Search Results (16,485)

Objectives: Individuals with type 2 diabetes (T2D) remain at high cardiovascular disease (CVD) risk. The pan-immune-inflammation value (PIV) integrates circulating neutrophils, monocytes, platelets, and lymphocytes but does not capture albumin-related nutritional and inflammatory reserve. We investigated associations between the PIV-to-albumin ratio (PIVA) and incident CVD, cardiovascular mortality, and disease progression in individuals with T2D. Methods: This prospective study included 15,355 UK Biobank participants with T2D and no baseline CVD. PIVA was calculated from peripheral blood cell counts and serum albumin and was natural log-transformed. Fine–Gray competing-risk and cause-specific Cox models were used to evaluate incident CVD and cardiovascular mortality. Multi-state models characterized transitions from T2D to CVD and death. We also examined nonlinear associations, renal biomarker mediation, joint associations with the CVD polygenic risk score and triglyceride–glucose index, sensitivity analyses, and external validation of cardiovascular mortality in the National Health and Nutrition Examination Survey. Results: During median follow-ups of 12.94 years for incident CVD and 14.49 years for cardiovascular mortality, 4829 incident CVD events and 514 cardiovascular deaths occurred. Each 1-unit increase in lnPIVA was associated with higher risks of incident CVD (subdistribution hazard ratio [sHR], 1.140; 95% confidence interval [CI], 1.088–1.194) and cardiovascular mortality (sHR, 1.449; 95% CI, 1.247–1.684). Associations were nonlinear. Higher lnPIVA was also associated with transitions from T2D to CVD, from T2D directly to cardiovascular death, and from incident CVD to cardiovascular death. Cystatin C explained a larger proportion of these associations than creatinine. Elevated lnPIVA identified excess cardiovascular risk across strata of genetic susceptibility and insulin resistance, and the findings were generally supported by sensitivity and external validation analyses. Conclusions: lnPIVA was associated with incident CVD, cardiovascular mortality, and adverse cardiovascular transitions in individuals with T2D. As an immune-inflammatory and albumin-based index, PIVA may help identify high-risk individuals beyond conventional cardiometabolic and genetic risk profiles. Full article

Familial hypercholesterolemia (FH) has been associated with an increased risk of major depressive disorder (MDD), but their shared molecular signatures remain unclear. This study aimed to identify candidate genes associated with FH-MDD co-occurrence through integrative transcriptomic analysis, machine learning, summary-data-based Mendelian randomization (SMR), and clinical validation. Transcriptomic datasets from the Gene Expression Omnibus were analyzed, including GSE6054 and GSE13985 for FH and GSE98793 for MDD. Differential expression analysis and weighted gene co-expression network analysis were used to identify shared candidate genes. Candidate biomarkers were screened using least absolute shrinkage and selection operator regression and Random Forest algorithms, followed by the construction of an exploratory nomogram. SMR analysis was performed to assess genetically supported associations between candidate-gene expression and MDD risk. Selected genes were validated by PBMC RT-qPCR in an independent four-group clinical cohort comprising healthy controls and participants with FH, MDD, or co-occurring FH and MDD. Flow cytometry was subsequently used to characterize the peripheral CD4+ T-cell profile. A total of 54 shared candidate genes were identified. CD4, MRPS21, and CRTC2 were selected by machine learning and incorporated into the nomogram, which showed good discrimination in the training set and moderate performance in external validation. Immune infiltration and enrichment analyses highlighted monocyte alterations, reduced T-cell-related signals, and enrichment of T-cell receptor and TNF-mediated pathways. SMR analysis indicated that genetically predicted higher CD4 expression was inversely associated with MDD risk, whereas RT-qPCR showed higher CD4 expression in patients with FH-MDD. Flow-cytometric analysis showed that FH-MDD participants had a higher circulating CD3+CD4+ T-cell proportion, an increased effector-memory CD4+ T-cell proportion, and a higher proportion of HLA-DR+ CD4+ T cells than participants in the comparison groups. These findings suggest that CD4 may represent a promising immune-related candidate signature associated with the co-occurrence of FH and MDD, warranting further functional validation. Full article

Background: Brain MRI in patients with autism spectrum disorder (ASD) is generally considered when additional neurologic, developmental, or syndromic concerns warrant structural evaluation. In the study practice, ASD alone was not used as the reason to obtain MRI. We examined documented MRI use and broad result coding while explicitly separating selection for imaging from abnormal-result status. Methods: This retrospective specialty-practice cohort included 1884 patients with ASD. The primary outcome was the proportion of documented MRI examinations coded abnormal. Secondary analyses examined associations of age, sex, seizure history, EEG status, and genetic test status with abnormal versus normal MRI coding and with documented MRI utilization. MRI categories and the pediatric restriction were exploratory and sensitivity analyses. Results: An MRI result was recorded for 704 patients (37.4%; 95% CI 35.2–39.6); 322 were coded abnormal (45.7%; 95% CI 42.0–49.5). The abnormal-result models had low in-sample discrimination (AUC 0.528 and 0.553), and adjusted confidence intervals for all measured variables included 1.00; these results do not demonstrate equivalence between clinical groups. Seizure history was associated with documented imaging in the full cohort (aOR 2.47, 95% CI 1.94–3.14), and abnormal EEG was associated in the exploratory complete-case utilization model (aOR 2.83, 95% CI 1.93–4.14). Conclusions: Broad MRI abnormalities were frequent among patients selected for imaging because of additional clinical concerns, but a broad abnormal code is not equivalent to clinically actionable yield. The routinely captured variables available in this dataset were insufficient to distinguish abnormal from normal MRI coding. These findings favor individualized MRI decisions based on the clinical question prompting imaging and motivate future studies with richer neurologic and developmental phenotyping. Full article

Background/Objectives: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by pathogenic variants in the ATP7B gene. Early diagnosis and appropriate treatment are essential for preventing irreversible complications. This study demonstrated the clinical utility of integrated high-throughput genomic analysis for molecular diagnosis and genetic counseling in a large Thai family affected by WD. Methods: A 32-year-old woman with clinical features suggestive of WD underwent clinical, biochemical, and molecular genetic evaluations, including sequencing of the entire ATP7B gene and SNP microarray. Fluorescent PCR followed by capillary electrophoresis was used for segregation analysis in available family members. SNP microarray analysis and whole-exome sequencing were performed on the proband’s husband to identify pathogenic variants in the ATP7B gene and other disease-associated genes for reproductive risk assessment. Results: The proband presented with hepatic dysfunction, Kayser–Fleischer rings, low serum ceruloplasmin, and a family history of fatal liver disease. She also developed progressive weakness, with nerve conduction findings consistent with axonal sensorimotor polyneuropathy predominantly affecting the lower limbs. Sequencing identified a novel homozygous 28-bp splice-junction deletion, c.4022-24_4025del, which disrupted the canonical splice acceptor site at the intron 19/exon 20 boundary and was classified as pathogenic variant. Segregation analysis confirmed carrier status in the proband’s father and identified heterozygous carrier or homozygous wild-type status among her living siblings. SNP microarray analysis revealed a 46.7 Mb copy-neutral long contiguous stretch of homozygosity (CN-LCSH) encompassing ATP7B, with CN-LCSH regions accounting for 2.046% of the total autosomal genome. These findings potentially reflected segmental uniparental isodisomy or identity by descent, while the overall homozygosity pattern did not support recent consanguinity. Combined genomic analyses of the proband’s husband revealed no pathogenic or likely pathogenic ATP7B variants. Based on the available testing, all offspring are expected to be heterozygous carriers, and the risk of an affected child is considered very low. Conclusions: This study highlights the value of integrated genomic analysis for molecular diagnosis, cascade testing, and reproductive risk counseling. Further functional studies should be conducted to validate their pathogenicity. Full article

Human immunodeficiency virus (HIV) is an enveloped virus with a remarkable capacity for genetic diversification, enabling rapid escape from host immune responses and therapeutic interventions. Despite extensive global efforts, the development of an effective vaccine has remained elusive owing to the virus’s high genetic variability and antigenic diversity. Consequently, considerable effort has been directed toward the development of therapeutic agents targeting viral entry, reverse transcriptase, integrase, protease, and more recently, capsid. Although antiretroviral therapy (ART) remains the cornerstone of HIV treatment, it is associated with challenges including drug resistance, adverse side effects, and limitations in access and affordability. Targeting viral entry offers distinct advantages by blocking infection at the earliest stage of the viral life cycle and enabling the neutralization of free virions, as well as Fc-mediated elimination of HIV-infected cells in some cases. This review highlights promising protein-based HIV entry inhibitors that have demonstrated efficacy in preclinical studies, and discusses ongoing efforts to optimize their valency, avidity, specificity, serum half-life, effector functions, and production platforms to improve their therapeutic potential and economic feasibility. Full article

PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataracts) syndrome is a rare neurodegenerative inherited disorder characterized by a spectrum of these clinical phenotypes. Due to the considerable heterogeneity in the age of onset of the different clinical features and the similarities with other conditions, it is often misdiagnosed. Variants in the ABHD12 gene have been identified as a genetic cause of PHARC syndrome and are predicted to result in loss-of-function or severely reduced protein synthesis. ABHD12 (α/β-hydrolase domain-containing protein 12) is responsible for the breakdown of very-long-chain lysophosphatidylserines (VLC-lyso-PS). When ABHD12 is dysfunctional, VLC-lyso-PS accumulates in the brain, producing inflammation. In this study, the clinical phenotypes of five patients with molecularly confirmed ABHD12 pathogenic variants from Moorfields Eye Hospital together with those of 64 patients reported in the literature were analyzed to investigate genotype–phenotype correlations. We report a novel variant c.985del p.(His329Thrfs*57) associated with PHARC syndrome. Moreover, patients with two null variants in ABHD12 manifest more of the clinical features of PHARC syndrome than those with at least one missense variant. Our study shows the importance of a complete clinical and genetic diagnosis to enable accurate diagnosis and genetic counselling for affected individuals. Full article

The Bcl-2-associated athanogene (BAG) gene family plays vital roles in plant growth, development, and biotic and abiotic stress responses. Previous work has demonstrated that tomato SlBAG9, a group II BAG member, negatively regulates plant thermotolerance. However, the regulatory mechanisms governing SlBAG9 expression remain poorly understood. In this study, we isolated and characterized the authentic 1486 bp full-length promoter (P1) of SlBAG9 from the tomato genome. Building upon our previous transcript-level observations, we provide here a detailed functional characterization of this promoter at the cellular and tissue level. In silico analysis identified several key cis-acting regulatory elements, including abscisic acid-responsive elements (ABRE), anaerobic response elements (ARE), and a heat shock element (HSE1). We used stable transgenic tomato plants carrying SlBAG9pro::GUS to verify that the full-length promoter was capable of driving the expression of β-glucuronidase reporter gene (GUS) in transgenic tomato plants, showing GUS staining was detectable in the roots, stems, leaves, flowers, fruits, and seeds, with the highest activity in red-ripe fruits. Notably, GUS activity was significantly upregulated by high temperature (HT) but not by PEG, NaCl, ABA, or cold treatments. To further dissect the HT-responsive regulatory module, we generated three 5′-terminal deletion fragments (−386 bp, P2; −239 bp, P3; and −113 bp, P4) and fused them to GUS. Under HT stress, the smallest deletion P4 showed negligible GUS activity, whereas P1, P2, and P3 retained significant activity. Furthermore, site-directed deletion of the HSE1 element in the full-length context (MU-P1) abolished HT inducibility, confirming that HSE1 serves as a critical positive HT-responsive element. Collectively, these findings confirm and extend our observations that SlBAG9 is a stress-responsive gene, and the characterized HSE1-dependent promoter module represents a promising candidate for genetic engineering aimed at enhancing thermotolerance in crops. Full article

Macrobrachium nipponense is an economically important freshwater crustacean in China, and growth-related traits are major determinants of its commercial value. Identifying single nucleotide polymorphisms (SNPs) associated with growth-related traits may provide useful molecular markers for the genetic improvement of growth performance. Previous studies have suggested that the cAMP-dependent protein kinase type I regulatory subunit-like gene (Mn-PKA-R1) is involved in the regulation of growth and molting in M. nipponense. In the present study, a cultured full-sib family comprising 120 females and 120 males was used to screen SNPs within the coding region of Mn-PKA-R1, and evaluate their associations with body weight, body length, full length, and abdominal width. Seven SNPs were identified in exon 12, including five nonsynonymous missense variants and two synonymous variants, whereas no SNPs were detected in the other exons examined. The mean effective number of alleles (N_e), observed heterozygosity (H_o), expected heterozygosity (H_e), Nei’s gene diversity (Nei), and polymorphic information content (PIC) were 1.3561, 0.3048, 0.2350, 0.2340, and 0.1962, respectively, in females, compared with 1.3118, 0.2714, 0.1868, 0.1861, and 0.1512, respectively, in males. Four SNPs were significantly associated with growth-related traits in females: C+82748G and A+82750G were associated with body weight and abdominal width, T+82810G was associated with abdominal width, and A+83324G was associated with body weight, full length, and abdominal width (p < 0.05). No significant genotype–trait associations were detected among the SNP loci that could be statistically evaluated in males. Pairwise r² values ranged from 0.001 to 0.693 in females and from 0.000 to 0.351 in males, with generally higher values observed in females within the investigated full-sib family. Females also showed slightly higher mean genetic polymorphism parameters than males, while significant SNP–trait associations were detected only in females within this family. These findings provide candidate SNPs for further validation of their potential utility in marker-assisted selection in M. nipponense. Full article

Background/Objectives: Embryo donation/adoption separates the recipient environment from the genetic origin of the embryo and provides a clinical model for studying offspring sex distribution after assisted reproduction. We evaluated whether recipient body mass index (BMI) was associated with sex distribution among live-birth events after frozen embryo transfer involving embryo donation/adoption. Methods: This retrospective cohort study included frozen embryo transfer cycles involving embryo donation/adoption performed between January 2018 and December 2024 at a tertiary fertility center. All embryos were generated by intracytoplasmic sperm injection, cultured to the day-5 blastocyst stage, transferred singly, and not subjected to preimplantation genetic testing. The analytical cohort comprised 104 independent live-birth transfer events representing 104 unique recipients and 104 unique embryo–donor couples. Recipient BMI was evaluated across quartiles and in an exploratory adjusted logistic regression model including female embryo donor BMI and age, endometrial thickness, serum progesterone concentration, and top-quality embryo status. Results: The cohort included 51 male and 53 female live-birth events. Recipient BMI was higher in female than male live-birth events (25.6 ± 4.3 versus 23.5 ± 4.2 kg/m²; p = 0.007). In a descriptive quartile analysis, male live-birth event proportions were 69.2% in the lowest BMI quartile and 34.6% in the highest quartile, with corresponding female proportions of 30.8% and 65.4% (p for trend = 0.007). In the primary adjusted model, higher recipient BMI was associated with lower odds of a male live-birth event (adjusted OR 0.88 per 1 kg/m²; 95% CI 0.80–0.98; p = 0.017). Conclusions: Recipient BMI was associated with sex distribution among live-birth events after embryo donation/adoption. The observed pattern is compatible with a recipient-side post-fertilization association but does not establish a selection mechanism, causality, or the developmental stage at which the association arose. Full article

Upland cotton (Gossypium hirsutum, AD1) is the most important fiber crop for the world’s textile industry. The genetic base of Upland cotton is narrow, and the introgression of germplasm from other species into Upland cotton can broaden its genetic diversity, including the introduction of new qualitative traits. The objectives of this study were to determine the inheritance, allelism, and linkage relationships of the red anther trait introduced into Upland from the red anther donor G. armourianum (D2-1) through crosses involving a synthetic tetraploid A1D2-1. After two generations of backcrossing to Upland cotton, followed by inbreeding, homozygous red-anthered plants (RA) were selected and used for crosses with two Upland lines, the Upland standard TM-1, the multiple recessive marker line T582, and the multiple dominant marker line T586. All Upland cotton parents, except the RA parents and T586 (possessing yellow anthers), had cream anthers. The anther color of the F₁ plants was red, indicating that the red anther trait is dominant. In nine of ten F₂ populations and four of five testcross populations, the segregation of anther color followed a 3:1 and 1:1 ratio, respectively, as expected under a one-gene model. In three F₂ populations with a total of 885 plants between RA with green leaf and T586 with red leaf (R₁ on chromosome D07), no double recessive genotype (yellow/cream anther and green leaf) was observed, indicating the allelic relationship between R₁ and red anther allele, designated R₁^a. The recombination frequency between R₁^a and cluster-1 (cl₁) on D07 was estimated to be 0.112 in 256 F₂ plants of a cross between RA and T582 based on the maximum likelihood estimation. This new red anther trait and its associated new gene allele provide an important genetic source for understanding the biosynthesis of anthocyanins and may have utility for improving resistance to anther-feeding insects in cotton. Full article

The genus Sigara Fabricius, 1775 (Hemiptera: Corixidae) is an important freshwater bioindicator, but its conservative morphology complicates traditional species identification. This study combines DNA barcoding, traditional taxonomy, and climatic factors within an integrative framework to provide new insights into species delimitation. We analyzed cytochrome c oxidase subunit I (COI) sequences from 501 Sigara specimens collected from 15 countries, including 95 newly generated COI barcodes. Our integrated approach included phylogenetic analyses, genetic distance assessments, and ecological niche modeling. The results revealed remarkable diversity, with sequences clustering into 46 Barcode Index Numbers (BINs). COI genetic distances showed a pronounced bimodal pattern, with most intraspecific divergences below 1% and interspecific divergences mainly ranging from 8–16%, while the few intermediate divergences (4–8%) suggested potential cryptic diversity or recent species divergence. Most morphologically defined species corresponded to distinct molecular lineages, supporting traditional taxonomy, whereas some morphospecies exhibited genetic discordance potentially associated with species divergence. Integrative analyses revealed that climatic factors, particularly isothermality and seasonal temperature and precipitation, are major drivers of Sigara MOTU distributions, highlighting the important role of climate in shaping their geographic patterns. These findings indicate that although COI barcodes are not sufficient to define the species boundaries of Sigara alone, they provide a key entry point for the accurate division of species, which in turn promotes the development of molecular tools for freshwater ecological monitoring and conservation. Full article

Nicotinamide adenine dinucleotide (NAD⁺) is a fundamental metabolic cofactor and signaling molecule that supports redox reactions, DNA repair, chromatin regulation, stress adaptation, inflammation, and neuronal maintenance. Age-associated NAD⁺ decline has been implicated in brain aging and neurodegenerative disorders, but the causal node and limiting compartment differ across tissues and disease states. Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT-1) catalyzes the final step in NAD⁺ biosynthesis and represents the major nuclear isoform of the mammalian NMNAT family. Direct human genetic evidence establishes NMNAT-1 as a causal gene in inherited retinal degeneration, whereas evidence linking endogenous NMNAT-1 to broader brain aging or sporadic neurodegeneration is mainly convergent preclinical, preliminary, or indirect. Beyond NAD⁺ synthesis, biochemical and Drosophila studies suggest possible chaperone-like and proteostasis-supporting functions, but a separable NAD⁺-independent function of endogenous mammalian NMNAT-1 has not yet been established in vivo. Here, we review the molecular structure, localization, and regulation of NMNAT-1, emphasizing calibrated distinctions among catalytic nuclear NAD⁺ supply, engineered axonal protection, pathway-adjacent NAD⁺ interventions, and putative non-catalytic protection. We further discuss how NMNAT-1 dysfunction may contribute to aging-associated genomic instability, neuroinflammation, synaptic impairment, retinal degeneration, selected neurodegenerative models, and glioma biology. Finally, we evaluate therapeutic strategies targeting NMNAT-1 and NAD⁺ pathways, noting that no human trial has yet established efficacy for an NMNAT-1-directed neurological therapy. A compartment-aware and evidence-stratified view is therefore essential for translating NMNAT-1 biology into interventions for age-related neural disease. Full article

Yiyuan jade, a specific gem-quality jade variety in the East Qinling Orogen, occurs as lenticular and vein-shaped bodies hosted within the dolomite and biotite-quartz marble of the Neoproterozoic Meiyaogou Formation. Based on detailed petrological and mineralogical characterization, three subtypes are defined: tremolite jade (nephrite), serpentine jade (a green variety of serpentine group minerals that resembles true jade), and their transitional varieties. Among these, tremolite jade is predominantly white, moon-white, and light green, whereas serpentine jade (gem-quality serpentine) exhibits dark green, yellow-green, and yellow coloration. Comprehensive mineral composition analyses are presented, encompassing amphibole, serpentine, carbonate minerals, and titanite in metagabbro, aiming to constrain the physicochemical conditions and genetic model of these jades. We propose that tremolite jade and serpentine jade are probably formed simultaneously via metasomatic processes, primarily governed by variations in fluid volume and the activities of SiO₂ and CO₂. The serpentine jade is interpreted as serpentinized marble, within which local serpentine aggregation forms serpentine jade akin to Lantian jade in the western East Qinling region. The tremolite jade closely resembles Hetian tremolite jade within geochemical and mineralogical characteristics but differs significantly from serpentine-type tremolite jade associated with ultramafic rocks, thereby confirming its classification as dolomite-type jade. Application of the Ti-in-tremolite geothermometer yields a formation temperature exceeding 400 °C. Integrated with regional geochronological constraints, our findings link the formation of Yiyuan tremolite jade and serpentine jade to tectonic activity driven by the Late Devonian subduction of the Erlangping back-arc basin. This study not only enhances the current understanding of jade mineralization within collisional orogenic settings but also establishes a robust foundation for future exploration in the East Qinling Orogen. Full article

A secreted protein toxin encoded by a satellite dsRNA-enabled dissection of the genetic control of replication and expression of a single-segment dsRNA virus, the first Totivirus, L-A. Among the then-novel findings were i. “head-full replication”, ii. a supposedly forbidden “T = 2” capsid symmetry based on an asymmetric dimer, iii. a host N-acetyltransferase whose modification of the coat protein is necessary for packaging, iv. Kex1 and Kex2 pro-toxin peptidases leading to discovery of the pre-pro-insulin processing enzymes, and v. specific viral (+) strand sites/structures needed for RNA packaging and (-) strand synthesis. L-A viral (+) strands made in the particle are extruded to the cytoplasm. Those destined for translation are 5′ 7meGMP-capped by a coat protein activity that steals the cap from cellular mRNAs. (+) strands destined for encapsidation in new coats are not capped. Three host-encoded anti-viral systems were found, one based on blocking translation of the viral non-polyA mRNAs (Ski2,3,8 complex), another a 5′->3′ exoribonuclease specific for uncapped molecules (such as the viral (+) strands)(Ski1/Xrn1), and the third a mitochondrial nuclease released in cells undergoing meiosis/sporulation (Nuc1). All of these systems protect cells from virus-induced pathology and have clear animal homologs. The 3′ polyA of yeast mRNAs is dispensable for translation in ski2Δ slh1Δ cells, and such cells are healthy unless the L-A and M dsRNAs are present, suggesting that this polyA is primarily a device allowing cells to distinguish viral and cellular mRNAs. We suggest that the ribosome-associated Ski2,3,8 proteins block 60S subunit joining on polyA⁻ mRNAs. Recent evidence of roles for other cellular components controlling viral expression and replication suggests that yeast viruses will continue to be a fertile area for study of viral pathogenesis and host anti-viral systems. Full article

Background/Objectives: Achondroplasia is the most common genetic skeletal dysplasia associated with disproportionate short stature and is primarily caused by gain-of-function variants in the fibroblast growth factor receptor 3 (FGFR3) gene. Constitutive FGFR3 activation disrupts growth plate homeostasis and endochondral ossification through complex alterations in chondrocyte proliferation, differentiation, hypertrophy, extracellular matrix organization, and intracellular signaling. The increasing understanding of these mechanisms has enabled the transition from exclusively supportive management toward disease-modifying and precision-based therapeutic strategies. This narrative review aimed to critically synthesize current evidence on the genetic basis, molecular pathogenesis, growth plate abnormalities, and current and emerging targeted therapies in achondroplasia. Methods: A narrative literature review was conducted using PubMed/MEDLINE, Scopus, and Web of Science Core Collection, with Google Scholar used as a supplementary source, together with manual screening of the reference lists of relevant original studies, clinical trials, reviews, consensus documents, and clinical guidelines. The principal literature search covered publications from January 2010 to March 2026, while selected seminal primary studies published before 2010 were included when necessary to document the original identification of pathogenic FGFR3 variants and foundational mechanisms of FGFR3-mediated growth plate regulation. Particular emphasis was placed on FGFR3 variants, receptor activation mechanisms, growth plate dysfunction, intracellular signaling pathways, vosoritide, C-type natriuretic peptide-based therapies, FGFR3 inhibitors, ligand–receptor blockade, drug repurposing, Wnt/β-catenin modulation, and gene-based therapeutic approaches. Results: Achondroplasia is characterized by marked molecular homogeneity, with the recurrent p.Gly380Arg substitution accounting for most cases. Mutant FGFR3 displays sustained activity through partial ligand independence, enhanced receptor dimerization and kinase activation, increased receptor stability, and reduced degradation. Excessive signaling through MAPK/ERK, STAT, PI3K/AKT, IHH/PTHrP, and related pathways impairs chondrocyte proliferation and hypertrophic differentiation, alters extracellular matrix turnover, disrupts primary cilium function, and reduces longitudinal bone growth. Vosoritide provides clinical proof that pharmacological modulation of FGFR3-related signaling can improve growth velocity. Additional therapeutic strategies under clinical or preclinical investigation include long-acting CNP analogues, selective FGFR inhibitors, decoy receptors, RNA aptamers, repurposed drugs, Wnt/DKK1 pathway modulation, and gene- or enhancer-targeted interventions. Conclusions: Achondroplasia is increasingly understood as a disorder of dysregulated growth plate signaling rather than solely a condition of reduced stature. Although vosoritide has established the feasibility of disease-modifying treatment, substantial uncertainty remains regarding final adult height, skeletal proportionality, cranio-spinal development, orthopedic outcomes, and long-term safety. Future progress will depend on mechanistically informed therapeutic combinations, improved biomarkers, advanced cellular and animal models, and long-term clinical and real-world evidence. Full article