Biomedical subjects

Xin Zhang

Publications and source records attributed to Xin Zhang.

12 recordsLinked to original sources

PubMed2026

Multi-omics and spatial transcriptomics reveal that S100A10 drives CD8+ T-cell exhaustion and immune evasion in hepatocellular carcinoma through cPLA2-5-LOX-mediated arachidonic acid metabolism and ferroptosis.

Immune evasion in hepatocellular carcinoma (HCC) represents a major biological barrier limiting the efficacy of immunotherapy, yet its molecular basis remains incompletely understood. Increasing evidence indicates that tumor metabolic reprogramming and ferroptosis-related signaling play critical roles in shaping an immunosuppressive tumor microenvironment (TME); however, the specific regulatory factors involved remain unclear. This study aims to systematically elucidate the functional role of S100 calcium-binding protein A10 (S100A10) in immune evasion in HCC, with a particular focus on the molecular mechanisms by which S100A10 regulates CD8+ T-cell exhaustion through arachidonic acid (AA) metabolism and ferroptosis, as well as its potential therapeutic implications. To this end, data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort are integrated to analyze the expression patterns of S100A10, its prognostic value, and its association with the immune microenvironment. S100A10 overexpression and knockout models are established in HCCLM3 and MHCC97L cell lines, and S100A10-mediated metabolic pathway reprogramming is characterized using transcriptomic profiling, untargeted metabolomics, and ferroptosis-related functional assays. In parallel, single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics are employed to delineate the cell-type specificity and spatial distribution of S100A10. Furthermore, human CD8+ T-cell co-culture systems and orthotopic mouse HCC models are used to evaluate the impact of S100A10 on immune function and responsiveness to anti-programmed cell death protein 1 (anti-PD-1) therapy. The results demonstrate that S100A10 is significantly upregulated in HCC and is closely associated with poor prognosis and an immunosuppressive state. Mechanistically, S100A10 activates cytosolic phospholipase A2-arachidonate 5-lipoxygenase (cPLA2-5-LOX)-mediated AA oxidative metabolism, leading to the accumulation of lipid peroxidation products and ferroptosis-associated signals, thereby driving CD8+ T-cell exhaustion and promoting immune evasion. Significantly, inhibition of S100A10 reshapes the tumor immune microenvironment (TIME) and enhances the therapeutic efficacy of anti-PD-1 treatment. Collectively, these findings identify S100A10 as a critical regulator of metabolic-immune coupling in HCC and provide a theoretical basis for combinatorial strategies targeting metabolism and immunotherapy.

Arachidonic acid metabolism↗

PubMed2026

Transmitochondrial pigs reveal causal effects of mitochondrial DNA on backfat thickness via nuclear epigenetic reprogramming.

Mitochondrial DNA (mtDNA) polymorphisms have been associated with production traits in farm animals, including backfat thickness in pigs, yet direct in vivo evidence establishing a causal link between specific mtDNA haplotypes and fat deposition remains limited. In this study, we generated transmitochondrial pigs (mitopigs) by combining the Dapulian nuclear genome with Wuzhishan mtDNA via somatic cell nuclear transfer, introducing 23 mtDNA mutations relative to controls. Mitopigs exhibited significantly increased backfat thickness at 5 months, a difference that persisted in their offspring, without significant differences in body weight, body size, or litter size. Fibroblasts derived from mitopigs exhibited reduced mtDNA copy numbers, decreased expression of mitochondrial biogenesis genes (PPARA, PPARGC1A, RRM2B, and LRPPRC), impaired mitochondrial respiration, elevated reactive oxygen species (ROS), and upregulated adipogenic transcription factors (CEBPA, CEBPB, and PPARG). Consistent with these fibroblast findings, backfat tissue of mitopigs showed corresponding upregulation of adipogenic transcription factors and downregulation of mitochondrial biogenesis genes. Integrated transcriptomic and whole-genome bisulfite sequencing (WGBS) analyses revealed nuclear transcriptional reprogramming that was closely associated with differential DNA methylation, predominantly affecting mitochondrial function and lipid metabolism pathways. Mitopig fibroblasts also showed a pro-inflammatory response to lipopolysaccharide stimulation, with elevated expression of IL-12, NOS2, RELA, and TNF-α. Our findings provide direct in vivo evidence that mtDNA variants regulate adiposity in pigs through mitochondrial dysfunction, oxidative stress, and nuclear epigenetic modulation, highlighting the potential for incorporating mtDNA haplotype information into pig breeding programs as a complementary strategy to nuclear genomic selection.

Adipogenesis↗

PubMed2026

Rab10 coordinates SADS-CoV non-lytic egress through the ERGIC-TGN-lysosome trafficking pathway.

Swine acute diarrhea syndrome coronavirus (SADS-CoV) is a bat-originated alphacoronavirus that causes devastating enteric disease in neonatal piglets and possesses significant potential for cross-species transmission. While the early stages of the coronavirus life cycle have been extensively characterized, the host factors indispensable for virion assembly and subsequent export remain largely enigmatic. Here, by performing a genome-wide CRISPR-Cas9 knockout screen using a recombinant icSADS-CoV-GFP reporter virus, we identified the small GTPase Rab10 as a critical host dependency factor for SADS-CoV infection. Viral life cycle analysis revealed that Rab10 is not required for viral attachment, entry, or initial genome replication, but is essential for the virion transport and non-lytic egress. Rab10 deficiency markedly reduced the extracellular release of viral RNA, viral proteins, and infectious progeny, as well as the secretion of SADS-CoV virus-like particles. Confocal imaging showed that Rab10 and viral protein-positive intracellular structures were associated with LMAN1, TGN46, and LAMP1 positive compartments. These findings support a model in which Rab10 coordinates a virus-containing vesicles trafficking pathway associated with ERGIC-TGN-lysosome compartments. Mechanistically, Rab10 facilitates the loading of the viral envelope (E) protein into transport vesicles derived from the ERGIC. Rab10 associates with the SADS-CoV E protein, and mapping analyses implicated the C-terminal PDZ-binding motif, particularly residue V75, in efficient Rab10 association and viral release. Collectively, our findings identify Rab10 as a host regulator of SADS-CoV non-lytic egress and highlight the E-Rab10 interaction and the vesicular trafficking machinery as a potential target for developing antiviral strategies.

Animals↗

PubMed2026

Systematic mining and characterization of metal transporter families regulating zinc homeostasis provide insights into metal homeostasis in Camellia sinensis.

BACKGROUND AND AIMS: Zinc is essential for tea plant growth and quality formation, yet its homeostatic mechanisms remain poorly understood. This study identified metal transporter families regulating zinc homeostasis, analyzed their evolution, structure, and expression, and clarified zinc uptake, transport, detoxification networks, and their links to metabolism. METHODS: This study identified zinc homeostasis-related metal transporter families in the tea plant genome, characterized their structural features and expression profiles across tissues and developmental stages through integrative bioinformatics and transcriptomic analyses, and delineated the molecular mechanisms underlying zinc uptake, translocation, and detoxification by systematically integrating published evidence. RESULTS: This study identified 74 metal transporter genes from six families: 13 CsZIPs, 12 CsNRAMPs, 10 CsHMAs, 10 CsYSLs, 14 CsMTPs, and 15 CsCAXs in the 'Shuchazao2' genome, revealing closer affinity to woody species than to Arabidopsis. These proteins exhibit conserved domains, diverse subcellular localizations (cell membrane, vacuole, chloroplast, and Golgi apparatus), and tissue-specific expression with abundant stress/hormone-responsive cis-elements. At the plant-soil interface, tea plants mobilize rhizospheric zinc via proton and organic acid secretion; CsYSLs, CsNRAMPs, and CsZIPs mediate zinc uptake, aided by arbuscular mycorrhizal fungi (AMF) and plant growth-promoting rhizobacteria (PGPR) that expand root absorption zones. Xylem CsHMAs and phloem CsYSLs coordinate root-to-shoot zinc translocation, and vacuolar transporters (CsMTPs, CsCAXs), cell wall immobilization, and antioxidant systems alleviate high-zinc stress injury. CONCLUSIONS: These findings collectively delineate an integrated zinc "acquisition-distribution-buffering" network in tea plants, offering a repertoire of candidate genes with potential utility in zinc biofortification breeding and improving acid soil adaptation. Further experimental validation, including tea transgenesis, zinc-stress qRT-PCR, and heterologous functional complementation, is essential to substantiate their biological roles.

Camellia sinensis↗

PubMed2026

CAGNet: a structure-aware clustering-alternated graph network for cell-cell interaction inference in spatial transcriptomics.

MOTIVATION: Understanding cell-cell interactions (CCIs) in spatial transcriptomics is crucial for uncovering the spatial organization and functional heterogeneity of tissues. However, existing graph-based models typically rely on static clustering or fixed adjacency structures, which limits their ability to capture dynamic cellular relationships. RESULTS: We propose CAGNet, a two-stage framework for CCI inference from spatial transcriptomics data. In Stage 1, a Graph Attention Network encoder with joint feature and graph reconstruction learns structure-aware node embeddings from spatial gene expression profiles. In Stage 2, an alternating optimization mechanism iteratively updates cluster centers via KL-guided soft assignment and refines node embeddings through spatial graph reconstruction, establishing a closed-loop between representation learning and clustering. Experiments on three 10x Genomics Visium datasets demonstrate that CAGNet consistently outperforms six CCI inference baselines across ACC, AUC, AP, Precision, Recall, and F1. CAGNet also achieves the highest Adjusted Rand Index on all three datasets against six spatial domain identification methods, confirming that the learned embeddings capture biologically relevant spatial organization. Information-theoretic analysis further shows that CAGNet retains the highest mutual information between input features and learned embeddings among all compared methods. Ablation studies and 5-fold cross-validation confirm the contribution of each component and the reproducibility of the results. AVAILABILITY: The proposed method is implemented in the CAGNet package available at http://github.com/mahan1233333-maker/CAGNet .

Spatial Transcriptomics↗

PubMed2026

Large-Scale Plasma Proteomics Reveals Preclinical Biomarkers of Incident Severe Liver Disease.

The absence of robust biomarkers for early detection of severe liver disease (SLD) highlights the critical need for high-throughput proteomics-driven discovery. In this prospective cohort study, we aimed to identify plasma protein signatures associated with incident SLD and assess their clinical utility. Using the large-scale Olink Explore 1536 platform, we quantified 1461 plasma proteins in 46951 participants from the UK Biobank community-based cohort without baseline liver disease. Over a median follow-up of 14.1 years, we identified 490 proteins significantly associated with incident SLD risk. Growth differentiation factor 15 (GDF15) emerged as the strongest predictor, achieving a C-index of 0.80 and outperforming conventional clinical indices (LiverRisk score: 0.75; FIB-4: 0.68; APRI: 0.68). Temporal trajectories revealed that GDF15 levels began increasing up to 10 years before diagnosis, with progressive elevation as the diagnosis timepoint approached. Mendelian randomization analysis supported genetic associations linking higher protein levels of GDF15, FABP1, SPON2, CHI3L1, and PIGR with SLD risk. Our large-scale proteome-wide study not only reveals significant proteomic changes preceding SLD diagnosis but also establishes GDF15 as both a promising preclinical biomarker, opening new avenues for early intervention in at-risk individuals.

Humans↗

PubMed2026

Exploring Causal Links Between 91 Circulating Inflammatory Proteins and Hashimoto's Thyroiditis: A Bidirectional Mendelian Randomization Study.

BACKGROUND: Increasing evidence has linked inflammation to Hashimoto's thyroiditis (HT) etiology. However, the causal role of circulating inflammatory proteins in HT remains uncertain. To investigate this, we conducted a bidirectional Mendelian randomization (MR) study. METHODS: Genetic data for 91 inflammatory proteins and HT were sourced from publicly available GWAS databases. The PhenoScanner database was then searched for pleiotropic SNPs associated with potential confounders. Inverse variance weighted (IVW) analysis was used as the primary analysis, simultaneously supplemented by five sensitivity analyses to strengthen the results. RESULTS: The results revealed that, after false discovery rate (FDR) correction, interleukin (IL)-12p40 was causally associated with increased risk of HT (OR [95% CI] = 1.295 [1.172, 1.431], p = 3.66 × 10-7, PFDR = 3.33×10-5). Conversely, none of the inflammatory proteins was a consequence of HT. CONCLUSION: This study suggests that IL-12p40 is probably one of the factors correlated with HT etiology, contributing to a better understanding of the pathogenesis of HT and underscoring the potential for therapeutic interventions targeting inflammatory proteins.

Humans↗

PubMed2025

A deep-sea hydrothermal vent worm detoxifies arsenic and sulfur by intracellular biomineralization of orpiment (As2S3).

The alvinellid worm Paralvinella hessleri is the only animal that colonizes the hottest part of deep-sea hydrothermal vents in the west pacific. We found P. hessleri accumulates exceptionally high level of toxic element arsenic (>1% of wet weight) and tolerated elevated concentrations hydrogen sulphide. Using advanced microscopy, elementary analysis, and genomics and proteomics approaches, we identified a previously unrecognized arsenic-sulfide biomineralization process in P. hessleri. Our data suggest that arsenic accumulates within epithelial cell granules, where it likely reacts with sulphide diffused inward from the hydrothermal vent fluid, resulting in the intracellular formation of orpiment (As₂S₃) minerals. In this "fighting poison with poison" manner, the highly toxic arsenic and sulphide were simultaneously detoxified in the form of orpiment minerals within the intracellular granules of the single layer of epithelial cells. This process represents a remarkable adaptation to extreme chemical environments. Our study provides new insights into understanding animals' environment adaptation mechanisms and the diversity and plasticity of biomineralization.

Animals↗

PubMed2025

Individualized patient tumor organoids faithfully preserve human brain tumor ecosystems and predict patient response to therapy.

Tumor organoids are important tools for cancer research, but current models have drawbacks that limit their applications for predicting response to therapy. Here, we developed a fast, efficient, and complex culture system (IPTO, individualized patient tumor organoid) that accurately recapitulates the cellular and molecular pathology of human brain tumors. Patient-derived tumor explants were cultured in induced pluripotent stem cell (iPSC)-derived cerebral organoids, thus enabling culture of a wide range of human tumors in the central nervous system (CNS), including adult, pediatric, and metastatic brain cancers. Histopathological, genomic, epigenomic, and single-cell RNA sequencing (scRNA-seq) analyses demonstrated that the IPTO model recapitulates cellular heterogeneity and molecular features of original tumors. Crucially, we showed that the IPTO model predicts patient-specific drug responses, including resistance mechanisms, in a prospective patient cohort. Collectively, the IPTO model represents a major breakthrough in preclinical modeling of human cancers, which provides a path toward personalized cancer therapy.

Humans↗

PubMed2025

Analysis of prenatal diagnosis and pregnancy outcomes for rare autosomal trisomies detected by non-invasive prenatal testing in 33,079 cases.

BACKGROUND: Non-invasive prenatal testing is widely used for screening common fetal aneuploidy disorders such as trisomy 21, trisomy 18, and trisomy 13. However, its ability to detect rare autosomal trisomies has introduced a new layer of complexity and clinical uncertainty. METHODS: A retrospective analysis was conducted on the prenatal diagnostic results and pregnancy outcomes of cases identified as high-risk for rare autosomal trisomies through non-invasive prenatal testing at the reproductive medicine center, Renmin hospital, Hubei university of medicine, from 2015 to 2023. RESULTS: 66 cases identified as high-risk for rare autosomeal trisomies, yielding a detection rate of 0.20% (66/33,079). 7 declined amniocentesis, while the others underwent the procedure. Prenatal diagnostic procedures did not confirm the presence of the corresponding rare autosomal trisomy in any of these cases. Among the 66 cases of rare autosomal trisomies (RATs), 5 cases were lost to follow-up, and 1 case underwent termination of pregnancy (TOP) for personal reasons, leaving 60 cases with valid pregnancy outcomes. Of these 60 valid outcomes, 50 (83.33%) resulted in full-term births, while 10 (16.67%) experienced adverse pregnancy outcomes. CONCLUSION: Prenatal diagnosis for high-risk rare autosomal trisomies typically reveals a normal karyotype with no detectable chromosomal abnormalities, and most cases can achieve full-term pregnancy outcomes. However, adverse pregnancy outcomes such as preterm birth, fetal demise, placental abnormalities, and intrauterine growth restriction are common and should be given clinical attention and consideration.

Humans↗

PubMed2025

Association of MTHFD1 G1958A (rs2236225) gene polymorphism with the risk of congenital heart disease: a systematic review and meta-analysis.

BACKGROUND: We did this study to better clarify the correlations of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1)-G1958A (rs2236225) gene polymorphism with the risk of congenital heart diseases (CHD) and its subgroups. METHODS: Relevant articles were searched in PubMed, Web of Science, Cochrane Library, Embase, CNKI, VIP database and Wanfang DATA until October 2023. We will use odds ratios (ORs) and 95% confidence intervals (CIs) to examine the potential associations of MTHFD1- G1958A gene polymorphism with CHD and its subgroups. RESULTS: We included a total of 9 eligible studies, encompassing 1917 children with CHD, 1863 healthy children, 1717 mothers of the children with CHD and 1666 mothers of healthy children. In our study, the meta-analysis of fetal group revealed no significant association between any of the five genetic models for the MTHFD1-G1958A polymorphism and the risk of CHD. Subgroup analysis showed that associations between the MTHFD1-G1958A polymorphism and Tetralogy of Fallot (TOF) risk in the homozygote model (AA vs. GG, OR = 2.82, 95%CI [1.16, 6.86], P = 0.02) and recessive model (AA vs. GG + GA, OR = 3.09, 95%CI [1.36, 7.03], P = 0.007). In addition, the MTHFD1-G1958A polymorphism was associated with the risk of CHD in racial subgroup, increasing the risk of CHD in Caucasians. In maternal analysis, 2 genetic models of MTHFD1-G1958A polymorphism increased the risk of CHD: the heterozygote model (GA vs. GG, OR = 1.22, 95%CI [1.04, 1.42], P = 0.01), and the dominance model (GA + AA vs. GG, OR = 1.17, 95%CI [1.01, 1.34], P = 0.03). CONCLUSIONS: The fetal MTHFD1-G1958A (rs2236225) gene polymorphism increase their risk of TOF. The maternal MTHFD1-G1958A polymorphism has a strong correlation with the risk of CHD, and there are racial differences in this correlation. Compared with GG genotype, the GA genotype increases the risk of CHD.

Humans↗

PubMed2025

Sensitive and Visualized Detection of Hantavirus Using CRISPR/Cas12a Based on AutoCORDSv2 Design.

In recent years, detection technologies based on the CRISPR/Cas12a method have been extensively utilized in the fields of nucleic acid, enzyme, and macromolecule detection, thereby reinforcing their significant role in the detection landscape. Enhancing the simplicity of design, efficiency, and automation of the CRISPR/Cas12a detection system is essential for advancing its application in diagnostics. Recently, we developed an automated CRISPR/Cas12a design system named AutoCORDSv2. This system can process published genomic sequences of pathogenic bacteria in a high-throughput manner and automatically generate conserved and highly specific crRNA sequences, along with primer sequences for target amplification. This capability facilitates the specific and precise design of the CRISPR/Cas12a detection system. In this study, crRNAs targeting the Hantaan virus (HTNV) and Seoul virus (SEOV), as well as RT-PCR primers and RT-RPA primers, were designed using AutoCORDSv2. The experimental results demonstrated that the CRISPR/Cas12a system, automatically designed by AutoCORDSv2, was specific for the detection of both the HTNV and SEOV, with no cross-reactivity observed with other pathogens. The detection sensitivity reached 6 copies/μL (equivalent to 111 copies per amplification reaction), whether measured by a microplate reader or directly observed with the naked eye. The detection results for 50 samples were consistent with those obtained from commercial RT-qPCR kits, indicating high precision. Furthermore, the CRISPR/Cas12a system designed by AutoCORDSv2 can also be utilized for the development of a single-tube detection system with a sensitivity of 42 copies per reaction. This system combined with a 5-min extraction step and RT-RPA, further underscoring its potential for application.

CRISPR-Cas Systems↗