Biomedical subjects

Wei Li

Publications and source records attributed to Wei Li.

At least 19 recordsLinked to original sources

PubMed2026

A wild soybean MADS-box gene GsAGL62 improves seed weight by enhancing cytokinin signaling and cell proliferation.

Soybean seed weight is a key yield determinant, but the transcriptional mechanisms connecting hormone signaling to seed growth are poorly understood. Here, we identify GsAGL62, a wild soybean MADS-box transcription factor located within a previously mapped hundred-seed weight (HSW) locus and a domestication-associated selective sweep. Functional analyses show that overexpression of GsAGL62 in cultivated soybean significantly increases HSW, whereas ethyl methanesulfonate (EMS)-induced gmagl62 mutants reduce it. Integrated transcriptomic and metabolomic analyses reveal that GsAGL62 enhances cytokinin accumulation and signaling cytokinin-associated responses, accompanied by increased expression of genes involved in cell proliferation. Mechanistically, GsAGL62 directly binds to the promoter of the conserved growth inhibitor GmATPK2 and represses its transcription. Consistently, independent EMS-induced gmatpk2 mutants exhibit increased seed weight, supporting GmATPK2 as a downstream negative regulator of seed growth. Population genetic analyses further reveal strong differentiation of GsAGL62 promoter haplotypes during soybean domestication and improvement. These haplotypes show differential promoter activities and are associated with distinct agronomic performance, suggesting that cis-regulatory variation at GsAGL62 contributes to its selection during soybean improvement. Collectively, our findings establish a regulatory module linking GsAGL62 to cytokinin-associated responses, cell proliferation, and seed growth, and highlight GsAGL62 as a potential target for soybean yield improvement.

Cell proliferation↗

PubMed2026

The Wild Soybean C3HC4-Type RING Zinc-Finger Protein ZFP4 Enhances Resistance to Soybean Mosaic Virus.

Soybean [Glycine max (L.) Merr.] is a globally important source of protein and edible oil, but is severely threatened by soybean mosaic virus (SMV). Wild soybean [Glycine soja Sieb. & Zucc.], the wild ancestor of cultivated soybean, exhibits high genetic diversity and strong resistance to pathogens. In this study, we identified a novel SMV resistance locus RSC7-4 and its candidate gene ZFP4 from wild soybean, encoding a C3HC4-type RING zinc-finger protein. The knockout mutants of ZFP4 showed enhanced susceptibility to SMV strains SC7 and SC3, while its overexpressing lines conferred resistance without yield penalty; ZFP4 mediates resistance by inhibiting GSTT1 to increase glutathione and reduce excessive reactive oxygen species accumulation. Domestication analysis revealed reduced genetic diversity of ZFP4 in cultivated soybean, with the resistant ZFP4Hap1 underutilized in breeding. In summary, this study provides not only excellent genetic resources for SMV-resistant soybean breeding but also new insights into the regulatory mechanisms of soybean resistance to SMV.

ZFP4↗

PubMed2026

Integrating GWAS and Transcriptome Analysis Identifies Candidate Genes for Kernel Starch Quality Traits in Maize.

Maize (Zea mays L.) starch quality is a complex trait with significant implications for grain processing and industrial applications. However, the genetic basis underlying starch quality, particularly for gelatinization and thermodynamic properties, remains poorly understood. In this study, we evaluated 12 starch quality traits, including seven gelatinization characteristics, four thermodynamic traits, and kernel starch content (KSC) in a diverse panel of 335 maize inbred lines. Considerable phenotypic variation was observed for all traits. A total of 228 quantitative trait loci (QTLs) were significantly associated with 12 starch quality traits through genome-wide association studies (GWAS). By integrating a dynamic transcriptome analysis of two maize inbred lines with contrasting starch quality, we identified 60 candidate genes. One gene, waxy1, encoding a starch synthase, was found to be associated with enthalpy of gelatinization (ΔHgel) and pasting temperature (Ptemp). Six variants in waxy1 contributed to natural variation in ΔHgel and Ptemp, and a cost-effective InDel and two PARMS-based molecular markers were developed and validated in 144 maize inbred lines, enabling efficient marker-assisted selection. Our findings provide key genes and molecular markers for high-quality maize breeding with improved starch properties.

Zea mays↗

PubMed2026

Precision UV-B irradiation for flavonoid biofortification in indoor-cultivated Morus nigra: Integrated multi-omics and molecular docking insights.

Precision application of UV irradiation represents an effective strategy for improving the quality of functional food crops under controlled environmental conditions. Morus nigra serves as a significant functional food resource in Xinjiang, with its leaves being rich in diverse bioactive compounds with nutritional and health-promoting properties. In this study, a low-dose UV-B treatment regimen was developed to enhance flavonoids in indoor-cultivated M. nigra without growth penalty. Multi-omics revealed a hormone shift (suppressed auxin vs. activated JA signaling). This triggered transcriptional reprogramming of PAL/4CL and CHS/CYP75B1, redirecting carbon flux towards flavonoid biosynthesis. Transient overexpression of MYB, NAC, and TIFY variants validated this regulatory network. The UV-B-induced NAC upregulated key genes and flavonoids, while different TIFY members showed diverse regulatory effects. Molecular docking predicted that the induced flavonoids had hypoglycemic, antioxidant, and anti-browning potential. This study indicates targeted UV-B as a green biofortification strategy for high-value crops in controlled environments.

Flavonoid biosynthesis↗

PubMed2026

Topologically distinct intratumoral heterogeneity scores for predicting high-risk pathological grades in invasive lung adenocarcinoma: A multicenter study across four institutions.

High-risk subtypes of invasive lung adenocarcinoma (IAC), particularly micropapillary- or solid-predominant patterns, are closely associated with poor prognosis. This multicenter retrospective study developed and validated a predictive model for the preoperative identification of these high-risk subtypes using topologically distinct intratumoral heterogeneity (ITH) scores derived from CT images. The study included 1,051 patients with IAC. Two complementary ITH scores were developed: a two-dimensional ITH score, which integrated local radiomics features with global pixel distribution patterns on the largest cross-sectional CT slice, and a three-dimensional ITH score, which extended this quantification across the entire tumor volume. Clinicoradiological features and ITH scores were incorporated as model inputs to construct six base machine learning classifiers and a final stacking ensemble classifier. Model interpretability and robustness were evaluated using SHapley Additive exPlanations (SHAP)-based ablation analyses. An independent dataset from The Cancer Imaging Archive (TCIA) was used for external validation to investigate associations between ITH scores and pathological characteristics, genomic features, recurrence-free survival, and overall survival. The stacking ensemble classifier achieved the best predictive performance, with an area under the receiver operating characteristic curve of 0.875, outperforming models based solely on radiomics features (0.834) or clinicoradiological features (0.792). SHAP analysis identified the 3D ITH score as the most influential contributor to model output, and TCIA validation showed that higher 3D ITH scores were associated with more aggressive tumor biology and poorer survival outcomes. The topologically distinct 3D ITH score may provide a clinically meaningful imaging biomarker for preoperative risk stratification in IAC.

Journal Article↗

PubMed2026

Natural occurrence of a slow lytic pseudomonas phage in a Pediatric case of multidrug-resistant P. aeruginosa severe pneumonia.

Pseudomonas aeruginosa (P. aeruginosa) is widely distributed in the environment. As an opportunistic pathogen, it commonly causes infections in immunocompromised individuals, including respiratory tract infections and burn wound infections. P. aeruginosa possesses multiple antibiotic resistance mechanisms, including efflux pumps, resistance genes, and population dynamics. Phage therapy is a potential approach for addressing drug-resistant P. aeruginosa infections; however, clinical experience and standardized guidelines for its application in severe pneumonia remain limited. A 14-month-old infant was hospitalized for pneumonia. Four days later, he developed acute pneumonia and was sent to the ICU for 38 days of antibiotic therapy; nonetheless, P. aeruginosa remained detectable in the patient's respiratory secretions. During the clinical course, phage zjk6 was detected from a longitudinal P. aeruginosa isolate in the absence of phage therapy. This finding documents the coexistence of a naturally detected phage and MDR P. aeruginosa during prolonged pneumonia, but does not establish that the phage mediated bacterial clearance or clinical recovery. We performed whole-genome sequencing on P. aeruginosa isolates from patients to ascertain if they were infected by the same infection and assessed their antibiotic resistance using drug sensitivity testing. We isolated phages using the drip technique and double-layer plate method, examined their appearance by transmission electron microscopy, and assessed their biological properties through one-step growth curve analysis and lysis spectrum detection. Genome sequencing and comparative genomic analyses were performed to characterize phage zjk6 and representative bacterial isolates and to evaluate phage-host genomic relatedness. P. aeruginosa was isolated repeatedly during 49 days of treatment. Comparative genomic analysis of representative longitudinal isolates revealed multiple strain backgrounds, including distinct ST508 and ST266 lineages and a closely related ST836 lineage. Phage zjk6 was isolated from the fifth clinical isolate, which served as the propagation/reference host. This phage possesses an elongated tail and a limited lysis spectrum, which is capable of gradually lysing the fifth isolated P. aeruginosa strain. Genomic analysis showed that zjk6 formed plaques and displayed slow lytic behavior under the tested conditions, while also carrying lysogeny-associated regulatory modules, indicating temperate potential rather than a strictly lytic lifestyle. A naturally detected slow lytic Pseudomonas phage may coexist with MDR P. aeruginosa during prolonged infection. These findings support further study of phage-bacterium interactions in clinical infections, while the therapeutic significance of zjk6 requires additional validation.

Antibiotic resistance↗

PubMed2026

The association between prenatal PM2.5 constituent exposure and gestational diabetes mellitus: Exploratory analysis of the potential modifying role of thyroid hormones.

The associations of PM2.5 constituents with blood glucose and GDM remain unclear, and the interplay between PM2.5 exposure and thyroid hormone levels in relation to GDM has not been well characterized. This retrospective cohort study included 1314 pregnant women with data collected through multiple methods. A generalized linear model analyzed PM2.5-glucose links, logistic regression assessed pollutant-GDM associations, and stratified analyses explored these relationships at different thyroid hormone levels. In the study population, first-trimester exposure to SO42- and BC correlated positively with FBG, as did PM2.5 and its components in the second trimester. First-trimester SO4²⁻ exposure (OR=1.26, 95% CI: 1.06, 1.51) and second-trimester exposures to PM2.5 (OR=1.67, 95% CI: 1.19, 2.35), NO3⁻ (OR=1.34, 95% CI: 1.06, 1.68), and NH4⁺ (OR=1.33, 95% CI: 1.06, 1.65) were associated with increased GDM risk. Stratified analyses showed that second-trimester BC and OM were positively correlated with FBG in the high-TSH and low-FT4 strata, respectively. In addition, first-trimester exposure to SO42- (high TSH: OR = 1.42, 95% CI: 1.10, 1.84; low FT4: OR = 1.35, 95% CI: 1.05, 1.74) and to PM2.5 (high TSH: OR = 1.93, 95% CI: 1.14, 3.27; low FT4: OR = 1.82, 95% CI: 1.46, 2.25) in the second trimester were associated with higher odds of GDM. These findings show that PM2.5 exposure was associated with glucose dysregulation and GDM in pregnant women differently by trimester and component. Across the separate TSH- and FT4-stratified analyses, women in the high-TSH and low-FT4 strata, respectively, appeared to show greater susceptibility to air pollution-related GDM. These subgroup findings should therefore be interpreted as exploratory and require validation in future studies.

Effect modification↗

PubMed2026

Identification of a novel and a recurrent CDC45 variant in a Chinese family with Meier-Gorlin syndrome 7 and a literature review.

INTRODUCTION: Meier-Gorlin syndrome 7 (MGORS7) is a rare autosomal recessive disorder characterized by primordial dwarfism, craniosynostosis, and patellar aplasia, caused by pathogenic variants of CDC45. Here, we report a Chinese patient presenting with classic hallmarks of MGORS7 alongside atypical clinical features, including hearing and visual impairments. METHODS: Clinical and radiological data were collected. Whole-genome sequencing and Sanger sequencing were performed to identify and validate the causative variants. Their functional effects were investigated using an exon-trapping assay, and a literature review of previously reported MGORS7 cases was conducted. RESULTS: Genetic analysis identified two compound heterozygous CDC45 variants: c.1416C>T (p.H472=) and c.1559+2T>A, which are a recurrent variant in the East Asian population and a novel variant, respectively. Our exon-trapping assay indicated that c.1559+2T>A induced aberrant splicing, generating transcripts predicted to undergo nonsense-mediated mRNA decay. Additionally, growth hormone therapy was initiated in our patient, with a noted improvement in growth parameters in the initial assessment and without immediate complications. The literature review identified a total of 32 CDC45 variants in 29 patients with MGORS7, who showed high heterogeneity in clinical phenotypes. DISCUSSION: Our study further expanded the mutational spectrum of CDC45 and provided a preliminary clinical observation suggesting that growth hormone therapy may be beneficial for growth retardation in patients with MGORS7.

CDC45↗

PubMed2026

Integrative cross-tissue transcriptome-wide association and metabolomic analysis reveals novel genetic risk loci for aortic aneurysm.

BACKGROUND: Aortic aneurysm (AA) is a life-threatening cardiovascular condition with a strong genetic component, however, its molecular mechanisms remain poorly understood. Although genome-wide association studies (GWAS) have identified numerous risk loci, most prior studies have investigated genetic and metabolic factors separately, leaving the causal pathways from genetic variants to disease largely unexplored. METHODS: We established an integrative framework combining cross-tissue transcriptome-wide association studies (TWAS) with metabolomic mediation analysis. First, we integrated GWAS data from FinnGen R12 with multi-tissue expression quantitative trait loci (eQTL) data from Genotype-Tissue Expression Project (GTEx) V8, then performed cross-tissue TWAS using the Unified Test for MOlecular SignaTures (UTMOST) and single-tissue validation with the Functional Summary-based Imputation (FUSION) to prioritize susceptibility genes. Second, we applied Mendelian randomization (MR), colocalization, and Fine-mapping Of CaUsal gene Sets (FOCUS) to assess causality and identify high-confidence genes. Third, we performed metabolite mediation analysis to uncover metabolic pathways linking genetic variants to disease risk. Finally, we validated key findings in mouse models of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) using Quantitative Real-Time Reverse Transcription Polymerase Chain Reaction (RT-qPCR) and Western blotting. RESULTS: We identified multiple novel susceptibility genes for AA and its subtypes. Key genes included ADH family members (ADH1A, ADH1B, ADH4, ADH6) and ZNF827, which showed cross-subtype associations with strong colocalization evidence in vascular tissues. Metabolite mediation analysis revealed significant pathways involving N-acetylphenylalanine and methionine sulfoxide. Functional enrichment revealed distinct biological mechanisms: AA and AAA were primarily associated with metabolic pathways, whereas TAA-related genes were enriched in developmental and contractile processes. PheWAS indicated no significant off-target associations. Critically, experimental validation in mouse models confirmed significant upregulation of ZNF827 in TAA and ADH6 in AAA at both mRNA and protein levels, corroborating the genetic predictions. CONCLUSION: This integrated cross-omics analysis identifies novel genetic loci and, crucially, uncovers specific nutrient-related metabolic pathways that mediate genetic risk. These findings provide a mechanistic basis for future nutritional and metabolic intervention studies in AA and its subtypes.

MAGMA↗

PubMed2026

Epidemiological Characteristics of Anthrax and Bacillus anthracis Strains - China, 2020-2024.

INTRODUCTION: The incidence of anthrax in China has declined since 1990 but has resurged in recent years. The purpose of this study was to describe the epidemiology of anthrax and Bacillus anthracis (B. anthracis) in China from 2020 to 2024 to inform control strategies. METHODS: A descriptive analysis was performed of case characteristics. B. anthracis strains underwent whole-genome sequencing, and phylogenetic relationships were determined by core-genome single nucleotide polymorphism (cgSNP) and canonical single nucleotide polymorphism (canSNP) analysis. RESULTS: Between 2020 and 2024, 1,870 anthrax cases were reported, with a 0.59% case fatality rate. The majority of cases were cutaneous and the incidence increased from year to year. Cases were distributed across 12 provincial-level administrative divisions (PLADs), with most regions showing an increased incidence between 2021 and 2024. Farmers and herders were the most affected occupational groups, and farmers accounted for an increasing proportion of cases. Cases were primarily concentrated among young and middle-aged men and peaked between July and September. A total of 185 B. anthracis strains were identified in the 12 PLADs and were classified into four sublineages (A.Br.001/002, A.Br.Ames, A.Br.Vollum, and A.Br.005/006). A.Br.001/002 was the most prevalent and widely distributed sublineage. Phylogenetic analysis revealed 14 branches, demonstrating population diversity. Cross-clustering was present among strains from different PLADs. CONCLUSIONS: From 2020 to 2024, anthrax cases generally followed historical patterns but the incidence increased, with broader geographical spread, more diverse clinical types, and interprovincial transmission. These findings highlight the need to strengthen anthrax control efforts, particularly in the central and eastern PLADs.

Anthrax↗

PubMed2026

Genomic and genetic dissection underlying seedling drought resilience in oats.

Drought threatens global crop yields, and common oat, a vital nutritional source for food and feed, is particularly constrained in the semi‑arid regions where it is widely cultivated. Here, we report two high-quality genome assemblies for drought-resilient (Borris37) and drought-sensitive (XymC06) oat accessions with distinct seedling survival rates and genome sizes of 10.92 Gb and 10.96 Gb, and construct comprehensive landscapes of insertion‑deletions (InDels) and structural variants (SVs). Integrating population-level genomic, transcriptomic and phenotypic (seedling survival rate), we demonstrate that InDels and SVs underpin divergent drought resilience and identify 52 candidate genes associated with drought resistance whose expression is significantly modulated by these variants. Borris37 accumulates 36 favorable alleles of these genes. An InDel in the AsNF-YB3 promoter enhances binding to AsARF1, upregulating AsNF‑YB3 under drought, and overexpression of AsNF‑YB3 reduces ROS accumulation. Our findings provide resources and targets for drought‑resistance breeding in oat, thereby supporting global food security.

Drought Resistance↗

PubMed2026

Cytokines and Inflammatory Gene Polymorphisms Associated With Nosocomial Pulmonary Infection After Spontaneous Intracerebral Hemorrhage.

Nosocomial pulmonary infection is a frequent complication after spontaneous intracerebral hemorrhage and may worsen neurological recovery, prolong hospitalization, and increase clinical burden. This retrospective clinical-laboratory study presents a reproducible workflow for evaluating inflammatory biomarker and host immune-genetic profiles associated with nosocomial pulmonary infection after primary spontaneous intracerebral hemorrhage. Patients are classified according to whether nosocomial pulmonary infection occurs after admission. Peripheral venous blood is collected in the early post-admission period under standardized pre-analytical conditions. Serum is separated, aliquoted, and stored for enzyme-linked immunosorbent assay measurement of IL-1β, IL-6, IL-10, IL-17, IFN-γ, TNF-α, TLR2, TLR4, and TLR9. In parallel, genomic DNA is extracted from anticoagulated whole blood and used for polymerase chain reaction-restriction fragment length polymorphism genotyping of selected cytokine- and Toll-like receptor-related loci. The workflow also includes quality-control procedures for sample handling, duplicate ELISA measurements, DNA purity assessment, genotype calling, and repeat genotyping. Statistical analysis includes between-group comparison of clinical characteristics and biomarker levels, Hardy-Weinberg equilibrium testing, logistic regression analysis for genotype and allele associations, adjustment for relevant clinical covariates, and false-discovery-rate correction for multiple genetic comparisons. This combined clinical, inflammatory, and immune-genetic workflow may help characterize infection-risk profiles after spontaneous intracerebral hemorrhage, although prospective multicenter validation is still required before routine clinical application.

Humans↗

PubMed2026

Genome-wide analysis of the plant-specific PLATZ gene family in Taraxacum kok-saghyz and its roles in response to drought and salt tolerance.

Abiotic stress severely limits plant growth and productivity. Taraxacum kok-saghyz Rodin (TKS), known for its environmental resilience, represents a valuable resource for identifying stress-tolerant genes to improve stress-adaptive crops. Plant AT-rich protein and zinc-binding protein (PLATZ) transcription factors serve as core regulators of plant growth, developmental processes, and adaptive responses to various stress conditions; however, they remain uncharacterized in TKS. Here, we identified 10 TksPLATZ genes through a whole-genome analysis. Phylogenetically, these genes were grouped into five distinct evolutionary branches. Promoter sequence analysis revealed multiple types of cis-acting regulatory elements that are connected with hormonal signal responses and environmental stress adaptation. Integrated analysis of transcriptome datasets and RT-qPCR validation demonstrated that TksPLATZ genes display tissue-specific expression profiles and show distinct responsive patterns to drought and salt stress treatments. Among them, TksPLATZ1, TksPLATZ2 and TksPLATZ7 were markedly induced under both stressors and were selected for further functional study. We demonstrated that TksPLATZ1, TksPLATZ2 and TksPLATZ7 localize to the cell nucleus and act as transcriptional activators and repressors, respectively. Phenotypic data from overexpression experiments in plants confirm that heterologous expression of TksPLATZ1, TksPLATZ2, and TksPLATZ7 enhances the tolerance of Arabidopsis to salt and osmotic stress. These findings provide valuable genetic resources for improving plant tolerance to environmental stresses.

Salt Tolerance↗

PubMed2026

Biosynthesis and heterologous production of the α-agarofuran scaffold of Celangulin V from Celastrus angulatus.

Celangulin V is a widely used biopesticide derived from Celastrus angulatus, and features antifeedant and insecticidal properties as a dihydro-β-agarofuran (DHβAF) sesquiterpenoid. Its biosynthesis remains largely unexplored. Here, we assemble a chromosome-level and haplotype-resolved reference genome of C. angulatus, with each haplotype assembled into 23 pseudochromosomes and achieving scaffold N50 of 14.31 and 14.01 Mb, respectively. This high-quality genome reveals that a recent β whole-genome triplication (β-WGT) event occurred ~34.3 million years ago, and that the expansion of sesquiterpene synthases and cytochrome P450s from the CYP71BE family results from whole-genome duplication (WGD) event and tandem duplication, respectively. We identify CaTPS16 as a γ-eudesmol synthase, and show that CYP71BE416 further catalyzes the γ-eudesmol to tetrahydrofuran ring α-agarofuran for Celangulin V biosynthesis. We further achieve the de novo synthesis of α-agarofuran in Saccharomyces cerevisiae through combined coexpression of these genes. This study has significantly increases the available genomic resources of the Celastraceae family, improves our understanding of the biosynthetic origins and evolution of the tetrahydrofuran ring in DHβAF sesquiterpenoids, and enables its heterologous bioproduction in microbial chassis.

Celastrus↗

PubMed2026

Chinese expert consensus on precision testing and molecular diagnosis of pancreatic cancer (2025).

This consensus by the CSCO Pancreatic Cancer Expert Committee establishes evidence-based guidelines for molecular testing in pancreatic ductal adenocarcinoma. It details recommendations for biomarkers (e.g., KRAS, BRCA, MSI), liquid biopsy, and precision imaging to direct targeted therapies and immunotherapy, aiming to standardize diagnosis and optimize individualized patient care. Pancreatic ductal adenocarcinoma (PDAC) is the most common pathological type of primary pancreatic malignancy, accounting for ~95% of cases and generally referred to as pancreatic cancer [1]. Its prognosis is extremely poor and its incidence continues to rise [2]. According to the most recent global cancer statistics, the incidence of pancreatic cancer ranks 12th among all cancers, and its mortality ranks 6th, making it one of the deadliest malignancies worldwide [3]. Approximately 57% of patients have metastatic disease at diagnosis and require systemic therapy, for which chemotherapy remains the standard first-line option [1]. However, the overall response rate to currently available systemic regimens is low, and the 5-year survival rate for patients with metastatic disease remains below 5% [3]. Although most pancreatic cancers harbor canonical driver mutations, they exhibit marked heterogeneity at the molecular level. Whole-genome sequencing (WGS) and integrative genomic analyses have identified molecular subtypes of PDAC with potential clinical relevance [4-9]. With the increasing implementation of precision oncology, the Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Pancreatic Cancer give a level 1 recommendation to perform genetic and other molecular testing on tissue or cytologic specimens as part of the pathological diagnostic work-up, in order to guide individualized treatment, including targeted therapy and immunotherapy [10]. To further promote the use of genetic and molecular testing in the precision treatment of pancreatic cancer, the CSCO Pancreatic Cancer Expert Committee convened a multidisciplinary panel to develop the present Chinese Expert Consensus on Precision Testing and Molecular Diagnosis of Pancreatic Cancer (2025), aiming to provide clinicians with an authoritative reference for precision diagnostics and treatment decision-making.

Humans↗

PubMed2026

C9orf72-associated poly-GR in skeletal muscle leads to neuromuscular junction deficits and muscle atrophy.

Hexanucleotide repeat expansions in C9orf72 produce dipeptide repeat (DPR) proteins that are widely expressed, including in the nervous system and skeletal muscle. Among these DPRs, arginine-containing proteins, poly-GR and poly-PR, are toxic in the nervous system, but whether DPRs in skeletal muscle contribute to amyotrophic lateral sclerosis (ALS) pathogenesis is unclear. Here, we show that muscle-restricted expression of poly-GR drives motor deficits in mice, including muscle atrophy and neuromuscular junction (NMJ) deficits. Poly-GR in muscle interacted with the NMJ key organizer MuSK and promoted MuSK degradation, disrupting postsynaptic structure and impairing neuromuscular transmission. Importantly, a MuSK agonist antibody (X-17) stabilized NMJs and rescued neuromuscular transmission. Moreover, poly-GR in muscle activated the integrated stress response (ISR), elevating eIF2α phosphorylation and broadly suppressing protein translation. ISR inhibition with ISRIB restored translation and MuSK protein levels and ameliorated both muscle atrophy and NMJ deficits. These findings demonstrate that skeletal muscle actively contributes to C9orf72-ALS pathology. Targeting muscle with ISRIB offers a therapeutic strategy to preserve motor function in C9orf72-ALS.

Animals↗

PubMed2026

Exploring the therapeutic targets and signaling mechanisms of quercetin activity against radiation skin ulcer based on the observational research of network pharmacology.

Radiation skin ulcer is a common adverse complication after radiotherapy. Currently, there is no efficient therapy for this complication. In this study, we searched for the potential pathological targets of radiation skin ulcer and the potential pharmacological targets of quercetin, respectively, and obtained the potential therapeutic targets after intersection. Subsequently, an array of bioinformatics assessments on possible therapeutic targets was conducted, encompassing functional enrichment studies, analysis of protein interaction networks, identification of key targets, and validation through molecular docking. The enrichment analysis of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways shows that the therapeutic effect of quercetin on radiation skin ulcer may be through targeting aging cells. In addition, we identified 5 core targets, including AKT1, EGFR, MAPK3, SRC, and TP53. They are significantly enriched in EGFR tyrosine kinase inhibitors (SRC, AKT1, EGFR, and MAPK3) and epidermal growth factor receptor signaling pathways (SRC, EGFR, and AKT1), indicating the importance of EGFR signaling. Quercetin may have a therapeutic effect on radiation skin ulcer by targeting aging cells. Specifically, it may act through 4 core targets, including AKT1, EGFR, SRC, and TP53.

Quercetin↗

PubMed2026

Targeting the METTL1/m7G axis as a therapeutic strategy in myeloid leukemia.

N7-methylguanosine (m7G), a prevalent modification in transfer RNAs (tRNAs), is primarily catalyzed by the methyltransferase METTL1. Although growing evidence supports a role for METTL1 in various tumors, its therapeutic potential and precise function in leukemia stem cell (LSC) homeostasis remain largely unexplored. Here, we identify METTL1 as a key regulator of LSC self-renewal and homing within bone marrow (BM) microenvironment through catalyzing m7G formation on a specific tRNA, tRNAPheGAA, thereby promoting leukemogenesis. Mechanistically, METTL1 loss significantly reduces m7G abundance and steady-state levels of tRNAPheGAA, leading to translation suppression and degradation of transcripts enriched with tRNAPheGAA-related codons, such as hematopoietic cell kinase (HCK). Decreased HCK expression disrupts CXCR4 signaling, impairing LSC self-renewal and BM homing. Therapeutically, we characterized a small-molecule METTL1 inhibitor (M1i; NSC137443), through high-throughput screening. Pharmacological inhibition of METTL1 demonstrated potent antitumor efficacy by reducing tRNA m7G levels and disrupting the tRNAPheGAA/HCK/CXCR4 cascade. Notably, targeting METTL1 significantly reduces LSC frequency, delays leukemogenesis, and prolongs survival in multiple acute myeloid leukemia models. Together, our findings establish a previously unrecognized role for METTL1 and its target tRNAPheGAA in LSC homeostasis and provide compelling proof-of-concept evidence that METTL1 is a druggable epitranscriptomic target for antileukemia therapy.

Humans↗