📋 Browse Articles

Recent advances in molecular pathology have transformed the diagnostic landscape and management of human cancer. Increasingly, integration of genomic and epigenomic data with conventional histopathology has improved tumor classification, refined prognostic assessment, and revealed previously unsuspected therapeutic targets. High-throughput techniques such as next-generation sequencing, gene fusion panels, and methylation arrays have expanded applicability to formalin-fixed tissue and enabled simultaneous evaluation of multiple cancer-defining alterations/genetic drivers. In optic nerve gliomas, MAPK pathway activation through BRAF or FGFR1 alterations, or NF1 inactivation, is a basic biological feature with diagnostic implications, while MEK inhibitors may be of clinical benefit in selected patients. Optic nerve sheath/orbital meningiomas demonstrate divergent molecular landscapes depending on location, with NF2-driven and non-NF2-driven pathways informing recurrence risk and behavior. In the orbit, characteristic genetic drivers facilitate diagnosis of mesenchymal tumors such as solitary fibrous tumor (NAB2::STAT6) and alveolar rhabdomyosarcoma (PAX3/7::FOXO1), while molecular profiling assists in distinguishing challenging peripheral nerve and melanocytic lesions. Similarly, lacrimal gland neoplasms parallel salivary gland counterparts, with recurrent fusions such as PLAG1, HMGA2, and MYB::NFIB of great diagnostic utility. These advances underscore the growing role of molecular diagnostics in improving accuracy, guiding prognostication, and refining the classification of rare ocular tumors. As high-throughput techniques continue to mature, integration with evolving spatial and single-cell-based approaches promises to expand our understanding and further personalize diagnostic and therapeutic strategies. Show less

We previously used a myoblast model of fusion-positive rhabdomyosarcoma (FP-RMS) to show that FGF8, a PAX3-FOXO1 (P3F) transcriptional target, is required for P3F-driven tumorigenicity and, when aberrantly expressed, can maintain tumorigenicity in P3F-independent recurrent tumors. We report in this study that FGF8, FGFR1, and FGFR4 are often highly expressed in FP-RMS tumors. High FGF8 expression in FP-RMS cells is associated with high sensitivity to an FGFR4 inhibitor and a pan-FGFR inhibitor. Although downregulating FGF8 resulted in loss of sensitivity to these inhibitors, FGF8 upregulation in myoblasts decreased FGFR4 expression and sensitized the cells to an FGFR1 inhibitor and a pan-FGFR inhibitor. FGF8 downregulation of FGFR4 expression was reverted by inhibitors of FGFR1, MEK, or ERK, thus defining a signaling pathway by which FGF8 mediates this regulatory effect. Finally, high FGF8 expression in P3F-independent recurrent tumors was attributable to a rearrangement of viral long terminal repeat (LTR) sequences into the FGF8 3' untranslated region, resulting in increased FGF8 mRNA stability. These findings indicate that FGF8 exerts oncogenic effects in FP-RMS via FGFR4 and may exert oncogenic effects in P3F-independent relapses via FGFR1. Our study reveals the functional significance of FGF8 in FP-RMS and provides a rationale for preclinical studies of FGFR inhibitors in FP-RMS. Show less

Obesity is a well-established risk factor for asthma pathogenesis. However, the underlying mechanisms remain incompletely understood, and effective therapeutic interventions are currently lacking, making asthma management in obese individuals particularly challenging. Asthma is characterized by chronic airway inflammation, eosinophilic infiltration, and airway hyperresponsiveness (AHR). In this study, we investigated the novel role of fibroblast growth factor 21 (FGF21), a stress-inducible hepatokine with pleiotropic metabolic regulatory functions, in obesity-associated AHR using a diet-induced obesity mouse model (n = 10). Serum samples were collected from obese and lean asthma patients, along with relevant clinical indicators, including body mass index (BMI), forced expiratory volume in 1 second (FEV1%), and the FEV1/forced vital capacity (FVC) ratio, to facilitate the investigation. Moreover, diet-induced obese mice with innate AHR (male, n = 10) were employed to clarify the effects of FGF21 and FGF21-neutralizing antibody on obesity induced AHR. In vitro, LAD2 human mast cells and P815 murine mast cells activated by compound 48/80 were used to elucidate the underlying mechanisms. Our findings demonstrate that serum FGF21 levels exhibit reportedly elevated in participants with obesity and are associated with impaired pulmonary function. In diet-induced obese (DIO) mice, FGF21 levels were increased in both serum and bronchoalveolar lavage fluid (BALF). In vivo investigations demonstrate that administration of recombinant FGF21 exacerbated AHR in DIO mice, whereas FGF21-neutralizing antibody treatment ameliorated obesity-induced AHR and suppressed mast cell infiltration. Mechanistically, FGF21 was found to potentiate mast cell activation through cholesterol biosynthesis modulation. Crucially, pharmacological inhibition of FGFR1 abrogated FGF21-induced mast cell hyperactivity and cholesterol synthesis, indicating FGFR1-dependent signaling in this process. These findings may represent the FGF21/FGFR1 axis as a potential therapeutic target for obesity-related AHR and asthma. Show less

This review examines the rapidly evolving landscape of myeloproliferative hypereosinophilic syndromes (HES) and related neoplasms. We aim to synthesize current understanding of their diverse molecular drivers, evaluate the efficacy of established and novel targeted therapies, and identify critical research gaps. The goal is to provide a clinically relevant update on how molecular precision is reshaping the diagnosis and management of these rare, often aggressive hematologic malignancies beyond the established standard of imatinib. The field has moved beyond generic HES diagnoses to a molecularly defined classification. While imatinib remains the standard for The management of myeloproliferative HES has transitioned from empirical therapy to a precision medicine paradigm. Early comprehensive molecular profiling is essential to guide therapy selection. While imatinib remains a cornerstone for select patients, novel agents like pemigatinib and avapritinib have filled critical therapeutic gaps. Future progress depends on the routine integration of comprehensive next-generation sequencing, the validation of minimal residual disease monitoring to guide therapy de-escalation, and international collaboration to conduct innovative trials for these rare patient populations. Show less

Myelin debris accumulation after spinal cord injury (SCI) drives persistent neuroinflammation, lysosomal dysfunction, and lipid overload in macrophages, ultimately impairing tissue repair. Here, we identify fibroblast growth factor 4 (FGF4) as a previously unrecognized regulator of macrophage-mediated myelin debris clearance. Endogenous FGF4 transiently increased in the early phase of SCI but rapidly declined. Using in vitro models, we demonstrate that exogenous FGF4 markedly enhances myelin debris phagocytosis through activation of the FGFR1-PI3K/AKT signaling pathway, leading to upregulation of Clec10a, a C-type lectin receptor not previously linked to myelin debris processing. Silencing Clec10a significantly mitigated the phagocytic and neuroprotective benefits of FGF4, supporting Clec10a as an important mediator of this response. D-GalNAc competitive inhibition assays showed that Clec10a does not rely on the conserved carbohydrate-recognition domain to bind to myelin debris. FGF4 enhanced the maturation and degradative efficiency of the endolysosomal system, driving internalized myelin debris through Rab5 The online version contains supplementary material available at 10.1186/s12974-026-03743-0. Show less

Sickle cell disease (SCD) is characterized by osteopenia and impaired bone mineralization, but the underlying mechanisms remain unclear. Fibroblast growth factor 23 (FGF23), elevated in SCD, regulates phosphate metabolism through FGFRs/klotho and contributes to bone loss. Although FGF23's systemic effects are known, its local actions in SCD bone remain poorly defined. Using bone marrow stromal cells (BMSCs) derived from SCD mice, we previously reported that enhanced local FGF23/FGFR1 signaling and increased osteopontin impair osteoblast mineralization, which is rescued by an FGF23-neutralizing antibody (FGF23Ab). Here, we further investigated downstream signaling and pyrophosphate/phosphate (PPi/Pi)-regulatory mechanisms contributing to mineralization defects. FGF23Ab reduced phospho-FGFR1, restored phospho-FGFR2 and phospho-AKT, and decreased pSTAT3 activation. SCD-BMSCs exhibited increased matrix inhibitors, matrix Gla protein (MGP) and matrix extracellular phosphoglycoprotein (MEPE), and reduced mineralization promoters PHEX and DMP1, which were partially normalized by FGF23Ab. FGF23Ab also corrected elevated PPi-generating enzymes ENPP1 and ANK and restored tissue-nonspecific alkaline phosphatase (TNAP). In contrast, the phosphate importer PiT2 was significantly reduced in SCD BMSCs and was further suppressed with FGF23Ab. These findings indicate that excessive local FGF23 signaling disrupts mineralization by upregulating matrix inhibitors and altering PPi/Pi-regulatory pathways. FGF23 neutralization partially restores mineralization capacity. Show less

Testicular adult granulosa cell tumors (AGCTs) are rare and show several clinical, pathological, and molecular differences with their ovarian counterparts. FOXL2 p.Cys134Trp, the ubiquitous molecular driver of ovarian AGCTs, is infrequent (~ 7%) in testicular AGCTs. Recently, FGFR1 hotspot mutations were reported as a potentially "alternative molecular driver" in FOXL2-wild type (WT) ovarian AGCTs. A systematic assessment of FGFR1 status has not been performed in testicular AGCTs. Recently, our group analyzed a series of twenty testicular AGCTs using two NGS panels that lacked coverage of FGFR1. Among twelve cases analyzed successfully, none harbored pathogenic FOXL2 variants. In this study, we reassessed the tumors from our prior series with an NGS panel that covers FGFR1. Among the 14 tumors (70%) that were sequenced successfully, none harbored pathogenic FGFR1 variants. Considering the AGCTs assessed in this study and those previously reported in the literature, none of the 24 tumors analyzed to date have shown pathogenic FGFR1 variants. The present study reinforces the concept that testicular sex cord-stromal tumors classified as AGCTs are different from ovarian counterparts. Show less

Endometriosis is a heterogeneous chronic inflammatory disorder associated with substantial diagnostic delay and limited therapeutic options, highlighting the need of robust non-invasive biomarkers and actionable molecular targets to complement existing low-sensitivity tests. To identify conserved pathogenic mechanisms with translational potential, here, we uniformly reprocessed three independent the Gene Expression Omnibus (GEO) microarray cohorts (GSE7305, GSE25628, and GSE11691) and applied a strict, directionally consistent intersection strategy to identify conserved transcriptional signals. We identified 262 consensus differentially expressed genes enriched for immunity/inflammation, cell adhesion and migration, and angiogenesis, consistent with key biological hallmarks of lesion establishment and persistence. Protein-protein interaction topology prioritized 11 highly connected hub genes ( Show less

What is the clinical and genetic overlap across subtypes of congenital gonadotropin (Gn) deficiency? This study reveals substantial clinical and genetic overlap among Gn deficiency disorders, with shared genetic and developmental features across congenital hypogonadotropic hypogonadism (CHH), combined pituitary hormone deficiency (CPHD), and syndromic forms of Gn deficiency. Congenital Gn deficiency includes a subset of hypogonadotropic hypogonadism (HH) and can result from defects at the level of the hypothalamus or the pituitary. It includes (i) CHH, further classified into normosmic CHH (nCHH) and Kallmann syndrome (KS); (ii) CPHD; and (iii) syndromic forms such as CHARGE syndrome and septo-optic dysplasia (SOD). The study included all probands with Gn deficiency recruited at a tertiary care center between 2011 and 2024 (n = 568), including 276 KS, 247 nCHH, 29 CPHD, and 16 syndromic Gn deficiency cases. All individuals underwent detailed clinical phenotyping followed by DNA sequencing. Genetic analysis focused on pathogenic (P) and likely pathogenic (LP) variants and variants of uncertain significance (VUS) within established CHH and CPHD genes. Oligogenicity was assessed in the CHH/syndromic HH cohort (n = 523) compared with controls from 1000 Genomes (n = 601). Genetic overlap among CHH, CPHD, and syndromic Gn deficiency was systematically investigated. Cleft lip/palate, dental agenesis, and ear abnormalities were recurrent across all Gn-deficient groups. Notably, some CPHD and SOD patients exhibited anosmia and a preserved Gn response to LH-releasing hormone (LHRH) stimulation, indicating a hypothalamic component to their HH. Rare variants in CHH genes were identified in 53% of KS probands (40% P/LP, 13% VUS) and 33% of nCHH probands (23% P/LP, 10% VUS). N/A. Non-coding and copy number variants were not studied. Functional studies of the new candidate genes for CHH were not undertaken. This study highlights the importance of comprehensive clinical evaluation and broadened genetic testing in patients with Gn deficiency. This work was supported by the Swiss National Foundation (NP) (Grant No. 310030B₂₀₁₂₇₅ to N.P.) and the Natural Science Foundation of Beijing (Grant No. 7244338 to Y.W.). The authors declare no competing interests. Show less

Accurately predicting the bioactivity of small molecules against cancer therapeutic targets remains a significant challenge at the intersection of cheminformatics and drug discovery. This study comprehensively evaluates chemical representations, including AtomPair Counts (APC),Avalon (AVN), Extended-Connectivity Fingerprint diameter 4 (ECFP4), Extended-Connectivity Fingerprint diameter 6 (ECFP6), Feature-based Morgan 2 (FM2), Feature-based Morgan 3 (FM3), Mol2Vec (M2V), Molecular ACCess System (MACCS), Mordred 2D Chi Kappa (MK2), RDKFingerprint (RDF), Rdkit PhysChem (RDC), Torsion (TSN) combined with machine learning algorithms (Bayesian Ridge (BRG), Elastic Net (ENT), Extra Trees (ETT), Hist Gradient Boosting (HGT), K-Nearest Neighbors (kNN), Lasso (LSS), Multi-layer Perceptron (MLP), Partial least squares (PLS), Random Forest (RFT), Ridge (RDG), Support Vector Regressor (SVR), and XGBoost (XGB)) for predicting cancer bioactivities. The results show that while AVN chemical representation, in conjunction with SVR algorithm, achieved the highest predictive accuracy, with R2 of 0.735 in FGFR1 dataset; The mTOR dataset demonstrated the highest average performance across all models and chemical representations, with an R2 of 0.592 across various cancer datasets. These findings demonstrate how cheminformatics tools like molecular fingerprints and quantitative structure-activity relationship (QSAR) modeling can significantly enhance bioactivity prediction, ultimately contributing to more efficient and targeted cancer drug discovery. Show less

Muscle satellite cells (SCs), essential for skeletal muscle regeneration, decline in number and function with age, contributing to sarcopenia. A fully defined viscoelastic hydrogel that preserves SC-myofiber interactions and supports tunable densities of fibronectin-derived RGD ligands was used to investigate age-related defects in extracellular matrix sensing by SCs. Elevating RGD density increased the number of activating and proliferating SCs on myofibers from young mice, whereas SCs from aged mice were unresponsive. Loss of FGF receptor 1 signaling in SCs from aged mice abrogated the coordinated Syndecan-4 and Integrin-β1 matrix response observed in SCs from young mice. Activating Integrin-β1 promoted asymmetric division and self-renewal in SCs from young mice whereas combined FGFR1 and Integrin-β1 signaling drove symmetric expansion. In SCs from aged mice, FGFR1 dysfunction disrupted this balance, impairing asymmetric division, but constitutive FGFR1 activation restored receptor co-localization, self-renewal, and fibronectin responsiveness. Therefore, FGFR1 integrates matrix and growth factor signals, suggesting that targeting the FGFR1-Integrin-β1 axis may enhance SC regenerative potential in aging organisms. Show less

Hypoparathyroidism is a rare endocrine condition characterized by insufficient secretion of parathyroid hormone (PTH), resulting in abnormally low calcium levels (hypocalcemia) and elevated phosphate levels (hyperphosphatemia) in the blood. This report describes a man in his late 30s with a chronic skin condition marked by dryness and desquamation. He occasionally experienced mild perioral numbness. Over the past year, he developed recurrent neuromuscular irritability, including worsening perioral numbness, tingling or numbness in the hands and feet, and muscle spasms consistent with tetany. He was diagnosed with hypoparathyroidism, and his symptoms improved markedly after calcium and calcitriol supplementation. Genetic testing revealed a novel heterozygous c.2298C>G (p. Tyr766Ter) mutation in exon 18 of the fibroblast growth factor receptor 1 gene. This case report aimed to describe this novel mutation and its potential role in the pathogenesis of primary hypoparathyroidism and to discuss relevant diagnostic and therapeutic management strategies. In addition, it broadens our understanding of genetic mutations associated with hypoparathyroidism and provides clinically relevant diagnostic information that may benefit future patients with the similar genetic alteration. Furthermore, it underscores the importance of genetic analysis in elucidating the heterogeneity and complexity of hypoparathyroidism, thereby supporting the development of more precise and tailored treatment approaches. Show less

Left ventricular noncompaction cardiomyopathy (LVNC; OMIM No. 604169) is anatomically characterized by excess trabeculation and deep intertrabecular recesses. It is the third most prevalent pediatric cardiomyopathy. Despite its clinical significance, the pathogenesis of LVNC remains uncertain. We examined Numb expression in epicardial cells (EpiCs) and epicardial-derived cells (EPDCs) using a mCherry::Numb knock-in mouse line; used Numb is enriched in EpiCs and EPDCs. In EDKO hearts, EPDCs displayed abnormal differentiation, and their migration was arrested at the outer compact zone, resulting in the absence of EPDCs in the inner compact zone and trabeculae. The EDKO hearts displayed LVNC, and inducible EpiC-specific Ablation of NFPs (Numb family proteins) in EpiCs disrupted the invasion and differentiation of EPDCs and the communication between cardiomyocytes and other cells, and caused LVNC. The epithelial-mesenchymal transition and compaction defects can be partially rescued by exogenous Fgf2 supplementation. Our findings highlight an essential role for the epicardial NFPs-Fgf/Fgfr axis in regulating ventricular compaction. Show less

Glaucoma is a leading cause of irreversible blindness worldwide. Current diagnostic methods often fail to detect disease at early stages. MicroRNAs (miRNAs), owing to their regulatory role in gene expression, have been investigated as potential biomarkers, although their diagnostic utility and clinical feasibility remain under evaluation. The aim of this work is to systematically review and synthesize evidence on the diagnostic significance of microRNAs and related genetic markers in glaucoma and its subtypes. A systematic review and meta-analysis was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, including 16 studies with 17,300 participants. Odds ratios (ORs) and log ORs with 95% confidence intervals (CIs) were pooled using fixed-effects models. Subgroup analyses were performed by sample type, glaucoma subtype, and molecular pathway. Specific miRNAs (e.g., miR-143-3p, miR-182) were significantly associated with glaucoma (OR 6.32, 95% CI 5.31-7.54, p < 0.001). Stronger correlations were observed in aqueous humor samples (OR 13.79, 95% CI 6.81-27.94, p < 0.001). Dysregulation of miRNAs was linked to increased retinal ganglion cell apoptosis and altered aqueous humor osmolality. Genetic analysis showed that common alleles in ATOH7 (OR 1.55, 95% CI 1.40-1.72) and CDKN2B (OR 1.66, 95% CI 1.55-1.78) significantly increased glaucoma risk, while miR182 variants also showed strong associations. The autotaxin (ATX)-lysophosphatidic acid (LPA) pathway was consistently implicated (OR 3.94, 95% CI 2.46-6.32). MiRNAs, particularly in blood samples, show promise as feasible biomarkers for early glaucoma detection, while aqueous-humor-based testing remains clinically limited owing to invasiveness. Genetic variants such as ATOH7, CDKN2B, and miR182 modestly but consistently contribute to glaucoma susceptibility. Large-scale longitudinal studies are warranted to validate these findings and translate them into routine clinical practice. Show less

Brain aging is characterized by memory loss and cognitive impairment. With the growth of the population and advances in medical care, the size of the aging population is increasing. Therefore, the discovery of anti-aging drugs has become a popular topic in recent years. Fibroblast growth factor 21 (FGF21) has been reported to inhibit oxidative stress, reduce inflammation, and delay senescence. The present study was designed to investigate the effects of recombinant human FGF21 (rhFGF21) on senescence in the brain in a mouse model of D-galactose (D-gal)-induced aging. The behavioral tests revealed that rhFGF21 improved D-gal-induced learning and memory impairment in mice. RhFGF21 improved the morphology of cortical and hippocampal neurons and increased the expression of PSD95 in the model mice. RhFGF21 reduced the number of microglia and astrocytes in the cortex and hippocampus, increased the activities of the antioxidant enzymes (GSH-PX, CAT, and SOD), and inhibited the expression of p-NFκB and p53 proteins, as well as the mRNA expression of the inflammatory cytokines (IL-1β, IL-6, TNFα, and iNOS). SIRT1 regulates senescence and inflammation, and FGF21 participates in physiological and pathological processes by binding to the FGFR1. Therefore, we measured SIRT1 and activated FGFR1 (p-FGFR1) levels. RhFGF21 administration increased the expression of cortical and hippocampal SIRT1 and p-FGFR1 in D-gal-induced aging mice. These data suggested that rhFGF21 alleviated learning and memory impairment in a mouse model of D-gal-induced aging by increasing antioxidant enzyme activity, inhibiting inflammation, and senescence-related gene expression via modulating FGFR1 and SIRT1. Show less

Cosmetic dermatology has largely focused on topical applications targeting the stratum corneum. However, emerging evidence suggests that visible aging is a systemic readout of internal "organ clocks" and molecular dysregulation across the epidermis and dermis. This review proposes an "inside-out strategy" that seeks to re-conceptualize aesthetic vitality as a measurable indicator of systemic physiological resilience. The author describes theoretically proposed organ-skin axes, including the role of molecular signaling of kidney-derived klotho (KL1 fragment) via FGFR1-α-klotho complexes and muscle-derived irisin through the AMPK/PGC-1-α pathway in modulating skin homeostasis. Drawing on recent breakthroughs in non-human primate models (2023-2025), this synthesis explores the potential of systemic interventions-including nicotinamide adenine dinucleotide (NAD+) precursors (sirtuin 1 SIRT1 activators), senolytics (targeting BCL-2/p16), and glucagon-like peptide-1 (GLP-1) receptor agonists-as candidates to potentially synchronize these internal clocks. Furthermore, the review identifies direct regenerative interventions, such as retinoids (RAR/RXR signaling), chemical peels (HIF-1-α induction), exosomes (miR-21/29 delivery), and poly-L-lactic acid PLLA (mechanotransduction via YAP/TAZ), positioning them as potential physical and chemical epigenetic modulators that may support the restoration of cellular transcriptional fidelity. This article proposes a new paradigm for regenerative aesthetics that focuses on restoring the youthful phenotype by optimizing systemic molecular crosstalk and epigenetic transcriptional fidelity. Show less

Advanced esophageal squamous cell carcinoma (ESCC) has a poor prognosis, and current treatments provide limited survival benefits. This study aimed to identify prognostic biomarkers and therapeutic targets by genomic profiling of advanced ESCC using circulating tumor DNA (ctDNA). The SCRUM-MONSTAR GOZILA study is a nationwide, plasma-based molecular profiling project using Guardant360, involving 31 core cancer institutions in Japan. We evaluated the genomic landscape of advanced ESCC and investigated associations between specific alterations and overall survival (OS). The correlation between blood tumor mutation burden (bTMB) and clinical outcomes in patients with PD-1 inhibitors was also assessed using multiple cutoff values (2, 4, 6, 8, and 10 mutations/Mb). Among 313 patients, alterations predominantly consisted of single nucleotide variants (SNVs, 68.9%) and copy number alterations (20.7%). ctDNA analysis identified key genomic alterations linked to poor outcomes in advanced ESCC, revealing potential prognostic biomarkers and therapeutic targets. In contrast, bTMB did not show predictive value for the efficacy of PD-1 inhibitors in this study. Show less

Fatty acids are important as structural components, energy sources, and signaling mediators. While studies have extensively explored genetic regulation of fatty acids in serum and other bodily fluids, their regulation within adipose tissue, a crucial regulator of cardiovascular and metabolic health, remains unclear. Here, we investigated the genetic regulation of 18 fatty acids in subcutaneous adipose tissue from 569 female twins from TwinsUK. Using twin models, the heritability of fatty acids ranged from 5% to 59%, indicating a substantial genetic regulation of fatty acid levels within adipose tissue, which was also tissue specific in many cases. Genome-wide association studies identified 10 significant loci, in SCD, ADAMTSL1, ZBTB41, SNTB1, EXOC6B, ACSL3, LINC02055, MKRN2/TSEN2, FADS1, and HAPLN across 13 fatty acids or fatty acid product-to-precursor ratios. Using adipose gene expression and methylation, which were concurrently measured in these samples, we detected five fatty acid-associated signals that colocalized with expression quantitative trait locus (eQTL) and methylation quantitative trait locus (meQTL) signals, highlighting fatty acids that are regulated by molecular processes within adipose tissue. We explored links between polygenic scores of common metabolic traits and adipose fatty acid levels and identified associations between polygenic scores of BMI, body-fat distribution, and triglycerides and several fatty acids, indicating these risk scores impact local adipose tissue content. Overall, our results identified local genetic regulation of fatty acids within adipose tissue and highlighted their links with renal and cardio-metabolic health. Show less

Liver metastasis is the predominant cause of mortality among individuals diagnosed with colorectal cancer (CRC). However, the mechanisms underlying the tumor-microenvironment interactions that promote this process remain poorly defined. Here, we developed an integrative multiomics framework to dissect the cellular and molecular determinants of colorectal cancer liver metastasis (CRLM). By analyzing 1,156 metastasis-associated genes, we identified three molecular subtypes with distinct prognostic and immunometabolic features: C1 with mixed phenotypes and favorable survival, C2 with metabolic activation and immune suppression, and C3 with immune activation and signaling dysregulation, which had the poorest outcomes. Mechanistically, we discovered that SPP1⁺ macrophages secrete PDGFB, which activates PDGFRB signaling in FADS1⁺ tumor cells to trigger epithelial-mesenchymal transition (EMT) and promote liver metastasis. This macrophage-tumor crosstalk was validated by single-cell transcriptomics, genetic perturbation, and coculture experiments. Collectively, our findings define a macrophage-derived PDGFB-PDGFRB axis that drives CRC liver metastasis and highlight a potential therapeutic target for overcoming metastatic progression and immune resistance. Show less

Crohn's disease (CD) is a chronic inflammatory bowel disease with unknown etiology. Inflammatory chemical mediators synthesized from arachidonic acid, an n-6 polyunsaturated fatty acid (PUFA), have been shown to activate CD. Additionally, n-3 PUFAs are metabolized by the same enzyme as n-6 PUFAs and known to inhibit the arachidonic acid cascade. Our previous study noted that the presence of erythrocyte membrane fatty acids is a characteristic finding in Japanese CD patients. It was thus speculated that To investigate the relationship of Using previously reported findings regarding The presence of the rs174538 mutation in The rs174538 mutation alters the fatty acid profile through strong linkage to the Show less

While active ingredients from compound Chinese herbal medicines (CCHMs) have demonstrated potential in alleviating symptoms of polycystic ovary syndrome (PCOS), their mechanisms of action remain insufficiently understood. This study aimed to identify key active ingredients and gene targets in Xiaochaihu Decoction, Sijunzi Decoction, and Shensiwei that contribute to their efficacy against PCOS. Transcriptomic data of PCOS were obtained from public databases. Information on gut microbiota metabolite-related targets and active ingredients of CCHMs was retrieved from relevant databases. Key gene targets and active ingredients were identified using Graph-based Bioactive Network Analysis (GraphBAN) and toxicological assessments. Molecular docking and dynamic simulations were conducted to validate interactions. Functional enrichment and regulatory network analysis were performed. LCT, FADS1, and CYP11A1 were identified as key genes associated with α-β T cell activation, immune receptor signaling, and adaptive immune responses. LCT and FADS1 were targeted by linolenic acid, while CYP11A1 was regulated by mandenol, EIC, and linolenic acid. Three microRNAs (hsa-miR-320a-3p, hsa-miR-4487, hsa-miR-6090) co-regulated these genes. Molecular docking and dynamics simulations confirmed stable binding between key genes and active ingredients, with binding energies < -5.0 kcal/mol. The findings indicate that CCHMs exert therapeutic effects on PCOS by multi-target regulation of key genes involved in androgen synthesis, metabolic regulation, and immune-inflammatory activation. The observed strong binding affinities provide a structural basis for these interactions. This study identified three key genes and three core active ingredients in CCHMs for PCOS treatment, laying a theoretical foundation for developing multi-target therapeutics. Show less

The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise, and the accurate, non-invasive assessment of liver fibrosis remains an important clinical challenge. This study aimed to identify ferroptosis biomarkers associated with MASLD-related liver fibrosis progression, explore their potential biological links with MRI-derived parameters, and provide new clues for developing non-invasive diagnostic strategies for ferroptosis. A MASLD-related liver fibrosis model was established using 30 Sprague-Dawley (SD) rats. Hub differentially expressed ferroptosis-related genes (DE-FRGs) were identified through the integration of weighted gene co-expression network analysis (WGCNA), differential expression analysis, and LASSO regression. The role of ferroptosis in MASLD was evaluated using transmission electron microscopy (TEM) and measurements of glutathione (GSH) and Fe²⁺ content. T2*, R2*, and proton density fat fraction (PDFF) were obtained through magnetic resonance imaging (MRI) and were analyzed for correlations with hub DE-FRGs and Fe²⁺ levels. A total of eight hub DE-FRGs were identified: Pck2, Idh2, Nr1d1, Fads1, Sat1, Abhd12, Got1, and Srebf1. Enrichment analyses revealed that these hub DE-FRGs were predominantly implicated in carbohydrate response, amino acid biosynthesis, insulin resistance, and the AMPK signaling pathway. TEM and biochemical markers analyses demonstrated an association between MASLD-related liver fibrosis and ferroptosis. MRI‑derived parameters were significantly correlated with Fe²⁺ levels and the expression of hub DE-FRGs. This study preliminarily identified hub DE-FRGs associated with liver fibrosis in MASLD and their signaling pathways, verified indirect indicators related to ferroptosis, and proposed their potential correlation with MRI-derived parameters. Show less

To characterize ultra-processed food (UPF) circulating metabolic signatures associated with Crohn's disease (CD) and to localize key metabolic mediators linking UPF intake to CD risk. Prospective cohort study. Two large multi-center cohorts (UK Biobank [UKB] and Whitehall II [WHII] study) across the UK and an Eastern multi-center cohort ONE-IBD Study from China. UK Biobank discovery cohort (n=10,229) for signature derivation, internal validation cohort (n=91,306), external validation cohort Whitehall-II (n=7,893), and three additional cohorts (two Western and ONE-IBD) for validation of key metabolic drivers. Primary outcomes were UPF-related circulating metabolic signatures and their associations with CD risk; secondary outcomes included evidence supporting causal roles of candidate metabolites and genetic pathways assessed by Mendelian randomization, colocalization, and gene-environment analysis. A UPF metabolic signature of 73 metabolites was constructed and validated across cohorts (Spearman ρ: 0.20-0.25). More pronounced UPF metabolic signature was associated with increased CD risk (HR The adverse effects of UPF on CD risk may be driven by a relative deficiency of protective metabolites such as DHA, apart from additive harm to metabolic depletion. This reframes UPF-related risk and highlighting potential targets for precision nutrition in CD prevention. Show less

Liver steatosis, fibroinflammation, and iron overload, are growing global health concerns, yet the genetic architecture and causal pathways linking liver pathology to systemic disease remain incompletely understood. We analysed MRI-derived liver traits—corrected T1 (cT1), proton density fat fraction (PDFF), and liver iron—in 37,626 UK Biobank participants. Genome-wide (GWAS), transcriptome-wide (TWAS), and GWAS identified 18 loci for cT1, 15 for PDFF, and 5 for liver iron, including six not previously reported. TWAS, This integrative imaging-genetics study reveals 13 potentially novel genes and several protein candidates implicated in hepatic steatosis, inflammation, and iron homeostasis. These findings enhance understanding of liver disease biology and may help identify new targets for early detection or treatment. This large imaging-genetics study in over 37,000 people identifies genetic and protein factors linked to liver fat, fibroinflammation, and iron levels. It shows that higher liver fat and inflammation are associated with increased cardiometabolic risk, while higher liver iron appears inversely linked to risk of heart disease. These findings highlight molecular targets such as The online version contains supplementary material available at 10.1186/s40246-026-00913-2. Show less

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and most often presents with an increase in the number of blasts in the peripheral blood and bone marrow. Although ALL typically presents with circulating blasts, atypical findings such as hypereosinophilia may obscure diagnosis and delay appropriate management. Severe eosinophilia in patients with ALL is a very rare phenomenon and is usually associated with specific genetic abnormalities or myeloid malignancies. The combination of severe eosinophilia, bicytopenia, and cardiac mass is unusual and challenging in diagnosis and treatment. A 4-year-old male patient, with no significant past or family history, presented to the emergency department with persistent fever. On initial examination, hepatosplenomegaly was evident. Blood tests showed WBC = 125,000cell per microliter, Hb = 8.7 g/dL, Plt = 77,000 per microliter, and severe eosinophilia (73.4%) absolute eosinophil count 91,250. A peripheral blood smear showed abundant mature eosinophils without blasts. Chest imaging showed bilateral pulmonary involvement, and ultrasonography showed bilateral pleural effusion. Echocardiography revealed a mass in the right ventricle suggestive of thrombus formation or infiltration, along with some degree of heart failure. Molecular tests for BCR-ABL, PDGFRα, PDGFRβ, FGFR1, and t (5:14) were negative, and bone marrow flow cytometry was also negative. Bone marrow biopsy with immunohistochemistry confirmed the diagnosis of Pre-B acute lymphoblastic leukemia with positive CD20 and TdT. The patient underwent protocol treatment and the MRD at the end of induction was reported to be 0.0011% and the biopsy was negative. The cardiac mass was also resolved during chemotherapy treatment. This case emphasizes the importance of noting unusual eosinophilia with bicytopenia, even in the absence of peripheral blasts, and the need for bone marrow biopsy and immunohistochemical examination for accurate diagnosis. Show less

Despite the rapid development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in recent decades, resistance remains a significant challenge in managing advanced non-small cell lung cancer (NSCLC). Elucidating the mechanisms underlying EGFR-TKI resistance and developing novel strategies are therefore crucial. In this study, we investigated the role of polo-like kinase 1 (PLK1) in EGFR-mutant NSCLC and evaluated the therapeutic potential of combining EGFR-TKIs with PLK1 inhibitors. We demonstrated that high PLK1 expression correlates with STAT3 signaling activation and decreased survival probability in EGFR-mutant NSCLC patients. Subsequent studies revealed that PLK1 inhibitors effectively reversed the activation of STAT3 induced by EGFR-TKIs. When used in combination with EGFR-TKIs, they promoted cell apoptosis, inhibited cell proliferation in vitro, and induced tumor regression in animal models. Mechanistically, our data demonstrated that PLK1 regulated STAT3 activity through protein-protein interactions and JAK1-mediated phosphorylation, while STAT3 reciprocally regulated PLK1 transcription, establishing a positive feedback loop between these signaling molecules. This PLK1/STAT3 loop was further reinforced by FGFR1 upregulation and directly linked to EGFR-TKI resistance. Targeting this axis with combinatorial inhibitors exerted synergistic anti-tumor effects, suppressing proliferation and migration in osimertinib-resistant models. In conclusion, concurrent inhibition of EGFR and FGFR1/STAT3/PLK1 signaling pathways provides a promising therapeutic strategy for NSCLC patients with EGFR mutations, enhancing efficacy and overcoming resistance. Show less

This study aimed to identify blood pressure-associated metabolites and explore their underlying pathways using multiomics data from 1188 Chinese participants. Serum metabolite levels were profiled using untargeted and widely targeted metabolomic technologies. The associations of metabolites as well as ratios with blood pressure were assessed using generalized linear models (GLM). Targeted metabolomics was used to replicate a subset of metabolites. Genome-wide association studies (GWAS) were performed on all metabolites identified. Potential causality was examined using two-sample Mendelian randomization (MR) analyses, with partial validation against GWAS results from an independent cohort. This study identified 10 blood pressure-associated metabolites supported by GLM and MR analyses. Cortisol demonstrated the strongest association with blood pressure, with l-glutamic acid and its ratios identified as key drivers. Multiomics integration revealed that a genetic variant near the omega-3 metabolism genes ( Show less

Gynecologic carcinosarcoma is an uncommon but aggressive malignancy that frequently requires systemic therapy but therapeutic options are limited. Development of preclinical models is therefore important for therapeutic advancement. Carcinosarcoma tumor (6 uterine and 1 tubo-ovarian) from 7 surgical samples were implanted into immunocompromised mice for patient-derived xenograft (PDX) and/or cell line development. The histologic, immunophenotypic and genetic features were characterized. Based on the observed molecular profiles and targetable molecular alterations, in vivo studies were conducted to evaluate the efficacy of targeted therapy on tumor growth. We established 1 cell line and 6 PDX models which recapitulated the dominant phenotype of the respective parental tumors with preserved mesenchymal differentiation lineage in the sarcomatous component. Genomically, the PDX/cell line models preserved similar complex pattern of copy number alterations and similar mutation landscape when compared to the respective parental tumors. All 7 parental carcinosarcoma tumors and PDX/cell line models harbored pathogenic TP53 mutations. Moreover, we identified recurrent copy number gain/amplification involving several receptor tyrosine kinases (RTK), including amplification and protein over-expression of FGFR1. In vivo drug evaluation using a small molecule inhibitor (AZD4547) of FGFRs showed significant growth inhibition in the carcinosarcoma PDX tumor with the highest FGFR1 amplification and protein expression whereas AZD4547 showed no significant growth effects on carcinosarcoma lacking high level FGFR1 amplification, indicating oncogenic dependency on the amplified RTK pathway. These findings demonstrate the utility of patient-derived tumor models in the identification and the functional validation of potentially targetable molecular alterations in preclinical setting. Show less