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PubMed2026

Single-cell analysis of the human retina reveals stage-linked microglial states and neural-immune circuit rewiring in diabetic retinopathy.

Diabetic retinopathy (DR) is a major cause of vision loss worldwide. Here, we conduct single-cell RNA sequencing of twenty human retina samples (from living and post-mortem donors) across non-diabetic, diabetic, and DR states to create a comprehensive transcriptomic atlas. We identify two stable microglial populations-homeostatic and inflammatory-that exist along a functional continuum, plus a neutrophil cluster within C1QA+ myeloid cells with dynamic transitions occurring throughout disease progression. Module-level analysis reveals divergent transcriptional trajectories: homeostatic microglia maintain energetic programs while selectively upregulating stress elements, whereas inflammatory microglia layer additional pro-inflammatory programs onto preserved biosynthetic foundations. Eleven co-expression modules organize into two major axes: an inflammatory-stress axis, and a regulatory/metabolic-motility axis, with a stable translation module persisting across disease stages. Cell communication analysis further highlights sophisticated neural-immune interactions, particularly between photoreceptors and microglia. Our findings provide insights into the complex cellular dynamics of DR progression and suggest potential therapeutic targets for early intervention.

Humans↗

PubMed2026

Mechanistic analysis of rice caryopsis morphogenesis regulated by exogenous hormones and related precursor substances under blue light conditions.

Rice caryopsis morphogenesis is regulated by light signals and hormonal networks. However, the mechanism by which exogenous hormones and related precursor substances modulate rice caryopsis morphogenesis under blue light remains elusive. In the present study, we aimed to elucidate the molecular mechanisms underlying the regulatory effects of exogenous phytohormones and related precursor substances on caryopsis development at 10 days after pollination (10 DAP) in the japonica rice cultivar 'Chujing 27' under blue light conditions. Results showed that tryptamine treatment increased caryopsis cell volume, thereby significantly driving caryopsis expansion; meanwhile, it markedly enhanced the activities of TDC and TAA, the key rate-limiting enzymes mediating the conversion of tryptophan to auxin, leading to a significant elevation in endogenous auxin content (P < 0.05). In comparison, exogenous auxin treatment significantly boosted carbohydrate accumulation and the activities of associated metabolic enzymes (P < 0.05). Integrated transcriptomic and metabolomic analyses revealed that tryptamine treatment led to significant enrichment of the starch and sucrose metabolic pathway, and drove the coordinated enhancement of carbon metabolic flux and auxin biosynthesis by upregulating key auxin biosynthetic genes (e.g., TAA1) and repressing auxin oxidative degradation. Genes Os04g0531100, Os03g0266100 and Os11g0221200 identified by weighted gene co-expression network analysis (WGCNA) may serve as important candidate targets regulating rice caryopsis morphology and physiological traits under blue light conditions. This study first uncovers the critical function of the "tryptamine-auxin axis" in regulating rice caryopsis development under blue light, laying a theoretical foundation for regulating caryopsis morphogenesis via exogenous hormones and their precursors.

Oryza↗

PubMed2026

A muskrat tissue atlas of small non-coding RNAs and their regulatory roles in muskrat musk secretion.

Muskrat musk, secreted by the male muskrat scent gland during the secretion period, is a valuable natural product with promising pharmacological activities. Its synthesis is regulated not only by coding genes but also by small non-coding RNAs (sncRNAs). However, a comprehensive tissue atlas of sncRNAs in muskrats has been lacking. To address this issue, we systematically profiled the expression levels of 6 sncRNA categories (piRNA [PIWI-interacting RNA], miRNA [microRNA], snoRNA [small nucleolar RNA], snRNA [small nuclear RNA], tRNA [transfer RNA], and other RNAs) across 13 tissues of the muskrat via deep sequencing. We identified 23,957 sncRNAs (∼ 65%) exhibiting tissue-specific expression patterns throughout the body. The results show that miRNA is the main contributor to tissue specificity. Eleven tissues showed a significantly higher number of miRNA-5p arm expressions compared to the 3p arm, although the brain was an exception. Quantitative results imply that miR-477-3p/5p and miR-794-3p are potentially involved in the regulation of muskrat musk synthesis and secretion in the muskrat scent glands. Their target genes were enriched in pathways related to energy supply, lipid metabolism, and cyclic morphological changes of the scent gland. Furthermore, we constructed a set of co-expressed miRNAs based on the hormone-dominated "brain-testis-scent gland" axis and the energy metabolism-dominated "brain-liver-scent gland" axis. These results provide the most comprehensive description to date of tissue-specific and ubiquitous sncRNAs in individual muskrat tissues. We anticipate that these data will enhance the understanding of the molecular regulation underlying muskrat musk synthesis and secretion.

Animals↗

PubMed2026

Single-cell spatial transcriptomic atlas of the mouse adrenal gland reveals sexual dimorphism in steroidogenic enzyme and hormone receptor expression.

The adrenal cortex shows sexual dimorphism in structure and function. We analysed adrenal glands from 7-week-old male and female BALB/c mice using Visium HD with Cellpose 3 segmentation, comprising 236,077 cells across eleven populations, including four cortical zones. Using curated marker-gene-based zonal annotation, we focused on steroidogenic enzymes and hormone receptors, complementing our companion study based on the same primary dataset. The X-zone was nearly absent in males but prominent in females. Females showed higher Hsd3b1 expression across cortical zones and higher Cyp11b1 expression in outer cortical compartments. The strongest sex difference involved Srd5a2, with markedly higher expression in male zona fasciculata (inner: 77.1% vs. 28.9%), independently supported by RNAscope and immunohistochemistry. Mc2r and Mrap showed discordant spatial distributions, with limited co-expression, suggesting potential MC2R-independent MRAP roles. Agtr1a dominated angiotensin II receptor expression in zona glomerulosa without major sex differences, providing a zone-resolved reference for adrenal sexual dimorphism.

Adrenal cortex↗

PubMed2026

A dual-dimensional CRISPR toolkit enables one-step high-efficiency multiplex genome editing in Komagataella phaffii.

Against the backdrop of green biomanufacturing, engineering methanol-utilizing Komagataella phaffii (K. phaffii) represents an effective strategy to expand the one carbon (C1) product profile and speed up the industrialization of C1-based bioeconomy. To address the technical challenges of low efficiency and cumbersome experimental procedures for multiplex gene editing and precise large-fragment integration during the reconstruction of complex metabolic pathways in K. phaffii, this study established a CRISPR toolkit - Efficient Multi-Gene Editing System 3.0 (EMGES 3.0) - which enabled one-step large-fragment integration coupled with multiplex gene knockout. EMGES 3.0 was constructed through the synergistic optimization of a repair-engineered chassis and an episomal CRISPR vector. For chassis engineering, five DNA repair modules: Δlig4 (DNA Ligase IV, non-homologous end joining end ligation), ppMRE11(The endogenous MRE11 gene from Pichia pastoris) overexpression (The Meiotic Recombination 11, DNA double-strand break end resection), Δrad9 (Radiation-Sensitive 9, DNA damage checkpoint regulation), Δmph1 (Mutator Phenotype Helicase 1, improvement of homologous recombinant strand extension), and PapRecT-PaSSB co-expression (stabilization of recombination intermediates) were integrated to generate the highly recombinogenic strain Y09. For vector engineering, cenARS was replaced by panARS and the endogenous promoter PGAP was employed to drive the double hammerhead ribozyme-single guide RNA-hepatitis delta virus ribozyme (double HH-sgRNA-HDV: dHgH)-mediated sgRNA expression, yielding the optimized vector Nov_pGAP_panARS_pLAT1_Cas9. These two features on K. phaffii together enhanced the EMGES 3.0 to a higher standard of transformation rate and editing efficiency. According to our results, EMGES 3.0 achieved dual-functional gene knockout efficiencies between 76.6% and 100%. For insertion of medium-long fragments (>4.5 kb), the efficiency achieved 93.3%. In addition, the one-step integration of ultra-long fragments (>16 kb) achieved 14.8%, which was reported for the first time. Furthermore, the efficiency of simultaneous long-fragment integration at three neutral loci reached 38.4% (>15 kb). We applied the system for one-step production of free fatty acids (FFAs, yield: 5.82 ∼ 7.30 mg/L/OD600) and resveratrol (yield: 1.14 ∼ 1.28 mg/L) using methanol as the sole carbon source. EMGES 3.0 provides a robust technical foundation for complex compounds biosynthesis and high-yield industrial strains, while also advancing K. phaffii as an industrial synthetic biology chassis for efficient C1 utilization.

CRISPR-Cas Systems↗

PubMed2026

THE1 repeats: Ancient endogenous retroviruses rampaging behind sarcoid myopathy.

Transposon-like human element (THE1) repeats are classified as part of the ERVL (endogenous retrovirus-like) -MaLR family and were previously thought to be remnants derived from retroviral infections in the germ cells of ancient primates. At present, at least 60,561 THE1 repeats have been mapped in the human genome, and they are divided into four subfamilies: THE1A, THE1B, THE1C, and THE1D. Although these repeats are largely silenced in somatic cells through multiple mechanisms, some of them are known to influence gene functions and genomic structures, particularly under disease conditions. Recently, we happened to identify the CIR1 driven from THE1B in the individuals with sarcoid myopathy (SM), which is characterized by the non-caseating granulomatous inflammation recognized in skeletal muscles biopsy. Retrotrans-genomics based on the COFFEE method showed that various THE1B fusion transcripts (THE1B/FTs) and retrotransposon-associated genomic dynamics in muscle of SM, including (1) splicing of THE1B to neighborhood exons, (2) expression of THE1B associated long noncoding RNAs in the intergenic regions, (3) ectopic expression of tissue specific transcripts driven by THE1B in SM, and (4) identification of a read through transcript, SIRPB1-SIRPD. Seven of eight THE1B/FTs downregulated by tofacitinib in cutaneous sarcoidosis were confined to the granuloma associated macrophage in sarcoidosis. The remaining transcript, SMFT4 exhibited stronger expression in mesenchymal stem cells. In addition, ectopic co-expression of canonical and LINE1 and THE1A-exonizing IL23R transcripts were identified in SM. This directory of THE1B/FTs in SM may serve as a fundamental molecular basis for understanding the pathogenesis of sarcoidosis.

Journal Article↗

PubMed2026

Integrated bioinformatics analysis reveals cross-talking hub genes and therapeutic agents between sepsis and acute myocardial infarction.

BACKGROUND: Sepsis and acute myocardial infarction (AMI) are two significant diseases that may share overlapping etiological mechanisms. This study aims to systematically identify core genes common to both conditions and to explore their potential as therapeutic targets and drug candidates through an integrative analysis of clinical data and bioinformatics. METHODS: The AMI dataset was obtained from the GEO database, and RNA sequencing data were collected from blood samples of patients with sepsis at our hospital. Common genes were identified using differential expression gene analysis (DEG) and weighted gene co-expression network analysis (WGCNA). Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, were performed. A protein-protein interaction (PPI) network was constructed, and hub genes were identified using the MCC/Degree algorithm. Diagnostic value was assessed via receiver operating characteristic curve analysis. Immune infiltration patterns, single-cell sequencing data, and molecular docking simulations were employed to evaluate immune relevance and identify potential therapeutic compounds. RESULTS: A total of 417 genes were identified between sepsis and AMI, with enrichment analysis revealing significant involvement in inflammatory responses. Three hub genes-JAK2, MYD88, and TIMP1-were selected for further investigation. ROC curves confirmed their strong diagnostic performance for both diseases. Immune infiltration analysis showed that these core genes were significantly correlated with the infiltration levels of various immune cell types. Molecular docking indicated that quercetin exhibited stable binding affinity with the proteins encoded by these genes. qPCR validation further confirmed the upregulation of these three genes, supporting the anti-inflammatory effects of quercetin as a potential targeted therapy. CONCLUSION: JAK2, MYD88, and TIMP1 were identified as shared core genes in sepsis and AMI. These genes not only serve as potential diagnostic biomarkers but also offer novel targets for developing common therapeutic strategies for both conditions. Furthermore, quercetin emerges as a promising candidate for targeted treatment.

Humans↗

PubMed2026

Haplotype-resolved genome of Forsythia suspensa reveals the reticulate evolution in Oleaceae and a novel gene cluster regulating stamen development.

The olive family (Oleaceae) comprises numerous species of economic, horticultural, and medicinal importance. Despite its significance, the evolutionary history of this complex family remains enigmatic. Here, we generated a high-quality haplotype-resolved genome of Forsythia suspensa, a distylous species that occupies a key phylogenetic position in Oleaceae. The 2 haplotypes exhibit significant allelic divergence with potential allele-specific regulation. We reconstructed the polyploidization history of Oleaceae by confirming and precisely dating a shared whole-genome triplication and an independent whole-genome duplication event. We revealed a complex reticulate evolution that gave rise to the tribe Oleeae: an initial hybridization between Forsythieae (♂) and Jasmineae (♀), a subsequent backcrossing event, and a final whole-genome duplication. We identified a novel tandemly duplicated pectin methylesterase inhibitor gene cluster that regulates filament length and pollen size via restricting cell elongation in the long-styled morph. Dosage augmentation via stepwise cluster formation (0.99 to 3.83 Mya) may contribute to maintaining stamen traits of the long-styled morph. These FsPMEIs are co-expressed with many cell wall-related genes, suggesting a functional link in cell wall modification. Our study reveals the reticulate evolution in Oleaceae and a novel gene cluster controlling stamen development in F. suspensa and provides valuable haplotype-resolved genomic resources for heterostylous species, offering novel framework and molecular pathways to understand plant adaptive evolution.

Forsythia↗

PubMed2026

Integrated Multi-Omics Analysis Reveals the Genetic Basis of Phenotypic Variation in Tibetan Sheep.

Body size is a key economic trait influencing the profitability of farmed animals. This study used genome-wide association studies (GWAS) to identify five single nucleotide polymorphisms (SNPs) significantly associated with body size in the Tibetan sheep population, advancing molecular breeding and providing a basis for genomic selection. These SNPs are located within five candidate genes. SNaPshot validated GWAS results, demonstrating significant correlations between candidate SNPs and body size traits in Tibetan sheep. Concurrently, hematoxylin and eosin staining, alongside muscle fiber analysis, confirmed pronounced morphological differences in muscle tissue between sheep of varying conformation. Therefore, transcriptome and proteomics were performed on the longest dorsi muscle from large and small Tibetan sheep of both sexes. The transcriptome, together with weighted gene co-expression network analysis (WGCNA), identified VEPH1 and PRKG1 as core genes regulating body characteristics in Tibetan sheep through their involvement in the PI3K-Akt signaling pathway and pathways related to fat deposition. The integrative analyses demonstrated significantly different expression of CARNS1 and CRYAB at both transcriptional and protein levels between the muscles of large- and small-sized Tibetan sheep of both sexes, suggesting their importance in body size traits by influencing muscle morphology. This study provides valuable genomic resources that advance sheep genetics research.

GWAS↗

PubMed2026

Natural leaf shape variation reveals diverse transcriptional targets of GmJAG1 during soybean leaf development.

The JAGGED transcription factor family regulates lateral organ development across angiosperms. In soybean (Glycine max Merr.), a D9H mutation in the EAR repression motif of GmJAG1 causes a narrow-leaflet phenotype and explains over 70% of phenotypic variance in leaf shape. Because this mutation does not affect the zinc finger DNA-binding domain, both alleles bind identical targets but differ in repressor recruitment. Previous studies mapped GmJAG1 binding sites, but the functional targets controlling leaf morphology are uncharacterized. Here, we used comparative transcriptomics across four soybean genotypes with contrasting leaf shape, spanning a developmental time series from shoot apex to mature leaf, and identified 1567 putative candidate target genes. GmJAG1 expression was confined to the shoot apex, yet 99.1% of candidate targets maintained differential expression throughout development. We found that neither Kip-Related Protein (KRP) cell cycle inhibitors nor Cyclin-Dependent Kinases (CDKs) showed differential expression despite binding evidence in Arabidopsis. However, D-type cyclins were upregulated in narrow-leaf genotypes suggesting that soybean GmJAG1 acts through cyclin-mediated rather than KRP-mediated cell cycle regulation described in Arabidopsis- a divergence in regulatory logic between the two species. Pathway analysis revealed enrichment of auxin (1.8-fold, P = 0.02) and salicylic acid (fourfold, P = 0.016) genes among JAG1D9H targets. Filtering by differential expression, binding data, phenotype correlation, and co-expression network membership identified 79 high-confidence targets, including orthologs of NPH3 (phototropin-mediated leaf flattening), MIK2 (cell wall integrity sensing), RD22 (ABA-responsive stress signaling), and SCL23 (GRAS transcription factor in bundle sheath development). These candidates provide targets for functional validation and breeding in legumes.

Glycine max↗

PubMed2026

Microglial GRB2 is essential for brain ventriculogenesis and CSF homeostasis.

Microglia play essential yet poorly understood roles in brain development, including axon guidance, regulation of neurogenesis, and pruning of neuronal projections. Congenital hydrocephalus (CH), characterized by enlarged cerebrospinal fluid (CSF)-filled ventricles, is a leading cause of pediatric brain surgery, but its molecular mechanisms remain unclear. We have identified what we believe to be novel, recurrent, damaging missense variants in the SH3-binding domain of the adaptor protein Growth Factor Receptor-Bound Protein 2 (GRB2) in unrelated patients with CH. GRB2 is significantly co-expressed with one of its known upstream receptor tyrosine kinase partners, CSF1R, in the developing human brain, particularly in a microglial subtype associated with regulation of neural stem cells. Immunoprecipitation validated GRB2-CSF1R binding in mouse microglial cells and human monocyte cell line. Cx3cr1-Grb2fl/fl mice engineered with conditional deletion of Grb2 in microglia exhibit congenital absence of microglia and early postnatal severe communicating (non-obstructive) hydrocephalus, mimicking GRB2-mutant patients. The severe ventriculomegaly of Cx3cr1-Grb2fl/fl mice is associated with both depletion of cerebral cortical neurons and impairment of glia-lymphatic-mediated CSF flow. Together, these findings implicate a role of GRB2 in microglia that could be essential for brain development and CSF homeostasis.

Genetics↗

PubMed2026

Multi-omics causal inference of childhood asthma triggered by ambient particulate matter.

BACKGROUND: The causal impact of fine particulate matter (PM2.5), an established environmental risk factor, on childhood asthma and its biological mechanisms remain to be elucidated. The objective of the present study was to evaluate the causal association between PM2.5 and childhood asthma and to dissect the mediating role of plasma proteins through a multi-omics integrated Mendelian randomisation (MR) framework. METHODS: Two-sample MR was performed on large-scale genome-wide association data to estimate the causal effect of PM2.5 on childhood asthma. Genes commonly associated with PM2.5 and childhood asthma were screened by transcriptome-wide association study (TWAS) and subjected to enrichment analyses and MR. Mediator proteins were identified by two-step MR. Potential adverse effects were scanned by phenome-wide MR (Phe-MR). RESULTS: MR revealed a significant positive causal effect of PM2.5 on childhood asthma (OR=1.897, 95% CI: 1.063-3.388, p=0.030). TWAS highlighted 70 genes co-expressed in PM2.5 and childhood asthma that were enriched in inflammatory pathways such as lysosome- and leukocyte-mediated immunity. MEAF6 was validated as a protective gene and RNF40 as a risk gene for childhood asthma. Two-step MR identified FUT10 as a positive mediator mediating 19.3% of the causal effect, and CD200 and MANBA as negative mediator proteins. Phe-MR indicated the association of these genes and proteins with multiple other diseases, implying possible adverse effects from therapeutic intervention. CONCLUSION: Long-term PM2.5 exposure is causally linked to childhood asthma with MEAF6, RNF40, CD200, MANBA and FUT10 identified as key molecules. The study provides new evidence for the biological mechanisms linking PM2.5 to childhood asthma.

Journal Article↗

PubMed2026

Hepatic metabolic adaptation to endurance exercise: temporal and sex differences by multiomics integration and validation.

BACKGROUND: Although endurance exercise benefits liver health, sex-specific adaptive trajectories remain unclear. This study mapped dynamic liver adaptation in males and females during prolonged training and identified underlying molecular programs. METHODS: Using publicly available time-resolved liver multi-omics data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we established a computational pipeline for differential analysis of transcriptomic, proteomic, phosphoproteomic, and metabolomic data with FDR correction, followed by FGSEA pathway enrichment. Kinase activities were inferred through ortholog mapping and PhosphoSitePlus. Cross-omics co-expression networks were constructed using WGCNA and topological overlap to link omics features with physiological phenotypes. For experimental validation, liver tissues were collected from endurance-trained Sprague-Dawley rats, and key nodes were confirmed by Western blotting, qRT-PCR, and immunofluorescence/immunohistochemical staining. Public scRNA-seq data were further integrated to map multi-omics signals to single-cell resolution and assess functional changes in specific cell types. RESULTS: The hepatic response to exercise stress was stage-specific, shifting from early transcriptional activation to later proteomic and metabolic remodeling. Multi-omics integration revealed distinct sex-associated adaptive trajectories: males were more strongly associated with energy metabolism, redox-related programs, and amino acid/organic acid catabolism, whereas females showed prominent membrane lipid remodeling, proteostasis -related programs, and mitochondrial/ribosomal translational features. Single-cell analysis showed that tissue remodeling occurred without major lineage turnover, instead involving altered communication among pre-existing cell communities. Validation of PPP1R3G identified a protein-dominant exercise-responsive marker, supporting the contribution of post-transcriptional or protein-level regulation. CONCLUSIONS: Hepatic adaptation to endurance stress follows a cross-omics evolutionary pattern with sex-specific reprogramming of energy supply and homeostatic maintenance. This time-resolved framework clarifies how exercise improves liver function and supports sex-oriented metabolic interventions and therapeutic target discovery.

Animals↗

PubMed2026

A modular γδ TCR-T platform combining KRAS pMHC targeting with re-dosable mRNA engager redirection.

Solid tumors often evade TCR-engineered αβ T cells when antigen expression varies or when the restricting Human Leukocyte Antigen (HLA) allele is lost. γδ T cells, in contrast, detect cellular dysregulation through non-peptide/Major Histocompatibility Complex (MHC) cues, including phosphoantigens and stress ligands, and can be developed as allogeneic therapies. Although intratumoral γδ T cell signatures are associated with improved outcome across cancers, γδ recognition itself is broad and still selected within the thymus just as αβ T cell receptors (TCRs) are. It does not, however, anchor specificity to a defined driver-mutation pMHC epitope. We therefore asked whether a high-affinity, co-receptor-independent αβ TCR could graft oncogenic-driver specificity onto γδ T cells while leaving the endogenous γδ TCR intact. We knocked the KRASG12V/HLA-A*11:01 TCR A11v into primary human γδ T cells. Engineered cells co-expressed the transgenic αβ TCR and the endogenous γδ TCR and lysed KRASG12V/HLA-A*11:01+ tumor cells in vitro and in vivo. To cover potential resistance through loss of HLA-A*11:01, we delivered an mRNA lipid nanoparticle (LNP) encoding a secreted mesothelin×CD3 (M5) bispecific T cell engager (TCE). LNP-M5 produced circulating TCE that redirected γδ A11v T cells and polyclonal bystander T cells to kill mesothelin+ targets, accompanied by development of higher γδ A11v T cell counts in vivo. In humanized mice bearing mixed HLA-A*11:01+ and HLA-A*11:01 - KRASG12V tumors, γδ A11v T cells produced transient control, whereas adding LNP-M5 yielded complete responses and prolonged survival. Thus, this two-part therapy couples invariant driver targeting to tunable redirection and addresses loss of the restricting HLA allele, a central escape route for TCR-based therapy. It provides an off-the-shelf reagent to enable KRAS-anchored treatment with the ability to redeliver the reagent.

Humans↗

PubMed2026

Metabolic-cell-death gene trio predicts survival and cuproptosis sensitivity in colorectal cancer.

BACKGROUND: Metabolic cell death (MCD) modulates colorectal cancer (CRC) progression, yet its prognostic value remains unexplored. We aimed to build an MCD-centred gene signature for outcome prediction and precision therapy. METHODS: Transcriptomes of 1,174 CRC patients were integrated. Weighted gene co-expression network analysis, differential expressions and least absolute shrinkage and selection operator (LASSO) + random survival forest were successively applied to derive a three-gene (CDKN2A/MPC1/AHCY) risk model. Functional, immune-infiltration, drug-sensitivity and genomic analyses were performed, followed by validation in fresh clinical specimens and cell lines. RESULTS: Integrative metabolic-death transcriptomics identified CDKN2A, MPC1 and AHCY as the hub drivers of CRC. Their three-gene signature robustly stratified patients into high- and low-risk subsets [3-year area under the curve (AUC) 0.83-0.85, P<0.001]. High-risk tumors were enriched for extracellular matrix (ECM)-receptor-interaction pathways, displayed abundant myeloid-derived suppressor cell (MDSC) infiltration and were more vulnerable to AZD8186, AZ960 and JAK inhibitors. Guided by these in-silico findings, we functionally confirmed that CDKN2A silencing markedly repressed proliferation, invasion and migration of SW480/HCT116 cells and potentiated cuproptosis via up-regulation of lipoylated DLAT/DLST and CTR1. CONCLUSIONS: We report the first MCD-derived prognostic platform for CRC that simultaneously predicts survival and therapeutic response. Targeting CDKN2A-enhanced cuproptosis represents a promising metabolic-precision strategy for high-risk patients.

Colorectal cancer (CRC)↗

PubMed2026

Gut microbiota-derived metabolites target C5AR1/KDM2A/HCAR3 axis in inflammatory bowel disease: a multi-machine learning algorithms and molecular docking study.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic recurrent disorder. Gut microbiota-derived metabolites regulate intestinal homeostasis, but their molecular mechanisms in IBD remain unclear. Current studies lack systematic "microbiota-metabolite-target" network mining with multi-method validation. This study integrates network pharmacology, three machine learning algorithms, and molecular docking to construct this regulatory network in IBD. METHODS: Transcriptome data were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using limma (p < 0.05, |log2FC| > 0.5). Weighted gene co-expression network analysis (WGCNA) with an optimal soft threshold of β = 7 was performed to identify key module genes. Candidate genes were obtained by intersecting DEGs, gut microbiota-associated genes from the gutMGene database, and WGCNA module genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to explore the functional roles of candidate genes. Core genes were identified using three machine learning algorithms (LASSO, Boruta, and SVM-RFE), followed by protein-protein interaction (PPI) network analysis. Molecular docking was performed to assess the binding affinities between hub proteins and gut microbiota-derived metabolites. RESULTS: A total of 885 DEGs were identified between the IBD and control groups, including 463 upregulated and 422 downregulated genes. WGCNA identified 280 key module genes from the purple and yellow modules. The intersection of DEGs, gut microbiota-associated genes, and WGCNA module genes yielded 19 core candidate genes. PPI network analysis combined with three machine learning algorithms jointly identified C5AR1, KDM2A, and HCAR3 as core hub genes. ROC curve analysis demonstrated that all three hub genes achieved AUC values greater than 0.7 in both the training and validation sets, indicating excellent diagnostic performance for IBD. Enrichment analysis revealed significant associations with the TNF, NF-κB, and IL-17 signaling pathways. Molecular docking confirmed stable binding of C5AR1 with 1,3-Diphenylpropan-2-Ol (-7.87 ± 0.83 kcal·mol-¹) and HCAR3 with 3-Indolepropionic Acid (-6.35 ± 0.70 kcal·mol-¹), both below -5.0 kcal·mol-¹. CONCLUSION: This study first constructs a "gut microbiota-metabolite-hub gene" axis in IBD, providing a computational framework for microbiota-targeted precision therapy, and identifying C5AR1/KDM2A/HCAR3 as computationally predicted diagnostic biomarkers and 1,3-Diphenylpropan-2-Ol/3-Indolepropionic Acid as candidate intervention molecules that warrant further experimental validation.

Molecular Docking Simulation↗

PubMed2026

Genome-wide cis-expression Quantitative Trait Loci (eQTL) and transcriptomic signals reveal distinct molecular regulation across correlated feed efficiency traits.

INTRODUCTION: Feed efficiency (FE) is a complex trait which determines livestock production profitability, yet the molecular mechanisms behind it remain unclear. This study investigated the blood transcriptomic profile of lambs, alongside genotype data with the aim to uncover the genetic basis of FE traits such as absolute dry matter intake (DMIabsolute), DMI adjusted for body size (DMIadjusted), average daily live weight gain (ADG), and residual feed intake (RFI). MATERIALS AND METHODS: Bulk RNA-Seq and genotype data were analysed using three complementary approaches: differential gene expression (DGE) analysis, weighted gene co-expression network analysis (WGCNA), and cis-expression Quantitative Trait Loci (cis-eQTL) mapping. These methods were used independently to identify genes and regulatory networks associated with FE traits and to investigate evidence supporting multi-trait candidate gene selection. RESULTS: DGE analysis revealed 2, 24, 85 and 4 differentially expressed genes for DMIabsolute, DMIadjusted, ADG, and RFI (Padjusted < 0.05), functionally enriched in sensory perception, ATP-dependent chromatin remodeling, Notch signaling and immune response pathways. 9 gene modules significantly associated with the FE traits (P ≤ 0.05) with correlations ranging from r = -0.56 to 0.49, were identified using WGCNA. Single nucleotide polymorphism (SNP)-level cis-eQTL analysis identified 93 eSNPs associated with 74 genes (false discovery rate (FDR) < 0.05), while permutation-derived gene level analysis identified 280 eGenes (FDR < 0.2, empirical P < 0.03). Across the three analyses, applying thresholds of DGE (Padjusted < 0.05), WGCNA (correlation, P ≤ 0.05), and cis-eQTL gene-level significance (empirical P < 0.05), multiple overlapping genes were identified including DNMT3A, KANSL1, NCOR1 for DMIadjusted, ACOX2, FANCF, CIMIP2B, LOC101115106, ARMH2, LOC132657496 for ADG, and LOC114114576 for RFI representing regulators of variations in FE. DISCUSSION: The integration of DGE, WGCNA, and cis-eQTL analyses identified key genes and regulatory mechanisms associated with variation in FE traits. These results highlight that integrated multi-trait candidate gene identification approaches can reveal key genes that lower feed intake while maintaining animal growth, supporting breeding strategies aimed at improving efficiency and long-term economic sustainability in sheep.

average daily gain (ADG)↗

PubMed2026

ZBTB16-associated NK cell alterations reveal shared immunometabolic signatures linking primary Sjögren's syndrome and type 1 diabetes mellitus.

BACKGROUND: Primary Sjögren's syndrome (pSS) and type 1 diabetes mellitus (T1DM) share immune-inflammatory features, yet conserved pathogenic signatures linking these autoimmune disorders remain incompletely understood. The present research sought to uncover common molecular markers and dissect the underlying immune-metabolic cross-talk underlying pSS and T1DM. METHODS: Gene expression profiles of patients with pSS and T1DM were retrieved from the Gene Expression Omnibus database, normalized, and corrected for batch effects prior to downstream analyses. Overlapping potential biomarkers were screened by integrating differential expression analysis, weighted gene co-expression network analysis and least absolute shrinkage and selection operator regression. Functional enrichment based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases was implemented to interpret gene biological properties, and a protein-protein interaction network was further established afterwards. Diagnostic performance was evaluated using receiver operating characteristic analysis. Experimental validation was conducted in non-obese diabetic (NOD) mice using quantitative PCR, immunohistochemistry, and flow cytometry. The CIBERSORT algorithm was adopted to quantify immune cell infiltration levels. RESULTS: ZBTB16 was identified as a shared hub biomarker in both pSS and T1DM and exhibited favorable diagnostic performance. Experimental validation confirmed significantly reduced ZBTB16 expression in peripheral blood mononuclear cells, salivary gland tissues, and pancreatic tissues of NOD mice. Gene Set Enrichment Analysis indicated that ZBTB16-associated signatures were enriched in mitochondrial-related processes, neuroactive ligand-receptor interactions, and ribosome-related pathways. Immune infiltration analysis revealed that resting natural killer (NK) cells were positively correlated with ZBTB16 expression in both diseases. Flow cytometric analysis further confirmed a reduced proportion of resting NK cells in peripheral blood of NOD mice, consistent with the CIBERSORT-based prediction. CONCLUSION: This study identifies ZBTB16 as a shared biomarker linking pSS and T1DM. Reduced resting NK-cell abundance was consistently observed in both computational and experimental analyses, and bioinformatic correlation analysis suggested a positive association with ZBTB16 expression. These findings provide evidence for shared molecular and immunological signatures underlying the two autoimmune disorders and support further investigation of the biological role and diagnostic value of ZBTB16 in pSS and T1DM.

Sjogren's Syndrome↗