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Genetic alterations in FGFR2 drive multiple malignancies, most notably intrahepatic cholangiocarcinoma, where they occur in ∼10-15% of patients. While approved pan-FGFR inhibitors provide clinical benefit, their durability is limited by acquired, often polyclonal, on-target resistance mutations affecting key regions of the FGFR2 kinase domain, including the gatekeeper residue (V565), molecular brake residues (N550, E566, K642), and other key variants. These liabilities motivate the development of next-generation inhibitors. Given FGFR2-associated toxicities and the need for subtype selectivity, FGFR4 inhibition was prioritized as a selectivity determinant, while sparing FGFR1 was considered less critical. Guided by structure-based drug design, a reversible aminopyrimidine screening hit was optimized into a novel covalent inhibitor series active against FGFR2 wild-type and clinically relevant resistance mutations. An advanced lead Show less

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

Dysembryoplastic neuroepithelial tumours (DNETs) are rare with only a few hundred cases reported in literature. The long-term natural history of paediatric DNETs is still poorly understood. We present a rare case of DNET with recurrent tumour bleeds over 26 years of follow-up and provide a brief literature review of similar events. The patient is a 30-year-old Chinese male who presented with right-sided seizures since 3 years old. Initial neuroimaging was suspicious of left fronto-parietal glioma and was conservatively managed due to its location near the motor strip and concerns of potential surgical complications. Over the follow-up period, the patient suffered three bleeds. Following the third bleed, tumour resection was performed under intraoperative motor mapping, with near total resection. Intraoperatively, the tumour involved the post-central gyrus, with histological findings suggestive of low-grade glioma with FGFR1 alteration, in keeping with DNET. The latest neuroimaging showed no new haemorrhages or infarcts. Features of small residual tumour around the tumour cavity were noted. The patient is currently well with marked reduction of seizure episodes. Our report provides new insight into the long-term natural history of DNET and adds value to limited existing literature of similar cases. Show less

Type 2 diabetes mellitus (T2DM) requires multi-target therapeutic approaches addressing both insulin resistance and insulin secretion deficits. Although natural compounds are promising multi-target candidates, systematic identification of their polypharmacological profiles remains challenging. The objective of this study was to establish a computational framework for identifying natural compounds with multi-target therapeutic potential against T2DM through integrated structure-activity analysis and experimental validation. We developed an SELFormer deep learning model to predict natural compound activities against six T2DM-related proteins including glucagon-like peptide-1 receptor (GLP1R), kinesin family member-11 (KIF11) for insulin secretion and insulin receptor (INSR), peroxisome proliferator-activated receptor-gamma (PPARG), fibroblast growth factor receptor-1 (FGFR1) and insulin-like growth factor-1 receptor (IGF1R) for insulin resistance. Uniform Manifold Approximation and Projection (UMAP) for dimension reduction clustering characterized chemical space distributions and molecular docking validated multi-target binding. Selected compounds were experimentally validated using 3T3-L1 adipocytes and mouse insulinoma (MIN6) pancreatic β-cells. The SELFormer model achieved Show less

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

This study characterizes the expression of fibroblast growth factors (FGFs) and their receptors in the porcine corpus luteum (CL) across distinct stages of the oestrous cycle, and evaluates the regulatory role of FGF2 on angiogenesis, steroidogenesis, and cell survival in vitro. The CL was classified morphologically into four phases: Phase I (days 1-8; corpus haemorrhagicum; ELP), Phase II (days 9-14; highly vascularized CL; MLP), Phase III (day 15 onward; ischemic regression; LLP), and Phase IV (corpus albicans; avascular and regressed; RR). Each phase included 10 biological replicates (n = 10). Quantitative RT-PCR revealed significant upregulation (p < 0.001) of FGF1, FGF2, FGF7, FGFR1, FGFR2, and FGFR4 during early and mid-luteal stages. FGFR3 and FGFR2IIIC showed no significant variation, while FGFR2IIIB was downregulated (p < 0.001) during early/mid-luteal stages and upregulated during luteal regression. FGF10 expression declined significantly (p < 0.001) during regression. Western blotting Densitometry confirmed trends mRNA expression. In-vitro supplementation of FGF2 (1, 10, and 100 ng/ml) during the mid-luteal stage enhanced mRNA expression of angiogenic (vWF), steroidogenic (StAR, CYP11A1, 3β-HSD), and cell survival (PCNA, BAX) markers. StAR, CYP11A1, and 3β-HSD were significantly upregulated (p < 0.001) from 24 to 72 h in a dose-dependent manner. vWF and PCNA showed significant increases at 48 and 72 h, while BAX expression progressively declined (p > 0.001). The 100 ng/ml dose elicited the most pronounced effects. These findings suggest that FGF family members exert autocrine/paracrine effects that support luteal cell proliferation, differentiation, angiogenesis, steroidogenesis, and survival, underscoring their critical role in porcine ovarian physiology. 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) 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

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

The global obesity epidemic necessitates therapies that enhance energy expenditure. Non-shivering thermogenesis (NST) in brown/beige adipose tissue represents a promising target, with fibroblast growth factor 21 (FGF21) emerging as a critical regulator linking environmental stimuli to adipose plasticity and mitochondrial function. However, the precise mechanisms of FGF21 secretion and its specific role in adipose tissue browning and subsequent NST potentiation remain incompletely elucidated. FGF21 regulates NST via distinct spatiotemporal mechanisms. Acute cold exposure triggers hepatic FGF21 secretion through a β FGF21 exhibits dual regulation: hepatic (acute lipid mobilization) and adipose-based (chronic browning); adipose-targeted FGF21 delivery is essential for therapeutic efficacy, and future studies should integrate FGF21 with UCP1-independent pathways (e.g., creatine/succinate cycles) to advance obesity treatment. Show less

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare lung malignancy characterized by an aggressive clinical course and an unfavorable prognosis. Next-generation sequencing (NGS) has revealed that LCNECs exhibit molecular features resembling either small-cell lung carcinoma (SCLC-like LCNEC) or non-small cell lung carcinoma (NSCLC-like LCNEC). This study aimed to characterize the incidence of actionable gene variants in a retrospective cohort of LCNEC patients using a targeted NGS approach. Microscopic diagnosis was established according to the 2021 World Health Organization (WHO) classification using a standard immunohistochemical (IHC) panel. In total, 216 LCNEC tumor samples were analyzed for molecular variants in 17 genes using the RNA-based Archer FusionPlex Lung NGS assay (Integrated DNA Technologies, USA) and the MiSeq platform (Illumina, USA)-an algorithm utilized for routine NSCLC diagnosis. Overall, 46 variants were identified in 46/216 (21.3%) tumor samples, with 28/216 (13%) LCNECs harboring at least one actionable molecular variant potentially targetable by registered or investigational agents. Show less

Myeloid/Lymphoid neoplasms with FGFR1 rearrangement (M/LN-FGFR1) are rare, heterogenous diseases due to fusion transcripts originated by translocations of FGFR1 with different partners, resulting in constitutive FGFR1-mediated signaling. Presentation varies from chronic myeloid neoplasms to acute leukemia or lymphoma and extramedullary localizations are common. Outside allogeneic stem cell transplantation (ASCT), survival with conventional therapy is dismal, representing an unmet clinical need. We summarize here the data that led to approval of pemigatinib, a FGFR1 inhibitor, showing unprecedented efficacy in M/LN-FGFR1. 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). 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 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

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

To analyze the clinical phenotype characteristics and genetic testing data of idiopathic hypogonadotropic hypogonadism (IHH) female patients, aiming to improve the understanding of genetic etiology and inheritance patterns among female patients. This study recruited twenty-one female patients and their clinical data were collected and analyzed. Based on the olfaction function, the patients were divided into normosmic IHH group and Kallmann syndrome (KS) group. Whole exome sequencing and Sanger sequencing were performed to screen for underlying genetic etiology including genetic variants of known pathogenic genes and PLEXIN pathway genes. Alphafold2 was used for mutant protein structure prediction of Normosmic IHH patients and KS patients had no difference in baseline clinical data. Among the 21 recruited patients, 17 patients and their immediate family members' peripheral blood was collected for sequencing, and four patients were found carrying pathogenic variants involving Female IHH patients have complex genetic etiology and polygenic inheri-tance mode. Both hereditary and sporadic patients may have various degrees of genetic inheritance risk. The missense variant Show less

Head and neck cancer (HNC) is a biologically heterogeneous malignancy with limited actionable therapeutic targets. The fibroblast growth factor receptor (FGFR) family comprises receptor tyrosine kinases implicated in tumor progression; however, their specific roles in HNC remain incompletely defined. Genomic alterations, transcriptomic profiles, and clinical relevance of Among FGFR4 functions as an oncogenic driver in HNC, promoting tumor progression through the ERK–RUNX3–MMP2 axis and mediating chemoresistance via FGFR4–ERK signaling. The ERK-dependent induction of FGF19 and FGFR4 establishes a positive feedback circuit that sustains oncogenic activation. Targeting the FGF19/FGFR4 axis, particularly when combined with MEK/ERK inhibitors, represents a promising strategy to overcome resistance in HNC. The online version contains supplementary material available at 10.1186/s12967-026-07999-1. Show less

Alginate oligosaccharides (AOS) have recently shown promising activities in inhibiting tumour growth in osteosarcomas. It is, however, unknown if AOS is also effective against nasopharyngeal carcinoma (NPC). To this end, the antiproliferation activities of enzymatically derived AOS were investigated against the EBV-positive NPC cell line, C666-1. MTT cytotoxicity assays revealed an antiproliferation effect against the C666-1 cell line, albeit at concentrations above 10 mg/mL, but promoting growth at lower concentrations. As a potential heparin sulfate analog, which also demonstrates a similar biphasic effect on cell proliferation, it was hypothesized that AOS may act on fibroblast growth factors (FGFs) and their receptors (FGFR) like heparin. This hypothesis was supported by in silico molecular docking, which discovered a similar binding pattern between AOS pentasaccharide and heparin pentasaccharide on FGF2, FGFR1 and FGF2-FGFR1 complex. Furthermore, all-atomic molecular dynamics simulations revealed that only the AOS pentasaccharide can pre-form the FGFR1 dimer for binding by FGF2 when one AOS molecule per FGFR1 dimer was simulated, while other AOS models (DP2-DP4) deformed the FGFR1 dimer to disfavour FGF2 binding during the simulations. In contrast, all AOS models (DP2-DP5) deformed the FGFR1 dimer when two AOS molecules per FGFR1 dimer were simulated without FGF2. These results suggest that the observed biphasic effects on cell proliferation by the AOS mixture may be attributed to the binding of the AOS pentasaccharide to the FGFR1/FGF2 proteins, although further experiments to validate this in silico observation are warranted. Show less

The current study reports the design and synthesis of novel totarol-based 1,3-thiazole derivatives DBT2-9 and evaluates their anticancer potential. The synthesis involved the reaction of totarol derivatives with thiosemicarbazone derivatives under optimized conditions. Structural characterization of the synthesized compounds was accomplished using high-resolution mass spectrometry (HRMS), infrared spectroscopy (IR), and nuclear magnetic resonance (NMR) spectroscopy, confirming their chemical identities and purity. The antitumor activity of these compounds was evaluated using the in vitro MTT and apoptosis assays. The compounds demonstrated selective anti-proliferative effects against MCF-7 breast cancer cells, and compound DBT9 had an IC Show less

Approximately 40% of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), advanced breast cancer (ABC) have PIK3CA alterations, which contributes to endocrine therapy resistance. Alpelisib, an α-selective phosphatidylinositol 3-kinase inhibitor and degrader, given in combination with fulvestrant, is approved for the treatment of PIK3CA-mutated, HR+, HER2- ABC, based on the SOLAR-1 trial. Aside from PIK3CA, other gene alterations are associated with poor prognosis and limited response to treatment in this patient population. In this retrospective analysis, we performed tissue-based next-generation sequencing of 398 patients (237 PIK3CA-altered, 161 PIK3CA-wild type) from SOLAR-1. Progression-free survival (PFS) correlative analysis was performed in the PIK3CA-altered cohort. PIK3CA-altered and PIK3CA-wild type tumors had distinct genomic profiles. In the PIK3CA-altered cohort, patients who received alpelisib plus fulvestrant had a median PFS (mPFS) of 11.01 months versus 5.55 months for those receiving placebo plus fulvestrant (P=0.0004). Patients in the lowest tumor mutational burden quartile as well as those with FGFR1 or FGFR2 alterations derived greater PFS benefit from alpelisib plus fulvestrant versus placebo plus fulvestrant (18.5 versus 3.22 months; HR 0.38; 95% CI 0.21-0.68. FGFR1 12.71 versus 3.75 months; HR 0.38; 95% CI 0.17-0.81; P=0.32. FGFR2: 9.63 versus 2.78 months; HR 0.31; 95% CI 0.1-0.94; P=0.29); patients with MYC or RAD21 alterations derived limited PFS benefit. Cox and multi-task machine learning models identified lower Eastern Cooperative Oncology Group performance status, prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) treatment, and PTEN or TP53 alterations among the most deleterious factors for PFS in the PIK3CA-altered cohort. Alpelisib plus fulvestrant provides clinical benefit for patients with PIK3CA-altered, HR+, HER2- ABC across a range of concomitant alterations, including those previously implicated in endocrine therapy or CDK4/6i resistance. Machine learning models identified factors including gene mutations that influenced PFS. Show less

Encephalocraniocutaneous lipomatosis (ECCL) is a neurocutaneous condition caused by postzygotic mosaic activating variants in genes including FGFR1, NRAS, or KRAS. It primarily affects the skin, eyes, and central nervous system. Diagnosis is typically based on characteristic clinical features and/or molecular confirmation. Here we report a unique case of ECCL in a 12-year-old female with abdominal wall lipoma, ipsilateral lower limb overgrowth, and brachydactyly, in whom somatic mosaicism for FGFR1 was identified using resected lipomatous tissue. Imaging studies confirmed additional spinal lipomas consistent with ECCL. This report expands the phenotypic spectrum of FGFR1-ECCL and underscores the importance of tissue-based somatic testing for diagnosis. Tumor risk is also discussed. Show less

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

Fibroblast growth factor 23 (FGF23) is a phosphate-regulating hormone produced by osteocytes. In iron deficiency anemia (IDA) and in chronic kidney disease (CKD), FGF23 is also produced by erythroid cells. Recent studies have suggested that rising circulating FGF23 is negatively associated with erythropoiesis in IDA and CKD. However, the distinct contributions of bone- and erythroid-produced FGF23 to anemia in IDA remain unclear. Using the conditional deletion of Fgf23 in osteocytes (Fgf23Dmp1-cKO) and in erythroid cells (Fgf23HbB-cKO) in mice fed a control (Ctr) or an iron deficient (ID) diet, we first determined that in ID, osteocytes and erythroid cells are distinct sources of circulating intact FGF23 (iFGF23) and FGF23 cleaved peptides, respectively. We further show that erythroid-specific deletion of Fgf23 corrected anemia in ID mice, and overexpression induced anemia in Ctr mice unlike osteocyte-specific deletion or overexpression of Fgf23. Importantly, erythroid-specific deletion of Furin (FurinHbB-cKO), the enzyme responsible for FGF23 cleavage, led to increased production of iFGF23 from erythroid cells and aggravated ID-induced anemia. iFGF23 also dose-dependently blocked the differentiation of erythroid progenitors in culture triggering mitochondrial dysfunction leading to impaired erythropoiesis. These effects were fully suppressed by co-treatment with an FGFR1 inhibitor. Finally, erythroid-specific deletion of Fgf23 in an animal model of progressive CKD prevented the development of anemia of CKD. In aggregate, our results show that erythroid-expressed FGF23 is a negative regulator of erythropoiesis that contributes to anemia via direct paracrine FGFR1 activation in erythroid precursors. Show less

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

This study aims to elucidate the role of FGFR1 in activating the Wnt/β-catenin signaling pathway and the underlying mechanisms by which it promotes malignant progression in lung squamous cell carcinoma (LUSC). By integrating multi-omics analysis with functional experiments, the clinical heterogeneity of FGFR1 amplification, signaling crosstalk, and their regulatory networks governing tumor phenotypes were revealed. Using TCGA data (n = 490), we analyzed the relationship between FGFR1 copy number variation (CNV) and mRNA expression in LUSC, and validated the correlation with protein expression in a clinical cohort (n = 38). GSEA and single-gene GSEA were performed to identify signaling pathways associated with high FGFR1 expression. The interaction between FGFR1 and the Wnt/β-catenin pathway was investigated by immunohistochemistry, immunofluorescence, stable cell lines, Western blot, qPCR, and functional assays. FGFR1 amplification correlated with increased mRNA and protein expression. The top 25% FGFR1 high-expression group enriched Wnt/β-catenin, PI3K-Akt, and cAMP pathways. Mechanistically, FGFR1 promoted β-catenin nuclear accumulation and enhanced β-catenin signaling through PKA-associated phosphorylation and Akt/GSK3β-related regulation of β-catenin stability, and these effects were attenuated by AKT inhibition. CTNNB1 knockdown significantly inhibited proliferation, migration, invasion, and tumor growth of LUSC cells. Our findings indicate that FGFR1 activates Wnt/β-catenin signaling through coordinated regulation of β-catenin phosphorylation, stability, and subcellular localization, thereby promoting malignant progression in LUSC. These results provide a rationale for targeting the FGFR1-Wnt/β-catenin axis as a potential therapeutic strategy. Show less

Chemotherapy has significantly improved survival in breast cancer and, in the neoadjuvant setting, contributes to tumor downstaging and increased rates of breast-conserving surgery while enabling in vivo assessment of tumor biology and chemosensitivity. Pathological complete response (pCR) is a key endpoint associated with favorable outcomes; however, tumor heterogeneity highlights the need for reliable predictive biomarkers. This study evaluated the mRNA expression of 13 candidate genes in relation to molecular subtypes and pathological response to neoadjuvant chemotherapy (NAC) to identify potential predictive and prognostic markers. Pretreatment core biopsies from 92 patients receiving NAC were analyzed by quantitative RT-PCR. Molecular subtypes were determined by immunohistochemistry (ER, PR, HER2, Ki67), and pathological response was classified using the Miller-Payne scale as good (MP 4/5) or poor (MP 1-3). Multivariate logistic regression assessed associations between gene expression, subtype, and pCR. Hormone receptor-positive tumors showed significantly higher expression of Show less