This study aims to investigate the effect of exosomes derived from olfactory mucosa mesenchymal stem cells (OM-MSCs-Exo) on microglial polarization and its potential therapeutic role in Alzheimer's di Show more
This study aims to investigate the effect of exosomes derived from olfactory mucosa mesenchymal stem cells (OM-MSCs-Exo) on microglial polarization and its potential therapeutic role in Alzheimer's disease (AD). OM-MSCs-Exo were isolated and purified from the mice olfactory mucosa, followed by phenotypic characterization. Proteins transferred by OM-MSCs-Exo were screened using proteomic analysis. The AD model was established in microglial cells and mice with Aβ 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
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 sha Show more
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
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
Microglia play dual roles in neuroinflammation, driving either detrimental M1 or protective M2 polarization, which critically impacts the outcomes of ischemic stroke. While fibroblast growth factor 20 Show more
Microglia play dual roles in neuroinflammation, driving either detrimental M1 or protective M2 polarization, which critically impacts the outcomes of ischemic stroke. While fibroblast growth factor 20 (FGF20) is established as a neurotrophic factor with neuroprotective properties, its role in regulating microglial polarization remains unclear. This study investigated a novel function of FGF20 in alleviating post-stroke neuroinflammation and its underlying mechanisms. In a rat model of middle cerebral artery occlusion (MCAO), intracerebroventricular administration of FGF20 significantly reduced infarct volume and improved neurological function. RT-PCR analysis revealed that FGF20 bidirectionally regulated cytokine expression, suppressing M1-associated markers (CD86, IL-1β, IL-6, iNOS, TNF-α) while enhancing M2-associated markers (IL-10, Arg-1). Immunofluorescence staining demonstrated that FGF20 attenuated microglia activation in peri-infarct striatum and hippocampus. In vitro, FGF20 counteracted LPS-induced M1 polarization in primary microglia, downregulated the TLR4/NF-κB pathway, and upregulated TREM2 expression. Notably, while the selective FGFR1 inhibitor PD173074 abolished FGF20-induced TREM2 upregulation, it did not reverse the suppression of TLR4/NF-κB, indicating that these two effects are mediated through distinct regulatory mechanisms. These phenotypic shifts were further confirmed by a reduction in CD32/16 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
The response rate to immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC) remains unsatisfactory, and the mechanisms of resistance are not fully understood. Here, we investigated the rol Show more
The response rate to immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC) remains unsatisfactory, and the mechanisms of resistance are not fully understood. Here, we investigated the role of fibroblast growth factor receptor 1 (FGFR1) in shaping the tumor microenvironment (TME) and mediating ICB resistance. An anti-PD-1-resistant HCC model was established in mice, followed by single-cell RNA sequencing to profile TME alterations. We observed that ICB resistance was associated with FGFR1 upregulation, which activated MAPK signaling and induced SPP1 expression. This cascade promotes macrophage infiltration and M2-type polarization, while simultaneously suppressing T cell recruitment and cytotoxic function, thereby fostering an immunosuppressive microenvironment. SPP1 knockdown or neutralization significantly reduced macrophage accumulation and restored intratumoral T cell infiltration. Importantly, pharmacological inhibition of FGFR1 using BGJ398 synergized with anti-PD-1 therapy, resulting in enhanced antitumor efficacy in preclinical models. Analysis of clinical datasets further revealed that high FGFR1 expression correlated with poor responses to ICB of HCC patients. Collectively, these findings identify FGFR1 as a key mediator of ICB resistance in HCC. Targeting FGFR1 represents a promising strategy to reprogram the immunosuppressive TME and enhance response to immunotherapy, with potential additional value as a predictive biomarker. Show less
To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies. Twenty-four patients wi Show more
To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies. Twenty-four patients with concern for NS underwent clinical and central radiological review in this multi-institutional study. Whole-exome sequencing, RNA sequencing, and methylation analyses of peripheral blood and/or tumor specimens were performed. Nineteen (79%) of 24 participants had NS, 17/19 (89%) of which had a germline The online version contains supplementary material available at 10.1007/s11060-026-05478-7. 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
Myelin debris accumulation after spinal cord injury (SCI) drives persistent neuroinflammation, lysosomal dysfunction, and lipid overload in macrophages, ultimately impairing tissue repair. Here, we id Show more
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
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
FGFRs genetic alterations such as mutations, amplifications, and chromosomal translocations are prevalent in cancers, leading to the initiation and progression of tumors by enhancing FGFR signaling. T Show more
FGFRs genetic alterations such as mutations, amplifications, and chromosomal translocations are prevalent in cancers, leading to the initiation and progression of tumors by enhancing FGFR signaling. The substantial problems arising from the lack of decisive clinical evidence have resulted in the cessation of some inhibitor applications, and identifying effective small molecule inhibitors that selectively target FGFRs can advance the therapy of cancers driven by FGFRs abnormalities. The three-dimensional structure of the FGFR1/2/3/4 protein and the amino acid positions within the tyrosine kinase domain were downloaded from the PDB database, and small molecule data were extracted from the ZINC15 database. Then, we used molecular docking and dynamics simulations to assess compounds interacting with FGFR proteins, and screening potential small molecules targeting FGFR. Finally, we evaluated its effects by two CRC cell line HCT116 and NCI-H716. In the study, by docking with 2.8 million small molecules, we identified three promising FGFR small molecule inhibitors ranked in the top average absolute difference in free energy. By evaluating the binding stability of the docking pose of the three compounds, we found that ZINC000101867325 could form the stable binding interactions with FGFR1/2/3. And, ZINC000101867325 inhibited the activity of FGFR signaling, and resulted in cell apoptosis and decrease in cell proliferation and migration in colorectal cancer cell lines. In addition, ZINC000101867325 is also predicted to target FGFR2 mutations in colorectal cancer patients. We predicted three small molecules targeting FGFRs, and ZINC000101867325 shows superior chemical bond types and stability with FGFR1/2/3, and inhibits FGFR signaling in CRC cell lines. This study provides novel FGFRs inhibitors, which enrich treatment strategies for cancers. 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
Uveal melanoma (UM), a rare yet aggressive ocular malignancy in adults, highlights the critical need for targeted therapies to improve clinical outcomes. Elevated FGFR1 expression in UM correlates wit Show more
Uveal melanoma (UM), a rare yet aggressive ocular malignancy in adults, highlights the critical need for targeted therapies to improve clinical outcomes. Elevated FGFR1 expression in UM correlates with aggressive disease progression and poor survival outcomes, underscoring its therapeutic value. This study reports the development of [ Show less
To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies. Twenty-four patients wi Show more
To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies. Twenty-four patients with concern for NS underwent clinical and central radiological review in this multi-institutional study. Whole-exome sequencing, RNA sequencing, and methylation analyses of peripheral blood and/or tumor specimens were performed. Nineteen (79%) of 24 participants had NS, 17/19 (89%) of which had a germline Show less
To characterize whole-brain cortical thickness alteration in Kallmann syndrome (KS), assess its correlation with cognitive impairment, and explore the genetic association and extrapolated transcriptio Show more
To characterize whole-brain cortical thickness alteration in Kallmann syndrome (KS), assess its correlation with cognitive impairment, and explore the genetic association and extrapolated transcriptional underpinning. We prospectively recruited 100 patients with KS and 100 age- and sex-matched healthy controls. All participants underwent high-resolution structural MRI and a comprehensive neuropsychological assessment targeting global cognition (Montreal Cognitive Assessment, MoCA), executive function and inhibitory control (Stroop Color and Word Test, SCWT), cognitive flexibility (Trail Making Test, TMT), working memory (Digit Span Test, DST), and visuospatial memory (Visual Reproduction task, VR). Cortical thickness and subcortical volumes were quantified using FreeSurfer. In the KS cohort, we examined brain-cognition correlations, performed exploratory genetic association analysis using whole-exome sequencing, and conducted extrapolated neuroimaging-transcription analysis using the Allen Human Brain Atlas (http://human.brain-map.org/) to identify underlying biological pathways. Compared to the healthy controls, patients with KS exhibited significant cognitive deficits, with 36% MoCA scoring below the clinical cutoff for cognitive impairment. Domain-specific analysis revealed impairments in SCWT-C, DST-Backward, TMT-B, and VR (all P-value < .05). Structurally, patients showed bilateral increased cortical thickness predominantly in the fronto-limbic circuit (orbitofrontal and subgenual cingulate cortices) and default mode network (voxel P-value < .001, cluster random field theory corrected P-value < .05), alongside bilateral hippocampal enlargement (P-FDR = .048). Crucially, the cortical thickness in these fronto-limbic regions was negatively correlated with SCWT-C and DST. Exploratory genetic analysis linked variants in genes such as OTUD4 and FGFR1 to cognitive variability (TMT-A and VR). Furthermore, the spatial pattern of cortical thickening was significantly associated with extrapolated gene expression profiles enriched for neurodevelopment, neuronal migration, and synaptic function. This study identified cortical thickening involved in fronto-limbic and default mode network as key neuroanatomical signatures of the patients with KS, which was associated with cognitive impairment. Specific genetic variants may further modulate the structural alterations and cognitive functioning in patients with KS. 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 ce Show more
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
Congenital hypogonadotropic hypogonadism (CHH) is a rare and genetically heterogeneous disorder characterized by absent or incomplete puberty due to impaired gonadotropin-releasing hormone (GnRH) func Show more
Congenital hypogonadotropic hypogonadism (CHH) is a rare and genetically heterogeneous disorder characterized by absent or incomplete puberty due to impaired gonadotropin-releasing hormone (GnRH) function. A subset of individuals with CHH also present with developmental anomalies, including midline defects such as cleft lip and/or palate (CLP). This study investigates the genetic overlap between CHH and CLP. A total of 336 individuals diagnosed with CHH were clinically assessed for associated phenotypes, including CLP. High-throughput sequencing was performed using a targeted gene panel encompassing known CHH- and CLP-related genes. Variants were analyzed and classified according to the American College of Medical Genetics and Genomics (ACMG) criteria for pathogenicity. CLP was present in 21 patients with CHH (6%). Pathogenic or likely pathogenic variants in genes associated with both CHH and CLP-such as FGFR1 and CHD7-were identified in eight individuals. Furthermore, 17% of the patients with CHH without CLP harbored deleterious variants in genes implicated in clefting, including DVL3, PLCB4, NIPBL, and EDNRA. Evidence of digenic inheritance involving both CHH- and CLP-related genes was observed in multiple cases. FGFR1 variants were the most frequently detected and were commonly associated with anosmia and additional developmental anomalies. These findings highlight a genetic and phenotypic continuum between CHH and CLP, underscoring the involvement of shared developmental pathways. The high prevalence of FGFR1 variants in patients with CHH and CLP supports its role as a pleiotropic gene. Understanding the overlapping genetic mechanisms may enhance diagnostic precision and inform personalized management strategies for affected individuals. Show less
Autophagy is integral to the rapid proliferation of esophageal squamous cell carcinoma (ESCC), and its regulation presents a promising avenue for therapeutic intervention. Recent studies have elucidat Show more
Autophagy is integral to the rapid proliferation of esophageal squamous cell carcinoma (ESCC), and its regulation presents a promising avenue for therapeutic intervention. Recent studies have elucidated the interplay between autophagy and glucose metabolism, while there is a paucity of anticancer drugs that concurrently target these 2 biological processes. In this study, we identified a natural compound, Show less
Focal articular cartilage defects often progress to osteoarthritis, imposing a substantial global health burden. Current neglect of cartilage developmental regulation and cartilage microenvironment co Show more
Focal articular cartilage defects often progress to osteoarthritis, imposing a substantial global health burden. Current neglect of cartilage developmental regulation and cartilage microenvironment compromises therapeutic efficacy. We developed an innovation CE-SKP/CPH/P2G3 scaffold which effectively repairs focal cartilage defects and emulates native cartilage ontogeny: the superficial CE-SKP hydrogel layer recruits SMSCs and promotes chondrogenesis; the middle CPH hydrogel layer induces chondrocyte hypertrophic calcification, forming cartilage calcified layer; and the basal P2G3 nanofiber membrane isolates subchondral cells, enforcing a top-down developmental sequence and preserving a localized hypoxic niche. Show less
This study evaluates the anti-sepsis efficacy and potential risks of the FGFR1 inhibitor PD-166866 by integrating network pharmacology, transcriptome sequencing, and network toxicology. In terms of dr Show more
This study evaluates the anti-sepsis efficacy and potential risks of the FGFR1 inhibitor PD-166866 by integrating network pharmacology, transcriptome sequencing, and network toxicology. In terms of druggability, network pharmacology was used to screen drug-disease common targets and conduct enrichment analysis. Meanwhile, transcriptome sequencing was performed on the LPS-induced Raw264.7 cell model for target validation. In terms of toxicology, network toxicology was applied to predict the potential toxicity of small molecules, which was further verified by gene expression and survival analysis using the TCGA and Kaplan-Meier Plotter databases. A total of 39 common targets between PD-166866 and sepsis were identified. The core pathways include the Rap1 signaling pathway, and the core targets are SRC, EGFR, and CCND1; molecular docking showed stable binding between PD-166866 and these targets. Transcriptomic analysis confirmed that PD-166866 can significantly regulate the expression of inflammation-related genes and inhibit the Rap1 pathway. Network toxicology indicated a significant risk of hematological toxicity associated with this drug. Transcriptome sequencing revealed that PD-166866 treatment led to the downregulation of IRAK3 and IKBKE, and the low expression of these two genes was significantly associated with poor prognosis in leukemia patients, confirming the potential hematological toxicity of PD-166866. This study confirms that PD-166866 exerts anti-sepsis effects by regulating pathways such as Rap1, but it also has the potential risk of inducing leukemia. More importantly, this study successfully established a comprehensive evaluation framework integrating in silico and in vitro experiments. It provides a feasible methodological reference for systematically evaluating the dual attributes of "efficacy-risk" in the early stage of drug development and reducing the initial reliance on traditional animal models. Show less
Fibroblast growth factor receptor 2 (FGFR2) has gained recognition as a compelling therapeutic target in oncology. We present LHQ766, a novel orally bioavailable FGFR2 inhibitor demonstrating exceptio Show more
Fibroblast growth factor receptor 2 (FGFR2) has gained recognition as a compelling therapeutic target in oncology. We present LHQ766, a novel orally bioavailable FGFR2 inhibitor demonstrating exceptional potency and selectivity, through optimization of our previously reported FGFR2 inhibitor 7. The structures and purity of all target compounds were confirmed by Show less
Breast cancer (BC) progression is intricately linked to the dysregulation of transfer RNA-derived fragments (tRFs). Through comprehensive analysis of The Cancer Genome Atlas (TCGA) data, it is demonst Show more
Breast cancer (BC) progression is intricately linked to the dysregulation of transfer RNA-derived fragments (tRFs). Through comprehensive analysis of The Cancer Genome Atlas (TCGA) data, it is demonstrated that 5'tRF-GlyGCC is overexpressed in BC tissues and negatively associated with patients' survival. Mechanistically, 5'tRF-GlyGCC binds to lactate dehydrogenase A (LDHA), enhancing its enzymatic activity and promoting glycolysis, which drives BC cell malignancy. This binding is mediated by the phosphorylation of LDHA at tyrosine 10, and facilitated by fibroblast growth factor receptor 1 (FGFR1), through the formation of a ternary complex that amplifies oncogenic signaling. Furthermore, 5'tRF-GlyGCC/LDHA axis induces macrophage infiltration and polarization toward an M2 phenotype, mediated by the chemokine CCL7, thereby reshaping the tumor microenvironment. Additionally, it is uncovered that the biogenesis of 5'tRF-GlyGCC is regulated by ALKBH3 and ANG, which also modulate LDHA activity. In vivo, targeting 5'tRF-GlyGCC/LDHA signaling significantly suppresses tumor growth and enhances the efficacy of immunotherapy. Collectively, these findings elucidate the pivotal role of 5'tRF-GlyGCC in BC progression, highlighting its potential as therapeutic target for BC treatment. Show less
Hepatitis B virus (HBV) infection can cause liver damage through oxidative stress (OS) and immune-inflammatory responses. This study aims to explore the clinical significance of fibroblast growth fact Show more
Hepatitis B virus (HBV) infection can cause liver damage through oxidative stress (OS) and immune-inflammatory responses. This study aims to explore the clinical significance of fibroblast growth factor 21 (FGF21) in the development and progression of chronic hepatitis B (CHB). A total of 336 participants were recruited, including 320 CHB patients and 16 healthy controls. The expression of FGF21, immune cytokines, and OS-related molecules in peripheral blood mononuclear cells (PBMCs) was detected using real-time quantitative polymerase chain reaction. The methylation level of the FGF21 gene promoter in PBMCs was detected using TaqMan probe-based quantitative methylation-specific PCR. The expression level of FGF21 in the peripheral blood of CHB patients was higher than that of HC, but the methylation level of the FGF21 promoter was lower than that of HC, especially in patients during the immune activation phase. The mRNA expression levels of CXCR3 and CCL5 in PBMCs of CHB patients during the immune activation and reactivation phases were higher than those in other clinical stages. Single-cell analysis revealed that CXCR3 and CCL5 expression in the immune tolerance and immune activation phases with high HBsAg expression was closely related to T lymphocytes (T cells) and natural killer cells (NK cells) and was highly expressed in CD4 and CD8 T cells and NK cells. In addition, the mRNA expression levels of Nrf2 and GPX4 in the reactivation phase were higher than those in other clinical stages. The mRNA expression level and methylation level of FGF21 in PBMCs of CHB patients were correlated with the viral load, immune inflammation, and OS levels during the antiviral treatment course of CHB. The methylation level of the FGF21 promoter has the potential to become a non-invasive biomarker for monitoring the progress of antiviral treatment in CHB.IMPORTANCEThis study conducted an in-depth exploration of the application of methylation detection technology, analyzing its value and driving mechanism in the oxidative stress and immune-inflammatory balance during the course of chronic hepatitis B. The study analyzed the methylation patterns of the FGF21 promoter and the expression levels of its receptor FGFR1, as well as the expression levels of chemokines CXCR3, CCL5, and oxidative stress factors GPX4 and Nrf2 in the immune tolerance period, immune clearance period, immune control period, and reactivation period of chronic hepatitis B. It clarified the association between these molecules and the FGF21/FGFR1 axis and revealed the synergistic or antagonistic mechanisms of these molecules in the oxidative stress and inflammatory vicious cycle. At the same time, this study also explored the value of FGF21 promoter methylation in disease diagnosis and prognosis, providing a theoretical basis for evaluating the antiviral treatment effect and disease progression of chronic hepatitis B. 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 import Show more
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
Early detection of myocardial abnormalities or other ischemic heart diseases is critical for effective treatment. Here, we aimed to engineer a cell-based system to sense cardiac troponin I (cTnI), an Show more
Early detection of myocardial abnormalities or other ischemic heart diseases is critical for effective treatment. Here, we aimed to engineer a cell-based system to sense cardiac troponin I (cTnI), an early marker of acute myocardial infarction (AMI), and respond by releasing a thrombolytic agent. To detect cTnI, we engineered a chimeric troponin receptor (TropR) that contains extracellular single-chain variable fragments (scFvs) and signals via intracellular domains of interleukin 6 receptor subunit beta (IL6RB), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor 1 (FGFR1), fibroblast growth factor receptor 2b (FGFR2b) or vascular endothelial growth factor receptor 2 (VEGFR2) that are associated with cardioprotective signaling. cTnI-dependent TropR functionality was confirmed in human embryonic kidney (HEK)-derived cell lines as well as iPSC-derived cardiomyocytes, and enabled rapid, reversible, tunable control of gene expression via synthetic-signaling-specific promoters. We then constructed monoclonal cell lines for cTnI-induced secretion of the thrombolytic protein tenecteplase (TNK), together with an off-switch triggered by FDA-approved doxycycline. We selected a clone, designated CardioProtect, whose sensitivity was optimized to detect human AMI-relevant cTnI levels. To validate thrombolytic efficacy, we established an ex vivo blood culture system and show that alginate-microencapsulated CardioProtect cells triggered complete lysis of fibrin clots in a strict cTnI-inducible, doxycycline-repressible manner. This closed-loop strategy serves as a proof-of-concept for using cell therapy in the early detection and treatment of AMI. Show less
This study aimed to integrate network pharmacology, bioinformatics analysis, molecular docking, and experimental validation to construct a "component-target-pathway" multidimensional network model, sy Show more
This study aimed to integrate network pharmacology, bioinformatics analysis, molecular docking, and experimental validation to construct a "component-target-pathway" multidimensional network model, systematically elucidate the potential mechanisms underlying the therapeutic effects of the extract of Potentilla freyniana Bornm. (PFB) on hepatocellular carcinoma (HCC), and thereby clarify its pharmacological basis. HCC datasets were retrieved from GEO and TCGA databases, and the DEGs were screened. The active components of the n-butanol extract of PFB were obtained by UHPLC-MS/MS, and the candidate target genes were predicted by the SwissTargetPrediction, Similarity Ensemble Approach, and SuperPred databases. The overlapping target genes were selected by GO and KEGG enrichment analysis, and the key target genes were screened by the SVM and RF algorithms. The verification of differentially expressed target genes and ROC analysis of key target genes were performed. Molecular docking was performed using CB-Dock2. We investigated the parameters of proliferation, migration, invasion, and apoptosis in the n-butanol extract of PFB treated HCC, and we verified the expressions of key proteins in HCC by Western blot. Toxicity experiments showed that the n-butanol extract of PFB did not cause significant toxic damage to the mice heart, liver, and kidney. CCK8 assays detected that the n-butanol extract of PFB had inhibitory effects on HCC. Through network pharmacology, we obtained a total of 17 overlapping genes and finally screened out 6 key target genes by SVM and RF algorithm analyses. Molecular docking and molecular dynamics results showed that the active components of PFB, such as ellagic acid, luteolin, berberrubine, procyanidin B1, and adenosine, had better affinity with these key target genes. By qPCR and Western blot assays, we verified that the expressions of CDK1 and EZH2 and the key factors of the MPAK signaling pathway were significantly down-regulated in HCC. This study demonstrated that the n-butanol extract of PFB exhibits a strong inhibitory effect on the proliferation of HepG2 cells and clarifies the underlying molecular mechanisms involved. By precisely modulating the expression levels of critical signaling molecules - including CDK1, PDGFRB, AKT1, FGFR1, MAPK1, and EZH2 - the n-butanol extract of PFB robustly disrupts cancer cell cycle progression and perturbs the activity of associated signaling pathways, thereby significantly curtailing the aberrant proliferation of tumor cells. This study not only elucidated the effects of the n-butanol extract of PFB on the aforementioned targets but also established a theoretical and experimental basis for further investigating their application in the treatment of HCC. Furthermore, it offers novel insights and research directions for the development of innovative therapeutic strategies derived from natural products, particularly those centered on multi-target synergistic approaches for liver cancer treatment. Show less
This study aims to demonstrate the effect of toadflax (bufalin) on erlotinib resistance in nonsmall cell lung cancer (NSCLC) by inhibiting the fibroblast growth factor receptor (FGFR). The microfluidi Show more
This study aims to demonstrate the effect of toadflax (bufalin) on erlotinib resistance in nonsmall cell lung cancer (NSCLC) by inhibiting the fibroblast growth factor receptor (FGFR). The microfluidic mobility transferase and caliper mobility-shift assays were employed to detect the FGFR inhibition by bufalin and the binding reversibility. Further, the inhibitory effects of bufalin were determined in HCC827 and HCC827/ER cells in vitro , investigating relative FGFR overexpression by quantitative reverse transcriptase-PCR (RT-qPCR) and FGFR downstream proteins, that is, FGFR substrate 2 (FRS2), extracellular signal-regulated kinase (ERK), and S6 by western blot analysis. Finally, HCC827/ER-inoculated xenograft tumors were constructed to observe the effects of bufalin and bufalin + erlotinib intervention on tumor growth. Bufalin inhibited FGFR by reversibly binding to FGFR1. In addition, the western blot analysis indicated a significant reduction in the expression levels of FGFR, FRS2, ERK, and S6 proteins in HCC827 and HCC827/ER cells, increasing the expression levels of apoptotic caspase-3 and poly-(ADP-ribose) polymerase proteins. Bufalin + erlotinib combination significantly inhibited the apoptosis of HCC827/ER cells and subsequent tumor growth in vivo . In addition, FGFR overexpression significantly reversed the sensitivity of bufalin to HCC827/ER cells, promoting the value-addition of HCC827/ER cells. Further, bufalin + erlotinib significantly reduced the growth of erlotinib-resistant HCC827/ER tumors, induced apoptosis, and inhibited the expression of FGFR and p-ERK proteins. These findings indicated that bufalin could reverse the erlotinib resistance in NSCLC by inhibiting the FGFR expression. Show less