to the activation of skin macrophages. Hyperactivation of P2Y6 receptor (P2Y6R) may be associated with MHC II M1 Show less