SEARCH · PubMed Health

Results for “target validation”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2026

GFPT1 as a cross-ancestry validated target for degenerative spinal disease: genetic association in a Chinese cohort and functional characterization in zebrafish.

Degenerative spinal disease (DSD), including spinal stenosis and spondylosis, lacks effective pharmacological treatment. To identify druggable targets and assess cross-ancestry applicability, we integrate multi-omics analyses using Summary-data-based Mendelian Randomization (SMR), colocalization, and two-sample Mendelian randomization with European whole-blood, peripheral-blood, and CSF eQTL/pQTL datasets, followed by whole-genome sequencing (WGS) validation in a Chinese cohort. We identify 7 genes/proteins associated with spinal stenosis and 5 with spondylosis, with GFPT1, GPX1, and SERPINA1 shared by both. Two-sample MR further supports the causal associations of these targets with DSD. Phenome-wide MR prioritization selects GFPT1 and GPX1 as favorable candidates with no predicted adverse effects and potential beneficial effects on hypertension. In the Chinese cohort (67 lumbar spinal stenosis patients and 100 controls), WGS identifies 4 GFPT1 cis-eQTL loci (rs13016371, rs35392088, rs12997521, and rs13019789) associated with lumbar spinal stenosis risk; all risk alleles are linked to increased GFPT1 expression, and all 24 variant carriers show L4/L5 stenosis on imaging. Druggability analysis identifies IOX1 as the sole preclinical-stage compound targeting GFPT1, and molecular docking supports robust binding to GFPT1 (- 6.39 kcal/mol). Functional assays show that IOX1 directly inhibits GFPT1 enzymatic activity and induces fructose-6-phosphate accumulation. In zebrafish, IOX1 significantly rescues GFPT1-induced degenerative phenotypes. These findings establish GFPT1 as a cross-ancestry validated therapeutic target for DSD and nominate IOX1 as a promising disease-modifying candidate.

Animals↗

PubMed2026

Prospective clinical validation of targeted long-read sequencing for preimplantation genetic testing of α-thalassaemia.

BACKGROUND: Preimplantation genetic testing for monogenic disorders (PGT-M) can prevent transmission of severe α-thalassaemia, but conventional workflows remain limited by family-specific assay design for direct variant detection, dependence on additional family samples for haplotype construction, and labour-intensive multi-step procedures across several platforms. Targeted long-read sequencing-based PGT-M for α-thalassaemia (tlrPGT-α-thal) integrates direct variant detection and haplotype linkage analysis within a single assay, but prospective clinical validation is lacking. METHODS: This prospective clinical study enrolled 103 families at high risk of transmitting α-thalassaemia at a reproductive medicine centre between August 2024 and March 2025. All families underwent blinded parallel analysis using both conventional NGS-based PGT-M (comparator) and tlrPGT-α-thal. RESULTS: In the primary concordance analysis, tlrPGT-α-thal was fully concordant with conventional NGS-based PGT-M (507/507, 100.0%; exact 95% CI, 99.3-100.0). Direct variant detection was successful in 501/507 embryos (98.82%; 95% CI, 97.4-99.6), haplotype linkage was established in 505/507 embryos (99.61%; 95% CI, 98.6-100.0), and one meiotic recombination event was identified. Among 93 families proceeding to embryo transfer, 57 pregnancies underwent invasive prenatal diagnosis, and all were concordant with the corresponding tlrPGT-α-thal results. Of the 26 comparator-inconclusive embryos, tlrPGT-α-thal resolved 6 complex cases, including cases with incomplete pedigrees or insufficient informative SNPs. Among the remaining 20 embryos with HBA-region aneuploidies, genotype and parental origin could be determined in 12. CONCLUSIONS: The findings show that tlrPGT-α-thal enables direct detection of diverse α-thalassaemia-causing variants together with efficient haplotype linkage analysis within a single workflow, without requiring family-specific assay design or additional family samples. The method demonstrated high diagnostic accuracy while providing added value in complex scenarios. Taken together, tlrPGT-α-thal represents a simplified and broadly applicable strategy for α-thalassaemia PGT-M.

Humans↗

PubMed2024

N-Glycosylation Deficiency in Transgene α7 nAChR and RIC3 Expressing CHO Cells Without NACHO.

The human neuronal nicotinic acetylcholine receptor α7 (nAChR) is an important target implicated in diseases like Alzheimer's or Parkinson's, as well as a validated target for drug discovery. For α7 nAChR model systems, correct folding and ion influx functions are essential. Two chaperones, resistance to inhibitors of cholinesterase 3 (RIC3) and novel nAChR regulator (NACHO), enhance the assembly and function of α7 nAChR. This study investigates the consequence of NACHO absence on α7 nAChR expression and function. Therefore, the sequences of human α7 nAChR and human RIC3 were transduced in Chinese hamster ovary (CHO) cells. Protein expression and function of α7 nAChR were confirmed by Western blot and voltage clamp, respectively. Cellular viability was assessed by cell proliferation and lactate dehydrogenase assays. Intracellular and extracellular expression were determined by in/on-cell Western, compared with another nAChR subtype by novel cluster fluorescence-linked immunosorbent assay, and N-glycosylation efficiency was assessed by glycosylation digest. The transgene CHO cell line showed expected protein expression and function for α7 nAChR and cell viability was barely influenced by overexpression. While intracellular levels of α7 nAChR were as anticipated, plasma membrane insertion was low. The glycosylation digest revealed no appreciable N-glycosylation product. This study demonstrates a stable and functional cell line expressing α7 nAChR, whose protein expression, function, and viability are not affected by the absence of NACHO. The reduced plasma membrane insertion of α7 nAChR, combined with incorrect matured N-glycosylation at the Golgi apparatus, suggests a loss of recognition signal for lectin sorting.

Animals↗

PubMed2025

From genetic causality to druggable targets: A multiomics framework identifies ZSCAN16 in gout pathogenesis.

ObjectiveGout is a prevalent form of inflammatory arthritis in which many patients respond suboptimally to current therapies. Drug development is hampered by a lack of genetically validated targets, leading to high clinical trial attrition. This study aimed to systematically identify and prioritize novel, druggable targets for gout via a multilayered genetic and functional genomics approach.MethodsWe performed two-sample Mendelian randomization (MR) using cis-expression quantitative trait locus (cis-eQTL) data and dual independent gout genome-wide association study (GWAS) cohorts (openGWAS and FinnGen). The candidate genes were subjected to a rigorous validation pipeline including Bayesian colocalization, phenome-wide association studies (PheWASs) to assess pleiotropy and on-target safety, and single-cell RNA sequencing (scRNA-seq) to delineate the cellular context. Molecular docking was used to evaluate the structural druggability of prioritized targets.ResultsMR analysis revealed 15 genes causally associated with gout. Colocalization analysis (PPH4 > 0.8) prioritized two targets: ZSCAN16 (risk-increasing, OR = 1.04, 95% CI [1.02-1.06]) and TRIM10 (protective, OR = 0.96, 95% CI [0.94-0.98]). Crucially, PheWAS revealed that ZSCAN16 is highly specific to gout, whereas TRIM10 exhibited extensive pleiotropy with hematological and cardiometabolic traits, indicating significant safety risks. Single-cell analysis provided orthogonal validation, demonstrating flare-specific upregulation of ZSCAN16 in cytotoxic T/NK cells. Molecular docking confirmed ZSCAN16 as a structurally druggable target, showing high-affinity binding with known compounds (e.g. digoxin, binding energy = -9.6 kcal/mol).ConclusionsOur study identifies ZSCAN16 as a high-potential, druggable therapeutic target for gout, highlighting its genetic influence on specific immune cell activities during acute flares. Conversely, TRIM10 was deprioritized owing to substantial pleiotropic liabilities and poor chemical tractability. These findings suggest that ZSCAN16 could play a crucial role in the pathogenesis of gout and may provide a valuable lead for future drug discovery efforts.

Humans↗

PubMed2026

Mitochondrial Function-Related Genes in Sleep Disorders: A Multi-Omics Mendelian Randomization Study.

Mitochondrial dysfunction is linked to sleep disorders in previous report, but the potential roles of specific genes remain unclear. This study aimed to dissect different subtype-specific genetic associations and their underlying mechanisms. A multi-omics Summary-data-based Mendelian Randomization (SMR) approach was performed to identify potential causal links between mitochondrial function-related genes and sleep disorders. We integrated GWAS data from FinnGen database (the discovery set), independent GWAS datasets (covering different sleep-disorder subtypes and used for validation), and cis-QTLs (including mQTLs, eQTLs, and pQTLs) to perform systematic exploration. Specially, we performed targeted validation of tissue-specific effects, leveraging gene expression data from disease-relevant brain regions within the GTEx database. Our SMR analysis identified mitochondrial function-related genes potentially modulating sleep disorders across biological layers, initially identifying 102 genes at the methylation level, 48 at the gene expression level, and 6 at the protein abundance level. Integrative analysis subsequently prioritized DCXR and ACADVL and revealed their distinct, subtype-specific associations. DCXR exhibited a protective role in sleep apnea while ACADVL showed a paradoxical risk conferring role in daytime sleepiness. In addition, the analysis identified an epigenetic regulatory mechanism for DCXR in which its expression and protein levels are modulated by DNA methylation. Finally, validation in brain-hypothalamus tissue confirmed DCXR as a significant potential protective factor (OR = 0.929, 95% CI: 0.887-0.973, P_HEIDI = 0.999, FDR = 0.2449). Our findings implicate key mitochondrial genes, particularly DCXR and ACADVL, in the pathophysiology of specific sleep disorder subtypes, highlighting potential avenues for precision medicine. Clinical trial number: Not applicable.

Humans↗

PubMed2026

Gravity-driven millifluidic platform for magnetic solid-phase extraction of Enterocytozoon hepatopenaei DNA from complex shrimp hepatopancreas.

Effective detection of Enterocytozoon hepatopenaei (EHP) in aquaculture is currently hindered by the lack of field-deployable extraction methods capable of processing complex, inhibitor-rich hepatopancreatic tissue. This study presents a gravity-driven millifluidic platform for the rapid extraction of EHP genomic DNA using an optimized, surfactant-compatible magnetic solid-phase extraction (MSPE) chemistry. Utilizing 5% PEG 8000 and 2.0 M NaCl, the platform facilitates the selectively capture of DNA from inhibitor-rich crustacean lysates. The 3D-printed device employs a tilting rocking plate to generate passive, gravity-driven flow, maintaining homogeneous magnetic bead suspension and maximizing solid-phase capture efficiency without external pumps. The integrated platform achieved a DNA yield of 2804.33 ± 15.31 ng/μL, a 5.9-fold increase over manual magnetic bead extraction. TaqMan quantitative PCR (qPCR) validation targeting the EHP SSU rRNA gene was developed. Using a standard curve spanning 101 to 107 plasmid copies (Ct = -3.611 log10 [copy] + 42.309, R2 = 0.998, amplification efficiency 89.2%), the on-chip MSPE achieved a validated analytical limit of detection (LOD) of 1 spore per reaction (100% detection rate, n = 21), whereas a commercial CTAB-based DNA extraction kit failed to achieve a validated LOD even at 10 spores (85.7%, 18/21). Nested PCR targeting the SWP gene was employed for field evaluation. A pilot study across two cohorts (N = 40) demonstrated consistent detection of confirmed EPH-positive cases; however, the small sample size precludes definitive diagnostic accuracy claims. With a total processing time under 30 min, this platform provides a high-efficiency extraction module. Future work will couple the device with isothermal amplification (e.g., LAMP or RPA) to realize a sample-to-answer system for resource-limited aquaculture.

Aquaculture diagnostics↗

PubMed2026

Genetic architecture of endometriosis: risk factors, comorbidities and clinical implications.

BACKGROUND: In 1999, Dr Susan Treloar and colleagues conducted a landmark twin study in Australia and reported their estimate of 51% for the heritability of endometriosis. This important result led several groups to begin mapping genetic factors contributing to increased endometriosis risk. Despite early challenges, advances in genome-wide association studies (GWAS) have identified multiple genetic risk factors and some target genes implicated in follow-up studies on genetic regulation of transcription. Access to large publicly available genetic datasets and analysis with endometriosis GWAS results is also providing new opportunities to answer important questions about comorbid conditions associated with endometriosis and their implications for clinical practice. OBJECTIVE AND RATIONALE: The objective of the review is to summarize the last 25 years of genetic studies in endometriosis, outline contributions to our understanding of the disease, and suggest future directions to accelerate biological insights from genetic studies to improve clinical outcomes. SEARCH METHODS: A comprehensive review of scientific literature on the genetics of endometriosis was conducted through searches in PubMed and Google Scholar up to June 2026. Search terms included "endometriosis AND (genetics OR GWAS OR genetic risk factors)", For studies addressing the functional characterization of genetic risk loci, additional searches employed the terms "endometriosis AND (genotype-phenotype associations OR colocalization OR eQTL OR mQTL OR multi omics methods)". To identify studies examining shared genetic risk between endometriosis and comorbid conditions, the search strategy included "endometriosis AND (genetic correlation OR colocalization OR Mendelian randomisation)". Publications reporting discoveries related to genetic risk factors for endometriosis and studies interpreting their biological and clinical significance were critically evaluated, and 144 publications were discussed in the review. OUTCOMES: Discovery of genetic risk factors started slowly and has accelerated in recent years with developments in technology and international collaborations to combine data and increase statistical power. GWAS have mapped 80 genetic risk factors that implicate gene regulation of hormonal targets, development of the reproductive tract, regulation of cell proliferation, and regulation of epithelial cell differentiation. In common with most other complex diseases, effects of individual common genetic risk factors are small. However, several examples demonstrate that small effect sizes are not a good predictor for the impact of drugs developed against genetically validated targets. Genetic risk factors implicate five genes regulating gonadotrophin release and oestrogen action, the major target pathway of current drugs for treatment of endometriosis demonstrating proof-of-principal for biologically meaningful results. Genetic correlation and Mendelian Randomization studies highlight important causal relationships between endometriosis and comorbid conditions including a possible role for testosterone during development and shared genetic risk factors for gynaecological, gastrointestinal, pain, psychiatric, and inflammatory conditions. Understanding causal relationships between endometriosis and related conditions will aid clinical management and more personalized treatments. WIDER IMPLICATIONS: Genetic studies provide novel insights into endometriosis pathogenesis and associations with related comorbid conditions. Genetic factors modifying gene regulation and disease risk likely act in specific cell types, and access to datasets from genetically informed cell-based models, single-cell and spatial omics data are needed to accelerate progress. Future studies should address critical questions of heterogeneity and disease subtypes, expand the search for genetic risk factors to non-European populations, evaluate the role of rare and structural variants, and better integrate data from functional, genomics, genetics, and clinical studies to reduce diagnostic delay, develop novel treatment strategies, and translate discoveries into personalized management strategies for affected individuals. REGISTRATION NUMBER: N/A.

comorbid conditions↗

PubMed2026

Multi-omics identification of therapeutic targets of compound sappan decoction in hepatocellular carcinoma.

BACKGROUND: Compound sappan decoction (CSD) is a multi-herbal traditional Chinese medicine formulation with clinical relevance in hepatocellular carcinoma (HCC). However, its therapeutic mechanisms remain unclear. METHODS: Bioactive compounds of CSD were identified and standardized using pharmacological and chemical databases. Potential targets were predicted via multiple target inference platforms. HCC-related genes were curated from comprehensive disease databases. Summary-data-based Mendelian randomization (SMR) was conducted to infer causal relationships between compound targets and HCC risk using large-scale quantitative trait loci (QTL) datasets and HCC genome-wide association study data. Colocalization analysis, protein-protein interaction (PPI) network construction, and GO/KEGG enrichment were performed on SMR-identified targets. Molecular docking evaluated binding affinities of representative compounds to prioritized targets. RESULTS: A total of 784 overlapping genes between predicted CSD targets and HCC-related genes were subjected to SMR analysis. Among these, 22 targets were significantly associated with HCC risk based on transcriptomic or proteomic QTLs and showed colocalization evidence. Notably, four targets (ADRB2, APOE, SYK, and PGF) were supported by both replication in an independent cohort and strong colocalization. These 22 targets were enriched in apoptosis, PI3K-Akt signaling, redox metabolism, and detoxification pathways. PPI analysis revealed central hubs including MMP9, BCL2, CASP1, and MCL1. Molecular docking demonstrated strong binding of APOE to quercetin, PGF to luteolin-7-olate, and SYK to kaempferol. CONCLUSIONS: CSD may exert therapeutic effects on HCC through modulation of genetically validated targets involved in tumor progression, inflammation, and metabolic reprogramming, supporting its potential clinical utility as an adjunctive treatment strategy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s12672-026-04740-8.

Caesalpinia↗

PubMed2026

Integrated Immunotherapy Target Atlas for Ewing Sarcoma.

BACKGROUND/AIM: Ewing sarcoma is a fusion-driven malignancy with low tumor mutational burden, making recurrent tumor-associated antigens with favorable tumor-to-normal contrast central to immunotherapy development. We converted the Deng et al.-defined 32-gene Ewing Sarcoma Specific Signature (ESS32) into a practical target atlas by integrating tumor RNA expression with normal-tissue context, protein evidence, subcellular localization, and therapeutic accessibility. MATERIALS AND METHODS: A 38-gene set was analyzed, including ESS32 and six comparator antigens (STEAP1, LINGO1, PRAME, CD99, CD276/B7-H3, and ENPP1). Eight Gene Expression Omnibus datasets (n=854 samples) were assigned predefined roles spanning tumor-versus-skeletal-muscle comparison, broad normal-organ context, EWSR1::FLI1 perturbation, tumor-only support cohorts, cell-line models, and cross-sarcoma comparison. Results were overlaid with Human Protein Atlas and published proteomic/surfaceome evidence. RESULTS: In GSE17674, the strongest tumor-enriched transcripts included NKX2-2, NPY1R, STEAP1, RBM11, RNF182, LIPI, CD99, STEAP2, LOXHD1, and DCDC2. Normal-tissue and compartment data substantially reordered RNA-only ranking. NKX2-2 showed the strongest Ewing-associated signal but encodes a nuclear transcription factor, favoring peptide-HLA/T-cell receptor (TCR) or vaccine development. RBM11 and LIPI emerged as high-interest intracellular/secretome-associated candidates, with an explicit epididymal/male reproductive caveat for LIPI. CD99 and NPY1R illustrated normal-cell reservoir and receptor-distribution constraints. CONCLUSION: ESS32 should be interpreted as an EWSR1::FLI1-associated RNA discovery set, not as a pre-validated target panel. Practical nomination requires integration of RNA enrichment, normal-tissue distribution, protein evidence, cellular compartment, and modality compatibility before nomination of TCR, vaccine, antibody-drug conjugate (ADC), chimeric antigen receptor (CAR), radioligand, or validation-first candidates.

Humans↗

PubMed2026

Mendelian randomisation for rheumatology: beyond hype-what it's good for, what it can't do, and how to read it critically.

Mendelian randomisation (MR) has become abundant in the literature, with variation in quality and frequent overinterpretation of causality. This creates a problem for clinical readers, reviewers, and editors: some MR studies can sharpen causal thinking, prioritise drug targets, and challenge misleading observational claims, whereas others are little more than automated exposure-outcome scans with causal claims disproportionate to the evidence. MR can strengthen causal inference when randomised trials are impractical and conventional observational studies are vulnerable to confounding, reverse causation, or selection bias. In rheumatology, credible MR can contribute to questions about disease aetiology, modifiable risk factors, therapeutic target validation, adverse-effect anticipation, and phenotype validation. However, its interpretation depends on whether the exposure is plausibly instrumentable, whether the genetic instruments are biologically defensible, whether assumptions are interrogated in ways appropriate to the design, and whether findings are triangulated with clinical, observational, experimental, and mechanistic evidence. Instead of recapitulating all methodological issues of MR, this review aims to help rheumatologists distinguish robust MR from weak or overinterpreted analyses quickly. We provide an accessible framework for reading and triaging MR studies in rheumatology. Papers that use poorly justified instruments, treat medication use as drug-target evidence, interpret genetic liability as diagnosis, rely on mechanical sensitivity analyses, ignore prior evidence or ask no clinically meaningful question can often be passed over by readers. The goal is not to discourage MR in rheumatology, but to raise the standard; useful MR should clarify causal reasoning rather than simply generate another statistically significant association.

Journal Article↗

PubMed2025

CNV-Finder: Streamlining Copy Number Variation Discovery.

Copy Number Variations (CNVs) play pivotal roles in the etiology of complex diseases and are variable across diverse populations. Understanding the association between CNVs and disease susceptibility is significant in disease genetics research and often requires analysis of large sample sizes. One of the most cost-effective and scalable methods for detecting CNVs is based on normalized signal intensity values, such as Log R Ratio (LRR) and B Allele Frequency (BAF), from Illumina genotyping arrays. In this study, we present CNV-Finder, a novel pipeline integrating deep learning techniques on array data, specifically a Long Short-Term Memory (LSTM) network, to expedite the large-scale identification of CNVs within predefined genomic regions. This facilitates efficient prioritization of samples for time-consuming or costly subsequent analyses such as Multiplex Ligation-dependent Probe Amplification (MLPA), short-read, and long-read whole genome sequencing. We incorporate four genes to establish our methods-Parkin (PRKN), Leucine Rich Repeat And Ig Domain Containing 2 (LINGO2), Microtubule Associated Protein Tau (MAPT), and alpha-Synuclein (SNCA)-which may be relevant to neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Progressive Supranuclear Palsy (PSP), or related disorders such as essential tremor (ET). By training our models on expert-annotated samples and validating them across diverse cohorts, including those from the Global Parkinson's Genetics Program (GP2) and additional dementia-specific databases, we demonstrate the efficacy of CNV-Finder in accurately detecting deletions and duplications. Our pipeline outputs app-compatible files for visualization within CNV-Finder's interactive web application. This interface enables researchers to review predictions and filter displayed samples by model prediction values, LRR range, and variant count in order to explore or confirm results. Our pipeline integrates this human feedback to enhance model performance and reduce false positive rates. Through a series of comprehensive analyses and validations using visual inspection, MLPA, short-read, and long-read sequencing data, we demonstrate the robustness and adaptability of CNV-Finder in identifying CNVs with regions of varied size, probe density, and noise. Our findings highlight the significance of contextual understanding and human expertise in enhancing the precision of CNV identification, particularly in complex genomic regions like 17q21.31. The CNV-Finder pipeline is a scalable, publicly available resource for the scientific community, available on GitHub (https://github.com/GP2code/CNV-Finder; DOI 10.5281/zenodo.14182563). CNV-Finder not only expedites accurate candidate identification but also significantly reduces the manual workload for researchers, enabling future targeted validation and downstream analyses in regions or phenotypes of interest.

Copy Number Variation (CNV)↗

PubMed2026

Mössbauer spectroscopy in drug discovery: revealing Fe- and Fe-S cluster dependent targets.

INTRODUCTION: Iron- and iron-sulfur cluster (Fe-S)-containing proteins are essential for diverse biological processes, including electron transfer, genome maintenance, metabolism, cellular signaling, and host-pathogen interactions. Despite their broad biological importance and growing links to human disease, Fe-S cluster-dependent proteins remain underexplored as therapeutic targets, largely because it is difficult to define their metal-dependent chemistry using conventional biochemical, spectroscopic, and structural approaches. AREAS COVERED: This review examines how Mössbauer spectroscopy can be integrated into workflows for metalloprotein characterization, target validation, and drug discovery. Using representative Fe-S cluster-containing proteins, the practical considerations for implementing Mössbauer spectroscopy are outlined, including 57Fe-enriched expression, sample preparation, and spectroscopic analysis. Two case studies of experimentally challenging viral Fe-S cluster proteins are then highlighted, the Hepatitis B virus X protein and the Porcine Reproductive and Respiratory Syndrome Virus Nsp1α protease, which demonstrate how direct characterization of metal cofactors can reveal previously unrecognized therapeutic avenues. Relevant literature published through March 2026 was identified using PubMed and Google Scholar with keywords related to Mössbauer spectroscopy, iron-sulfur proteins, viral metalloproteins, and drug discovery. EXPERT OPINION: As drug discovery increasingly seeks to exploit metal-dependent biology, Mössbauer spectroscopy will play an important role in identifying cryptic metalloproteins, defining their native states, and uncovering Fe- and Fe-S cluster-dependent targets. Mössbauer spectroscopy can also be complementary, and integrated with structural and AI-driven approaches to answer emerging challenges in medicinal chemistry.

Humans↗

PubMed2026

Proteomics as a theranostic compass in BCR::ABL1-negative myeloproliferative neoplasms: Integrating biomarker discovery with therapeutic stratification.

Classic BCR::ABL1-negative myeloproliferative neoplasms (MPNs)-polycythaemia vera, essential thrombocythaemia, and primary myelofibrosis-are clonal haematopoietic stem cell disorders with marked heterogeneity in clinical phenotype, disease trajectory, and therapeutic response. Genomic stratification by driver and cooperating mutations only partially accounts for this variability, leaving gaps in predicting thrombotic risk, fibrotic progression, leukaemic transformation, and treatment benefit. Proteomics bridges this gap by providing function-proximal readouts of protein abundance, post-translational modifications, pathway activity, and intercellular signalling that genomics and transcriptomics cannot capture, positioning it as a theranostic platform in which the same molecular readouts simultaneously inform diagnostic stratification and therapeutic decision-making. We propose a five-stage translational framework spanning from discovery-scale mass spectrometry and affinity-based plasma profiling to targeted validation, multicentre standardisation, and machine learning-integrated clinical panels. Proteomic evidence is synthesised across the following four disease axes: clonal fitness in haematopoietic stem and progenitor cells; bone marrow microenvironmental remodelling and fibrosis; chronic inflammation and thrombosis; and leukaemic transformation. We further describe how phosphoproteomics reveals resistance mechanisms to JAK inhibitors, including AXL-MAPK bypass and PP2A-autophagy-mediated tolerance, and how protein-level biomarkers (BCL2-BCL-XL, RAS-ERK, CAMK2G, and ROCK1/2) can guide individualised therapeutic selection. Affinity-based platforms (Olink PEA and SomaScan) and spatially resolved technologies (CODEX and single-cell proteomics) complement discovery proteomics. At present, however, this evidence base is constrained by small and heterogeneous cohorts, limited cross-platform reproducibility, and a scarcity of independent external validation for candidate protein panels. Realising this vision will require multicentre standardisation, analytically validated panel assays, and prospective clinical studies that translate molecular findings into decision-grade tools for patients with MPNs.

Humans↗

PubMed2026

Functional chimeric mRNAs encode proteins in mammalian immunity.

Individual mammalian mRNAs and proteins are typically believed to originate from single genomic loci, with isoform diversity arising through cis-splicing of pre-mRNA. Whether mRNA from distant genes can undergo trans-splicing to generate functionally relevant chimeric transcripts has remained unclear. Here we develop a pipeline combining long-read direct RNA sequencing with non-targeted and targeted validation to identify chimeric transcripts in macrophages. Chromatin conformation capture studies reveal that inflammation induces interchromosomal DNA interactions, positioning parent genes proximally to facilitate the formation of chimeric mRNA. Notably, we identify a protein-coding chimeric mRNA representing a fusion between the pore-forming protein gasdermin D (GSDMD)1,2 and a C-terminal domain translated out of frame from Tmem106a (Gsdmd-Tmem106a) in mice. We show that inflammasome priming upregulates Gsdmd-Tmem106a, with the protein localizing to the plasma membrane. After activation of the inflammasome, GSDMD-TMEM106A directly interacts with canonical GSDMD N termini to accelerate and enhance pore formation and IL-1β release. Finally, we show that GSDMD-TMEM106A balances host defence and immunopathology in vivo: its loss protects against lethal sepsis but compromises antibacterial defence, whereas overexpression enhances host protection while increasing sepsis lethality. We establish that protein-coding chimeric mRNAs formed by regulated transcript fusion events are operative during inflammation and immunity.

Journal Article↗

PubMed2013

Enhancing the utility of adeno-associated virus gene transfer through inducible tissue-specific expression.

The ability to regulate both the timing and specificity of gene expression mediated by viral vectors will be important in maximizing its utility. We describe the development of an adeno-associated virus (AAV)-based vector with tissue-specific gene regulation, using the ARGENT dimerizer-inducible system. This two-vector system based on AAV serotype 9 consists of one vector encoding a combination of reporter genes from which expression is directed by a ubiquitous, inducible promoter and a second vector encoding transcription factor domains under the control of either a heart- or liver-specific promoter, which are activated with a small molecule. Administration of the vectors via either systemic or intrapericardial injection demonstrated that the vector system is capable of mediating gene expression that is tissue specific, regulatable, and reproducible over induction cycles. Somatic gene transfer in vivo is being considered in therapeutic applications, although its most substantial value will be in basic applications such as target validation and development of animal models.

Animals↗

PubMed2026

Associations between gut microbiota on carcass traits and meat quality in Neijiang pigs, Yorkshire pigs, and their hybrids.

This study was designed as an exploratory analysis to compare carcass performance, meat quality traits, and gut microbiota of Neijiang pigs (NN), Yorkshire pigs (YY), and Yorkshire × Neijiang hybrid pigs (YN), with the goal of generating testable hypotheses regarding potential links between gut microbial composition and production phenotypes. Compared with NN pigs, YN hybrids exhibited improved carcass performance while inheriting the favorable meat quality characteristics of Neijiang pigs. The results of 16S rRNA sequencing analysis showed that the relative abundance of the microbiota was similar to that of NN pigs. LDA effect size (LEfSe) results showed that Streptococcus, Treponema, probable_genus_10 and Fibrobacter were the differentially enriched taxa in YN pigs (p < 0.05). Correlation analysis was performed on carcass, meat quality and intestinal microbiota screened out by LEfSe. The results showed that Akkermansia tended to positively associate with body length and oblique length in YN pigs; Dialister correlated positively with dressing rate and pH45min; Treponema showed positive trends with a*45min and a*24h (p < 0.05). Finally, the correlation network model preliminarily mapped associations among production traits, gut microbiota, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for exploratory screening. Nine core microbial taxa exhibited close correlations with phenotypic indicators, which implied that these microbes might modulate metabolic pathways to shape pig performance. Overall, hybrids inherited superior parental carcass and meat quality but harbored unique gut microbial communities relative to purebreds-these preliminary correlative observations generate new hypotheses that gut microbiota may contribute to heterosis-associated phenotypic advantages, which require further targeted validation.

Animals↗

PubMed2026

Identification and genetic validation of potential therapeutic targets for pulmonary hypertension through multi-omics causal inference.

Pulmonary hypertension (PH) underscores the urgent need for novel therapeutic targets. This study aimed to employ a proteome-wide Mendelian randomization (MR) approach to systematically identify circulating proteins causally associated with PH, thereby providing genetically validated candidate targets for drug development. We adopted a 2-sample MR design, integrating large-scale plasma proteomic quantitative trait loci (pQTL) data (encompassing 4148 proteins) and summary statistics from a large-scale PH genome-wide association study (2047 cases, 8301 controls). Candidate targets were screened through a multilayered analytical pipeline comprising proteomic MR, transcriptomic MR, and summary-data-based Mendelian randomization. The ultimately identified MR-Identified Causal Candidate Targets (MR-ICTs) underwent rigorous Bayesian colocalization analysis, followed by biological characterization through functional enrichment analysis, single-cell transcriptomics, and phenome-wide association studies. Through robust genetic causal inference, this study provides that circulating proteins such as LYZ, GREM2, NID1, and PF4V1 play causal roles in PH pathogenesis. These findings offer a set of rigorously genetically validated, high-priority therapeutic targets for developing novel PH treatments, specifically addressing key pathological mechanisms such as innate immunity, BMP signaling pathway dysregulation, and platelet activation. Our multi-dimensional analysis ultimately identified 6 MR-ICTs causally associated with PH. Notably, the causal associations for lysozyme C (LYZ), gremlin-2 (GREM2), nidogen-1 (NID1), and platelet factor 4 variant 1 (PF4V1) were stringently validated by Bayesian colocalization analysis (posterior probability for hypothesis 4 [PPH4], indicating a shared causal variant, > 0.99). Functional enrichment analysis revealed significant involvement of these targets in immune response and TGF-β signaling pathways. Single-cell analysis further elucidated their cell-type-specific expression, with LYZ predominantly expressed in monocytes and PF4V1 almost exclusively in platelets.

Hypertension, Pulmonary↗

PubMed2022

Inhibition of RAS-driven signaling and tumorigenesis with a pan-RAS monobody targeting the Switch I/II pocket.

RAS mutants are major therapeutic targets in oncology with few efficacious direct inhibitors available. The identification of a shallow pocket near the Switch II region on RAS has led to the development of small-molecule drugs that target this site and inhibit KRAS(G12C) and KRAS(G12D). To discover other regions on RAS that may be targeted for inhibition, we have employed small synthetic binding proteins termed monobodies that have a strong propensity to bind to functional sites on a target protein. Here, we report a pan-RAS monobody, termed JAM20, that bound to all RAS isoforms with nanomolar affinity and demonstrated limited nucleotide-state specificity. Upon intracellular expression, JAM20 potently inhibited signaling mediated by all RAS isoforms and reduced oncogenic RAS-mediated tumorigenesis in vivo. NMR and mutation analysis determined that JAM20 bound to a pocket between Switch I and II, which is similarly targeted by low-affinity, small-molecule inhibitors, such as BI-2852, whose in vivo efficacy has not been demonstrated. Furthermore, JAM20 directly competed with both the RAF(RBD) and BI-2852. These results provide direct validation of targeting the Switch I/II pocket for inhibiting RAS-driven tumorigenesis. More generally, these results demonstrate the utility of tool biologics as probes for discovering and validating druggable sites on challenging targets.

Biological Products↗