Myocardial infarction (MI) is the most severe clinical manifestation of coronary artery diseases (CVD) and serves as a critical driver of sudden cardiac death and heart failure (HF). Its pathophysiolo Show more
Myocardial infarction (MI) is the most severe clinical manifestation of coronary artery diseases (CVD) and serves as a critical driver of sudden cardiac death and heart failure (HF). Its pathophysiology begins with the abrupt cessation of coronary blood flow, leading to severe ischemia and subsequent cardiomyocyte necrosis. This study aimed to investigate the molecular mechanisms by which METTL14 regulates the progression of MI in mice via the OTUD1/DUSP6 signaling axis. An MI mouse model was established by ligating the left anterior descending (LAD) coronary artery. The progression of MI was evaluated through echocardiography, HE staining, Masson's trichrome staining, TUNEL assay, and assessment of inflammatory cytokines. Mechanistically, Me-RIP, PAR-CLIP Co-IP, and protein stability assays were performed to dissect the interactions within the METTL14/OTUD1/DUSP6 axis. Our results demonstrated that METTL14 was highly expressed in the MI mouse model. Silencing METTL14 significantly reduced the left Ventricular Internal Diameter at end-diastole (LVIDd) and left Ventricular Internal Diameter at end-systole (LVIDs), increased ejection fraction (EF) and fractional shortening (FS), and attenuated histopathological damage, apoptosis, and the levels of inflammatory cytokines (TNF-α and IL-β). Further analysis revealed that METTL14 promotes OTUD1 mRNA stability and expression by modulating its m Show less
Apoptosis plays a significant role in osteoporosis (OP), yet a causal relationship between apoptosis gene expressions and OP remains unexplored. This study applies an integrated multi-omics analysis t Show more
Apoptosis plays a significant role in osteoporosis (OP), yet a causal relationship between apoptosis gene expressions and OP remains unexplored. This study applies an integrated multi-omics analysis to establish causality between them, offering clinical treatment and prediction insights. Apoptosis-related genes are sourced from GeneCards, and 6 transcriptomic datasets from the cells in the circulation are obtained from GEO. Meta-analysis integrated differentially expressed apoptosis-related genes (DEGs) from the above 6 datasets. Causality between gene expressions, epigenetic changes, and OP is examined using OP genome-wide association study (GWAS), plasma expression quantitative trait loci (eQTL), and methylation quantitative trait loci (mQTL) data, while analysis of skeletal muscle eQTL and OP GWAS data is conducted. External validation is performed with the UK Biobank datasets. Meta-analysis of 6 GEO datasets identified 384 DEGs, including 78 apoptosis-related genes. The three-step analysis indicates 8 candidate causal genes in blood, including MAP3K3, DPP8, RPL3, PPP2CA, CD86, LRRFIP1, TRAP1, and DUSP6, with LRRFIP1 influenced by four methylation sites. Analysis of skeletal muscle data reveals 4 causal genes, including SIPA1L3, PDLIM7, CTNNB1, and DPP8. Among apoptosis-related genes causally linked to OP in both circulation and skeletal muscle, LRRFIP1 was validated based on methylation-associated regulation and demonstrated consistent, reproducible expression patterns. This study uses a multi-omics strategy to clarify the roles of apoptosis-related gene expressions and their corresponding methylation in OP, providing targets and a basis for early diagnosis, personalized treatment, and monitoring of OP. Show less
Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial i Show more
Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial intrinsic resistance factor in tumors, resulted in insufficient immune synapse formation and impaired CAR T-cell activation and cytotoxicity. However, the specific signaling pathway and transcriptional changes associated with CAR T-cell dysfunction have not been addressed. Here, we revealed that AP-1-mediated activation was attenuated in CAR T cells impaired by tumor CD58 loss, driving a decrease in mitochondrial biogenesis, metabolic kinetic impairment, mitochondrial membrane potential loss and ROS accumulation. Moreover, this AP-1 attenuation triggered death receptor-independent apoptosis through the intrinsic mitochondrial pathway. In seeking therapeutic strategies, we pharmacologically and genetically blocked three distinct inhibitory phosphatases positioned upstream of AP-1 signaling. Multifaceted validation has demonstrated that dual specificity phosphatase 6 (DUSP6) blockade is an effective approach to supplement AP-1 signaling while notably reducing CAR T-apoptosis and enhancing mitochondrial fitness, proliferation and long-term cytotoxicity. The transcriptomic profiles of DUSP6-ablated CAR T cells revealed markedly upregulated T-cell activation signatures and enriched metabolic pathways. Clinically, bulk and single-cell RNA-seq analyses revealed that DUSP6 was downregulated in patients who responded to T-cell-based immunotherapy, implying its relevance to patient outcomes. Our findings repositioned CD58 not merely as an immune synapse component but also a metabolic checkpoint in CAR T-cell biology, the loss of which triggers AP-1-dependent mitochondrial derangement and creates a permissive landscape for intrinsic apoptosis, which can be ameliorated by ablation of the inhibitory phosphatase DUSP6. Crucially, DUSP6 ablation represents a promising engineering target to potentiate CAR T-cell efficacy in broader applications. Show less
Pharmacological preconditioning of mesenchymal stem cells (MSCs) is a promising strategy to enhance their therapeutic efficacy for end-stage liver disease; however, maximizing this benefit remains a m Show more
Pharmacological preconditioning of mesenchymal stem cells (MSCs) is a promising strategy to enhance their therapeutic efficacy for end-stage liver disease; however, maximizing this benefit remains a major clinical challenge. Senkyunolide H (SNH), a small-molecule compound derived from Angelica sinensis, exhibits anti-inflammatory, antioxidant, and anti-apoptotic properties. Nevertheless, its capacity to optimize MSCs-based therapy for liver disease has not been fully elucidated. Here, we demonstrate that SNH preconditioning significantly enhances the therapeutic efficacy of bone marrow mesenchymal stem cells (BMSCs) in a murine model of liver cirrhosis. Specifically, SNH-pretreated BMSCs markedly alleviated hepatocellular injury, promoted hepatocyte proliferation, and attenuated collagen deposition. Mechanistically, SNH augments the therapeutic potency of BMSCs by partly binding to macrophage erythroblast attacher (MAEA), a subunit of the E3 ubiquitin ligase complex. This interaction stabilizes MAEA, which in turn facilitates the ubiquitination and proteasomal degradation of dual specificity phosphatase 6 (DUSP6), thereby activating ERK/STAT3 signaling and upregulating the secretion of hepatocyte growth factor (HGF). Collectively, our findings highlight SNH preconditioning as a robust approach to enhance the paracrine function and therapeutic potential of BMSCs, and identify MAEA as a novel therapeutic target for BMSCs-based interventions in liver cirrhosis. Show less
Inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) are chronic inflammatory diseases that share immune dysregulation and mitochondrial dysfunction. Understanding the molecular mechanisms l Show more
Inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) are chronic inflammatory diseases that share immune dysregulation and mitochondrial dysfunction. Understanding the molecular mechanisms linking these diseases to mitochondrial dysfunction is crucial for developing novel diagnostic and therapeutic strategies. Datasets related to IBD and RA were obtained from the Gene Expression Omnibus database. Differentially expressed mitochondrial dysfunction-related genes (MDRGs) were identified using differential expression analysis. Weighted gene co-expression network analysis was performed to identify crosstalk genes (CGs). Logistic regression and support vector machine (SVM) models were constructed using least absolute shrinkage and selection operator regression to identify hub genes. Additionally, the differential expression and diagnostic value of the hub genes were verified using quantitative reverse transcriptase-polymerase chain reaction and validation sets. Finally, immune infiltration analysis was conducted to assess the role of immune cells in IBD and RA. A total of 87 CGs associated with mitochondrial dysfunction were identified between IBD and RA, among which Show less
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related deaths. Immune checkpoint inhibitors (ICIs) of programmed death-1 (PD-1)/programmed de Show more
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related deaths. Immune checkpoint inhibitors (ICIs) of programmed death-1 (PD-1)/programmed death ligand-1 signaling induce tumor regression in some patients with NSCLC, but most patients with NSCLC exhibit resistance to ICIs therapy. NSCLC shapes the potent tumor immunosuppressive microenvironment (TIME) that underlies tumor immune tolerance and acquired resistance. Therefore, elucidating the cellular and molecular mechanisms by which NSCLC establishes and sustains the TIME is essential for developing novel strategies to overcome immune resistance and enhance the clinical benefit of ICIs. The correlation between sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) expression and ICIs was analyzed via immunohistochemistry. Cell migration assay was performed to assess the effect of SAMHD1 on macrophage recruitment. Multicolor flow cytometry was performed to analyze the effect of SAMHD1 knockdown on the tumor microenvironment. SAMHD1 regulation of the dual specificity phosphatase 6-extracellular regulated protein kinases 1/2 (DUSP6-ERK1/2) pathway was verified by RNA sequencing and western blotting. Here, we identify the SAMHD1 as a potential therapeutic target and a major determinant of poor response to ICIs in patients with NSCLC. Tumors with high SAMHD1 expression show resistance to anti-PD-1 antibody (αPD-1) treatment, whereas tumors with low SAMHD1 expression are highly sensitive. SAMHD1-dependent resistance to αPD-1 is characterized by increased tumor-associated macrophages (TAMs) infiltration and reduced CD8+T cell numbers. Mechanistically, SAMHD1 regulates the expression of macrophage-associated chemokines by influencing the activation of the DUSP6-ERK1/2 pathway, which contributes to TAMs aggregation within NSCLC tumors to shape an immunosuppressive microenvironment. The HIV accessory protein viral protein-x (VPX) specifically degrades SAMHD1 to promote HIV replication. Similarly, the vpx-engineered oncolytic adenovirus (oAd-vpx) targets SAMDH1 degradation to enhance oncolytic adenovirus replication and weaken the hostile immune microenvironment shaped by TAMs, thereby triggering a CD8+T-cell-dependent antitumor immune response. The combination of oAd-vpx and αPD-1 inhibits tumor growth and enhances sensitivity to ICIs in both mouse and human NSCLC. This research identifies a key mechanism of SAMHD1-driven immunosuppression and highlights its important role in oncolytic adenovirus therapy. This study provides a theoretical basis for targeting SAMHD1 as a drug therapy strategy in patients with NSCLC. Show less
DUSP6, a dual-specificity phosphatase, has become a focal point in understanding the pathogenesis of various liver disorders. This study aims to investigate the role of DUSP6 in liver fibrosis and exp Show more
DUSP6, a dual-specificity phosphatase, has become a focal point in understanding the pathogenesis of various liver disorders. This study aims to investigate the role of DUSP6 in liver fibrosis and explore the underlying mechanism. Using a CCL4-induced mouse model, the consistent upregulation of DUSP6 expression was observed. Notably, when Dusp6 was knocked down, liver fibrosis showed significant improvement, revealing a protective effect intricately linked to the ERK pathway. This was accompanied by an increase in ferroptosis-related proteins SLC7A11 and GPX4, underscoring the role of ferroptosis, an iron-dependent form of regulated cell death, in this process. Transcriptomic analysis further revealed a crucial downregulation of Cyp2e1 following Dusp6 knockdown. In vitro, DUSP6 knockdown not only promoted ERK phosphorylation but also suppressed CYP2E1 expression, enhancing cell proliferation, bolstering hepatocyte resistance to ferroptosis, and alleviating hepatocyte injury. Importantly, inhibiting CYP2E1 in mouse models of liver fibrosis effectively slowed the progression. These findings illuminate a critical regulatory mechanism that DUSP6 regulates liver fibrosis via targeting ferroptosis, offering new a direction for therapeutic strategies in liver disease. Show less
Lilan Su, Xiao Hu, Jing Dai+11 more · 2026 · Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics · added 2026-04-24
To explore the genetic etiology of 46 Chinese pedigrees affected with Hereditary multiple exostoses (HME) and provide genetic counseling and reproductive intervention. Whole-exome sequencing and Sange Show more
To explore the genetic etiology of 46 Chinese pedigrees affected with Hereditary multiple exostoses (HME) and provide genetic counseling and reproductive intervention. Whole-exome sequencing and Sanger sequencing were carried out on 87 patients from the 46 pedigrees to analyze the variants of EXT1 and EXT2 genes. Pathogenicity of the variants was assessed based on the guidelines from the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP). Prenatal diagnosis and preimplantation genetic testing (PGT) were provided for couples with identified pathogenic mutations. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: LL-SC-SG-2014-010). In total 17 and 22 pathogenic variants were respectively identified in the EXT1 and EXT2 genes, among which 5 EXT1 and 12 EXT2 variants were unreported previously. Three patients with no family history were found to harbor de novo variants of the EXT1 gene. Twenty nine couples had opted for PGT or underwent prenatal diagnosis following natural conception, and 17 healthy babies were born. This study has clarified the genetic etiology of 45 HME pedigrees and identified 17 novel variants, which has enriched the mutational spectrum of the EXT1 and EXT2 genes. Reproductive intervention through PGT and prenatal diagnosis have prevented the recurrence of HME in these families. Show less
Porcine enteric coronaviruses, including porcine deltacoronavirus (PDCoV), porcine epidemic diarrhea virus (PEDV), swine acute diarrhea syndrome coronavirus (SADS-CoV), and transmissible gastroenterit Show more
Porcine enteric coronaviruses, including porcine deltacoronavirus (PDCoV), porcine epidemic diarrhea virus (PEDV), swine acute diarrhea syndrome coronavirus (SADS-CoV), and transmissible gastroenteritis coronavirus (TGEV), can cause acute diarrhea, vomiting, dehydration, and high mortality in suckling piglets. Recent studies revealing human PDCoV infections and the potential of SADS-CoV to penetrate human cell lines have heightened apprehensions about the zoonotic transmission risks of these viruses. While heparan sulfate (HS) serves as a receptor in PDCoV binding, the key host genes involved in HS biogenesis and the specific molecular mechanisms underlying this process have not been fully examined. Enzymes involved in HS biosynthesis, including SLC35B2, EXT1, and NDST1, were identified as critical host factors via the use of CRISPR-Cas9 knockout cells. Moreover, inhibition assays using heparin sodium, a competitive HS mimic, demonstrated dose-dependent reductions in PDCoV infection Show less
Perioperative neurocognitive disorder (PND) is one of the most prevalent neurological complications in elderly surgical patients. Dysregulated lipid metabolism is a hallmark of aging and is strongly a Show more
Perioperative neurocognitive disorder (PND) is one of the most prevalent neurological complications in elderly surgical patients. Dysregulated lipid metabolism is a hallmark of aging and is strongly associated with cognitive dysfunction. This study aimed to investigate whether ω-6 polyunsaturated fatty acid (PUFA) metabolism contribute to PND and examined whether fatty acid desaturase 1 (FADS1) represents a key regulatory link between fatty acid metabolism and PND in aged mice. An anesthesia/surgery-induced cognitive dysfunction model was established Anesthesia/surgery significantly upregulated hippocampal FADS1 expression (1.91-fold [0.37] vs. 1.00-fold [0.43]; These findings highlight anesthesia/surgery could disrupt ω-6 PUFA metabolism, notably activating the PGD The online version contains supplementary material available at 10.1186/s12974-025-03678-y. 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 insuf Show more
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
Hepatocellular carcinoma (HCC) is a major malignancy with rising global incidence and mortality. Clinical treatment is limited by molecular heterogeneity and drug resistance. In recent years, endocrin Show more
Hepatocellular carcinoma (HCC) is a major malignancy with rising global incidence and mortality. Clinical treatment is limited by molecular heterogeneity and drug resistance. In recent years, endocrine-disrupting chemicals (EDCs) have attracted attention as emerging risk factors, but systematic pathogenic evidence for their roles in HCC initiation and progression remains insufficient. First, we predicted potential targets of EDCs using SwissTargetPrediction, STITCH, and ChEMBL, and intersected them with differentially expressed genes and key module genes from WGCNA in the GEO database to screen candidate key genes. Second, based on these candidates, we constructed diagnostic models using 14 machine-learning algorithms and evaluated feature importance via the SHAP framework to identify key biomarkers and their functional contributions. Molecular docking and molecular dynamics simulations were used to validate interaction mechanisms between EDCs and key target proteins. We then built a multivariable Cox proportional hazards model in the TCGA-LIHC cohort and performed stratified survival analysis, somatic mutation profiling, and immune evasion characterization. Subsequently, we evaluated the tumor immune microenvironment using CIBERSORT and ssGSEA, and integrated single-cell transcriptomic data to resolve cell-subtype heterogeneity, target expression distributions, and cell-cell communication. Meanwhile, we integrated the GDSC drug-sensitivity database to evaluate associations between risk scores and drug response, and conducted pan-cancer analyses to examine cross-cancer applicability. We identified 18 genes jointly associated with EDCs and HCC, significantly enriched in AMPK, p53, and FoxO signaling pathways and cell cycle-related pathways. Among models built with 14 machine-learning algorithms, CatBoost showed the best discriminative performance and identified CCNB2 and AKR1C3 as core driver genes. Docking and dynamics simulations indicated strong binding affinities and stable binding conformations between EDCs and target proteins including CCNB1 (-8.9 kcal/mol), AKR1C3 (-8.4 kcal/mol), and FADS1 (-8.5 kcal/mol). A multivariable Cox risk model based on nine key genes served as an independent prognostic predictor for HCC (HR = 1.746, 95% CI: 1.477-2.064, P < 0.001). The nomogram achieved AUCs of 0.836, 0.810, and 0.788 at 1, 3, and 5 years, respectively, indicating good predictive performance. The high-risk group was significantly associated with high tumor mutational burden (TMB), TP53 mutations, and low immune evasion scores. Regarding the tumor immune microenvironment, CIBERSORT and ssGSEA analyses showed marked enrichment of Tregs and M0 macrophages, while most effector immune cells and functions were suppressed. Single-cell transcriptomics further showed enrichment of endothelial cells, fibroblasts, hepatocytes, and macrophages in HCC tissues, with notable reductions in T cells, B cells, NK cells, and neutrophils, indicating an immunosuppressive microenvironment with stromal remodeling. Cell-cell communication analysis indicated that the MIF-CD74 receptor axis is central in immune-cell interactions. Drug-sensitivity analysis suggested that the high-risk group was more sensitive to GDC0810, BPD-00008900, and Fulvestrant, indicating potential beneficiary populations. Pan-cancer analysis showed that the risk model also had diagnostic and prognostic value in LUAD, KIRP, KIRC, and KICH, suggesting cross-cancer generalizability. This study systematically reveals that EDCs promote HCC initiation and progression by perturbing cell cycle, metabolic, and immune homeostasis through multi-target, multi-pathway mechanisms. The nine-gene risk model demonstrates superior performance in HCC diagnosis and prognosis and shows potential clinical translational value in drug-sensitivity prediction and pan-cancer analyses. This work provides a new perspective at the intersection of environmental toxicology and precision oncology and informs individualized therapeutic strategies. Show less
The hepatocytes orchestrate anabolic and catabolic pathways by dynamically modulating mitochondria–endoplasmic reticulum contacts (MERCs) in response to dietary fluctuations. While MERCs exhibit prono Show more
The hepatocytes orchestrate anabolic and catabolic pathways by dynamically modulating mitochondria–endoplasmic reticulum contacts (MERCs) in response to dietary fluctuations. While MERCs exhibit pronounced dietary sensitivity, the underlying regulatory mechanisms remain poorly elucidated. Here, a bimolecular fluorescence complementation-based proximity labeling strategy was utilized to identify the MERCs proteomes in hepatocytes under various nutritional conditions. As a result, many previously uncharacterized MERCs proteins were identified to be sensitive to nutritional state, suggesting that these proteins might play important roles in regulating hepatic metabolism. We further demonstrated that FADS3 accumulates at MERCs under starvation. FADS3 was proved to play important role for the maintenance of MERCs in both cell lines and mice liver. Deficiency of FADS3 in mice liver induces altered sphingolipid metabolism under starvation. Our study provided comprehensive insights into the composition and dynamics of mitochondria-ER contacts in hepatocytes under various metabolic conditions, and also revealed key regulatory proteins linking mitochondria-ER contacts and metabolic adaptation. [Image: see text] The online version contains supplementary material available at 10.1186/s12964-026-02679-5. Show less
Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that contribute to tumor progression and therapeutic resistance in non-small cell lung cancer (NSCLC). Howev Show more
Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that contribute to tumor progression and therapeutic resistance in non-small cell lung cancer (NSCLC). However, effective strategies targeting CAF regulation remain limited. Here, we investigated the effects of the plant-derived compound 20(S)-Ginsenoside Rg3 on CAFs using an integrated network pharmacology and experimental validation approach. Network pharmacology analysis identified 107 overlapping targets between Rg3 and NSCLC. PPI network analysis highlighted EGFR, JUN, TP53, and STAT3 as key hub genes. KEGG enrichment analysis indicated that these targets were significantly enriched in the IL-17 and MAPK signaling pathways. These genes and pathways have been associated with fibroblast activation and tumor stromal remodeling, suggesting a potential role of Rg3 in regulating CAF-related processes within the tumor microenvironment. Functional experiments demonstrated that Rg3 inhibited CAF proliferation, colony formation and migration, while inducing apoptosis and mitochondrial dysfunction. Mechanistically, Rg3 upregulated IL-17RD and suppressed FGFR1-MAP2K4-JNK-c-Jun signaling. Furthermore, co-culture experiments revealed that Rg3-treated CAFs exhibited reduced pro-tumorigenic effects on NSCLC cells, indicating impaired tumor-stroma communication. Collectively, these findings demonstrate that 20(S)-Ginsenoside Rg3 suppresses CAF activation and function associated with the IL-17RD-FGF-MAP2K4-JNK-c-Jun signaling pathway, highlighting its potential as a tumor microenvironment-targeted therapeutic agent in NSCLC. The online version contains supplementary material available at 10.1007/s10616-026-00957-1. Show less
Ovarian cancer (OC) is an aggressive gynecological malignancy with poor prognosis, largely due to late-stage diagnosis and high metastatic potential. However, the functional role and regulatory mechan Show more
Ovarian cancer (OC) is an aggressive gynecological malignancy with poor prognosis, largely due to late-stage diagnosis and high metastatic potential. However, the functional role and regulatory mechanisms of fibroblast growth factor receptor 1 (FGFR1) in OC remain incompletely understood. In this study, we investigated the expression pattern and biological function of FGFR1 in OC and explored its underlying molecular mechanisms. FGFR1 expression was analyzed using TCGA, GTEx, and tissue microarray datasets, and its prognostic significance was evaluated by Kaplan-Meier survival analysis. Functional assays were performed in OVCAR-3 and SK-OV-3 cells following FGFR1 knockdown or overexpression to assess cell proliferation, migration, invasion, and metabolic activity, including extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Lactate production and histone lactylation were measured by biochemical assays and Western blotting. Protein interaction between FGFR1 and SIRT3 was examined by co-immunoprecipitation and immunofluorescence, and rescue experiments were conducted to determine SIRT3 dependency. In vivo subcutaneous xenograft models were used to evaluate the role of FGFR1 in tumor growth. We found that FGFR1 expression was significantly reduced in OC tissues and that low FGFR1 levels were associated with unfavorable clinical outcomes. Functionally, FGFR1 silencing promoted OC cell proliferation, migration, invasion, and metabolic activity, whereas FGFR1 overexpression exerted inhibitory effects. Mechanistically, FGFR1 interacted with SIRT3 and stabilized its protein expression. Importantly, SIRT3 knockdown abrogated the FGFR1-mediated reductions in lactate production, glycolytic enzyme expression, ATP levels, and histone lactylation, indicating that FGFR1 regulates metabolic reprogramming through a SIRT3-dependent mechanism. Consistently, FGFR1 knockdown promoted the formation of larger and more invasive tumors in vivo. Collectively, these findings demonstrate that FGFR1 functions as a context-dependent tumor suppressor in OC by modulating SIRT3-mediated metabolic reprogramming and histone lactylation, suggesting that targeting the FGFR1-SIRT3 axis may represent a potential therapeutic strategy for ovarian cancer. Show less
High mobility group AT-hook 1 (HMGA1) is a chromatin regulator overexpressed in various cancers, often predicting poor outcomes. However, its role in head and neck squamous cell carcinoma (HNSCC) rema Show more
High mobility group AT-hook 1 (HMGA1) is a chromatin regulator overexpressed in various cancers, often predicting poor outcomes. However, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. A hallmark of HNSCC is the rapid growth of its vasculature. Here, we identify an epigenetic mechanism whereby HMGA1 promotes tumor progression and angiogenesis via upregulation of fibroblast growth factor-binding protein 1 (FGFBP1). 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, mak Show more
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
Short-chain fatty acids (SCFAs) are key microbial metabolites that support intestinal and skeletal development, yet their coordinated effects during early life remain poorly defined. In this study, ne Show more
Short-chain fatty acids (SCFAs) are key microbial metabolites that support intestinal and skeletal development, yet their coordinated effects during early life remain poorly defined. In this study, neonatal mice were administered SCFAs for 28 days to evaluate their impacts on growth, intestinal barrier integrity, immune modulation, bone development, and gut microbiota composition. Valerate supplementation significantly increased body weight and intestinal length. It enhanced the villus structure, crypt depth, and goblet cell number, alongside upregulation of tight junction and mucin genes, indicating improved barrier function. Valerate and propionate also promoted the expression of interleukin-4 (IL-4) and interleukin-10 (IL-10) and reduced pro-inflammatory cytokines, suggesting an immunomodulatory shift. In the skeletal system, valerate improved the microarchitecture, increased bone mineral density (BMD), and upregulated osteogenic genes runt-related transcription factor 2 (Runx2), fibroblast growth factor receptor 1 (FGFR1), and growth hormone receptor (GHR). Microbiota profiling showed enrichment of several genera ( Show less
Aging worsens Alzheimer's disease (AD) peripheral metabolism and central pathology, yet few interventions are effective when started late. Methionine restriction (MR) induces the hepatokine FGF21 and Show more
Aging worsens Alzheimer's disease (AD) peripheral metabolism and central pathology, yet few interventions are effective when started late. Methionine restriction (MR) induces the hepatokine FGF21 and may protect brain function, but its efficacy and mechanisms when started late are unclear. Fourteen-month-old male APP/PS1 mice received 17 weeks of MR (0.17% methionine); behavioral, histological, and molecular assays were performed and hippocampal FGFR1 was knocked down by adeno-associated virus. Late-life MR improved peripheral glucose/lipid profiles, reduced Aβ deposition, preserved synaptic markers, and suppressed neuroinflammation. MR-induced hepatic FGF21 and brain FGFR1-AMPKα signaling to inhibit NFκB; hippocampal FGFR1 knockdown abolished MR's neuroprotective effects while leaving peripheral metabolic changes intact. Even when initiated in late life, MR robustly reduces AD pathology via the hepatic FGF21-brain FGFR1 axis, independent of peripheral metabolic changes. These preclinical findings position MR and FGF21-FGFR1 axis as actionable late-life intervention targets with potential for clinical translation. Show less
Intervertebral disc degeneration (IVDD), a major cause of low back pain, is primarily characterized by compromised regeneration ability of nucleus pulposus-derived stem cells (NPSCs) owing to their se Show more
Intervertebral disc degeneration (IVDD), a major cause of low back pain, is primarily characterized by compromised regeneration ability of nucleus pulposus-derived stem cells (NPSCs) owing to their senescence. The role of NPSCs as major regenerative cells in IVDD is garnering attention. However, the drivers and mechanisms of NPSCs reactivation and regeneration are poorly understood, limiting the development of targeted therapies. The fibroblast growth factor (FGF) family has shown increasing promise in tissue regeneration; however, the key factors involved in IVDD remain unclear. To elucidate the regenerative driver of NPSCs and the underlying anti-senescence mechanism to provide a potential therapeutic strategy. Single cell RNA sequencing (scRNA-seq) and bulk RNA sequencing were performed to identify the key NPSCs clusters and regenerative drivers in IVDD. Clinical IVDD samples were collected to determine the alterations in the NPSCs subset proportion and the expression of regeneration factors. Further, NPSCs senescence and in vivo models were utilized to investigate the specific mechanisms and therapeutic effects. Thy-1 membrane glycoprotein (THY1) Our findings elucidate the pivotal roles of THY1 Show less
Serous endometrial cancer (SEC) is an aggressive subtype of endometrial cancer (EC) with poor prognosis and limited treatment options. Here, we developed a clinically relevant, immunocompetent serous- Show more
Serous endometrial cancer (SEC) is an aggressive subtype of endometrial cancer (EC) with poor prognosis and limited treatment options. Here, we developed a clinically relevant, immunocompetent serous-like mouse model incorporating oncogenic Show less
Chronic hepatitis B virus (HBV) infection is a major risk factor of hepatocellular carcinoma (HCC), and hepatocyte-derived host factors play important roles in HBV-associated tumor progression. Alpha- Show more
Chronic hepatitis B virus (HBV) infection is a major risk factor of hepatocellular carcinoma (HCC), and hepatocyte-derived host factors play important roles in HBV-associated tumor progression. Alpha-1B glycoprotein (A1BG) is a plasma glycoprotein reported to be dysregulated in multiple cancers. In this study, we investigated the functional role of A1BG in HBV-associated HCC progression. Both the HepG2 and HBV-transfected HepG2 cell lines were used to examine the biological effects of A1BG. A1BG expression was modulated using siRNA and a plasmid vector. A series of functional assays were conducted to assess cell proliferation, apoptosis, stemness, migration, and invasion. RNA microarray analysis and gene set enrichment analysis (GSEA) were performed to identify A1BG-regulated pathways. Functionally, A1BG overexpression suppressed cell proliferation, stemness, migration, invasion, and HBV products while promoting apoptosis in both HepG2 and HBV-transfected HepG2 cells. In contrast, opposite effects were shown in the event of A1BG knockdown. Moreover, A1BG expression was reduced in HBV-associated HCC tissues and correlated with advanced pathological stage and poor prognosis. RNA microarray analysis and GSEA revealed the activation of anti-HBV-related genes and suppression of FGFR1 signaling and the matrix metalloproteinase pathway in A1BG-overexpressing cells. This study provides evidence that A1BG may be a novel host factor associated with the in vitro suppression of HBV replication and HCC progression by modulating pathways related to enhanced antiviral effects, reduced proliferative capacity and stemness, and suppression of EMT. These findings suggest that A1BG is a potential therapeutic target in HBV-related HCC. Show less
Hypertrophic scar (HS) represents a skin fibroproliferative disease characterized by a high incidence, frequent recurrence, and limited treatment options. Thus, identifying new targets to optimize the Show more
Hypertrophic scar (HS) represents a skin fibroproliferative disease characterized by a high incidence, frequent recurrence, and limited treatment options. Thus, identifying new targets to optimize the treatment of HS is of critical importance. Using summary statistics from the eQTLGen Consortium, Decode database, and FinnGen cohort, we conducted transcriptome-wide and proteome-wide Mendelian randomization (MR) to discover potential pharmacological targets against HS, with subsequent validation via RNA sequencing. Upstream regulators and downstream mechanisms were further investigated to better understand the roles of the pathogenic gene. Drug prediction, molecular docking, and molecular dynamics (MD) simulation were employed to estimate the value of potential drugs for HS. A high level of fibroblast growth factor receptor 1 (FGFR1) significantly increased the risk of HS according to transcriptome-wide (P = 0.011) and proteome-wide MR (P = 0.002) analyses. RNA-seq further validated the high expression of FGFR1 in HS. Gene-gene interaction network and enrichment analysis identified FGFR1 as the core gene driving the progression of HS, highlighting multiple biosynthetic processes. Pharmacological evaluation of candidate drugs predicted stable binding between Ro-4396686 and FGFR1. Our findings suggest that FGFR1 can serve as promising target for optimizing HS treatments, potentially reducing the costs of drug development. Show less
FGFR1 overexpression is strongly correlated with tumorigenesis, malignant progression, and poor clinical outcomes of nonsmall cell lung cancer (NSCLC). The development of PET radiotracers specifically Show more
FGFR1 overexpression is strongly correlated with tumorigenesis, malignant progression, and poor clinical outcomes of nonsmall cell lung cancer (NSCLC). The development of PET radiotracers specifically targeting FGFR1 holds significant clinical value for guiding FGFR1-targeted therapy, evaluating treatment efficacy, and monitoring drug resistance. In this study, we used computational simulation approaches to develop linear peptide RY9 along with cyclic peptides cRY9 and cRY9M, derived from FGF2, a particular ligand of FGFR1, and designed FGFR1-targeting radiotracers [ Show less
Gang Wang, Zengyaran Yue, Wen Zhou+12 more · 2026 · Phytomedicine : international journal of phytotherapy and phytopharmacology · Elsevier · added 2026-04-24
Distant metastasis of colorectal cancer (CRC) is strongly driven by metabolic reprogramming and epithelial-mesenchymal transition (EMT). Increasing evidence suggests that these two processes form a re Show more
Distant metastasis of colorectal cancer (CRC) is strongly driven by metabolic reprogramming and epithelial-mesenchymal transition (EMT). Increasing evidence suggests that these two processes form a reinforcing positive feedback loop; however, the integrated regulatory mechanism and its potential for pharmacological intervention remain insufficiently understood. This study aimed to elucidate the mechanistic coupling between autophagy, metabolic reprogramming, and EMT, and to develop a targeted pharmacological strategy capable of disrupting this positive feedback loop. We systematically constructed and validated an autophagy-metabolism-phenotypic transformation regulatory axis centered on ATG4B and PKM2, and evaluated the therapeutic efficacy of Curcumol as a pathway-specific natural compound intervention. Biochemical assays, protein-protein interaction analyses, and functional experiments were performed to determine how ATG4B regulates PKM2 Tyr105 phosphorylation, nuclear translocation, and glycolytic activity. Curcumol was applied to assess its ability to activate ATG4B-dependent autophagy and inhibit PKM2 activation. Anti-tumor efficacy was validated using colorectal cancer organoids, orthotopic implantation, and liver metastasis mouse models. ATG4B was identified as a core autophagy enzyme that directly binds to and shields the PKM2 Tyr105 site, preventing FGFR1-mediated phosphorylation and nuclear translocation. This blockade suppressed the Warburg effect, reduced lactate production, and synergistically inhibited EMT progression. Curcumol activated ATG4B-dependent autophagy, inhibited PKM2 activation, and effectively disrupted the metabolism-EMT positive feedback loop. In multiple CRC models, Curcumol markedly suppressed tumor growth and metastasis, supporting its therapeutic potential. This study reveals the ATG4B-PKM2 axis as a critical regulatory node linking autophagy, metabolic reprogramming, and EMT. Targeting this axis with Curcumol provides a precise strategy to interrupt metabolism-phenotype coupling, offering a mechanistically grounded and translationally promising approach for inhibiting CRC progression and metastasis. Show less
Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in men. Androgen deprivation therapy (ADT) has been widely used as the first-line treatment for PCa. H Show more
Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in men. Androgen deprivation therapy (ADT) has been widely used as the first-line treatment for PCa. However, most PCa will progress to castration-resistant PCa (CRPC) that resists ADT 1 to 3 years after the treatment. Steroidogenesis from cholesterol is one of the mechanisms leading to ADT resistance. In PCa cells, low-density lipoprotein (LDL) mediated uptake is the major venue to acquire cholesterol. However, the mechanism of regulating this process is not fully understood. Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase (RTK) that is ectopically expressed in PCa cells and promotes PCa progression by activating downstream signaling pathways. To comprehensively determine the roles of FGFR1 in PCa, we generated FGFR1-null DU145 cells and compared the transcriptomes of FGFR1-null and wild-type cells. We found that ablation of FGFR1 reduced the expression of genes promoting LDL uptake and de novo synthesis of cholesterol, thereby reducing the overall cholesterol pool in PCa cells. Detailed mechanistic studies further revealed that FGFR1 boosted the activation of sterol regulatory element-binding protein 2 (SREBP2) through ERK-dependent phosphorylation and cleavage, which, in turn, increased the expression of low-density lipoprotein receptor (LDLR) and enzymes involved in de novo cholesterol synthesis. Furthermore, in silico analyses demonstrated that high expression of FGFR1 was associated with high LDLR expression and clinicopathological features in PCa. Collectively, our data unveiled a previously unrecognized therapeutic avenue for CRPC by targeting FGFR1-driven cholesterol uptake and de novo synthesis. Show less
Approximately 10% of breast cancer cases are hereditary and associated with germline BRCA1/2 mutations. To characterize the somatic alteration landscape and HRD-related genomic features, we analyzed n Show more
Approximately 10% of breast cancer cases are hereditary and associated with germline BRCA1/2 mutations. To characterize the somatic alteration landscape and HRD-related genomic features, we analyzed next-generation sequencing and clinical data from 1,243 breast cancer patients treated at Tianjin Cancer Hospital Airport Hospital between October 2021 and November 2024. We compared mutation patterns and clinicopathological features between patients with and without germline BRCA (gBRCA) mutations and further assessed somatic alterations and homologous recombination deficiency (HRD) in those carrying pathogenic variants. PIK3CA mutations were significantly more frequent in the Non-Germline and non-gBRCA groups than in the Germline and gBRCA groups (49% vs. 6%; 47% vs. 0%; both P < 0.001), indicating mutual exclusivity with gBRCA mutations. Conversely, PTEN alterations co-occurred in 30% of gBRCA cases, while TP53 mutations were mutually exclusive with MDM2 and FGFR1. HER2 amplification was identified in 10% of gBRCA-mutated tumors, and somatic alterations in non-gBRCA tumors were enriched in endocrine-resistance pathways. HRD scores were markedly higher in gBRCA patients than in non-gBRCA patients (median 59 vs. 24.5, P = 0.015), driven by significant increases in large-scale state transitions (LST) and telomeric allelic imbalance (TAI). The overall gBRCA1/2 mutation frequency was 15.61%, and two previously unreported variants, BRCA1 NM₀₀₇₂₉₄.3:c.4185G>A and BRCA2 NM₀₀₀₀₅₉.3:c.439C>A, were identified in the Chinese population. These findings provide a biological rationale to explore AKT1/HER2-targeted combinations with PARP inhibition in future studies for gBRCA-mutated breast cancer and provide the first evidence of PIK3CA-gBRCA mutual exclusivity in Chinese patients. The elevated HRD scores further underscore the presence of homologous recombination deficiency in the gBRCA group. Show less