Search Results (10,395)

Background/Objectives: Periodontitis is characterized by the gradual breakdown of tooth-supporting tissues, including the periodontal ligament and alveolar bone, while current regenerative strategies remain limited. Palm mixed-carotenes (PMC), a natural carotenoid-rich compound with antioxidant and cytoprotective properties, may have potential in periodontal regenerative research. However, its effects on human periodontal ligament stem cells (hPDLSCs) remain underexplored. This study evaluated the effects of PMC on hPDLSC viability, wound closure, and osteogenic- and bone remodeling-related molecular responses. Methods: Primary hPDLSCs were isolated, characterized, and treated with PMC at concentrations ranging from 0 to 100 μg/mL. Cell viability was evaluated using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, wound closure using a wound-scratch assay, gene expression of osteoprotegerin (OPG), osteopontin (OPN), and osteocalcin (OCN) using real-time polymerase chain reaction (RT-qPCR), and secreted protein levels using enzyme-linked immunosorbent assay (ELISA). Results: PMC showed a biphasic viability response, with 6.25 μg/mL producing the most favorable effect by increasing the cell viability to 111.6% relative to the negative control. This concentration was selected, together with 12.5 μg/mL, for subsequent assays. In the wound-scratch assay, 6.25 μg/mL PMC significantly enhanced wound closure at 48 and 72 h, reaching 75.17% at 72 h compared with 52.69% in the negative control. Gene expression analysis showed that 6.25 μg/mL PMC significantly upregulated OPG mRNA expression compared with the negative control, 12.5 μg/mL PMC, and positive control groups. OPN and OCN showed limited responses, and PMC did not significantly increase secreted OPG or OCN protein levels. Conclusions: Overall, PMC at 6.25 μg/mL demonstrated the most favorable response in hPDLSCs, suggesting its potential as a bioactive candidate for further periodontal regenerative research. Full article

Background: Reliability-aware integration of heterogeneous data sources remains a fundamental challenge in multimodal deep learning: prevailing fusion strategies assume uniform reliability across sources and instances, limiting their responsiveness to data-dependent trustworthiness. Methods: We introduce REM-Fuse (Reliability-aware Evidential Multimodal Fusion), an evidential deep learning (EDL) framework in which per-source Dirichlet uncertainty adaptively weights each source through dual-channel weighting, asymmetric cross-scale enhancement, and Dempster–Shafer-inspired evidence accumulation. As a case study for cancer prognosis, REM-Fuse integrates multi-scale histopathology (10×, 20×) and RNA-seq on TCGA-BRCA (n = 831) via five-fold cross-validation with subtype- and stage-stratified analyses. Results: REM-Fuse attained a concordance index of 0.715 and a 60-month time-dependent AUC of 0.729, indicating moderate discrimination and significant risk separation (log-rank p < 0.001). Adaptive source weights and per-patient uncertainty varied significantly across molecular subtypes (Kruskal–Wallis p = 0.010 and p = 0.007), indicating patient-specific rather than fixed multimodal integration. Conclusions: REM-Fuse provides a compact reliability-aware fusion strategy for cancer prognosis, although external validation is needed before broader clinical or cross-cohort generalization. Full article

Background: The early-life gut microbiota plays a critical role in programming intestinal barrier function and immune homeostasis, with profound implications for long-term host health. However, the effects of early-life compound probiotic intervention on the maturation of intestinal barrier function and the underlying molecular mechanisms remain incompletely understood, particularly in large-animal models relevant to human physiology. Methods: In this preclinical study, 3627 neonatal piglets—a well-established translational model for human infant gut development—were orally administered a novel compound probiotic formulation comprising Bifidobacterium longum subsp. infantis BZ, Lactobacillus plantarum LZ, and Pediococcus acidilactici PZ during early life. A total of 1512 fecal samples collected at seven time points from birth to day 180 were analyzed by 16S rRNA sequencing, and 525 samples from three developmental windows (days 10, 25, and 70) were subjected to LC-MS-based metabolomics. The candidate metabolite indole-3-lactic acid (ILA) was further mechanistically validated in a DSS-induced colitis mouse model and in IPEC-J2 cells. Results: Early-life probiotic intervention significantly enhanced intestinal barrier integrity, as evidenced by improved intestinal morphology and upregulated expression of tight junction proteins—zonula occludens-1 (ZO-1), occludin (OCLN), and Claudin-1 (CLDN1)—in the jejunum (p < 0.05). Notably, intervention at birth was more effective than post-weaning administration, and two administrations (birth + weaning) yielded superior outcomes compared with a single administration (p < 0.05). Microbiome analysis revealed enhanced microbial diversity and enrichment of beneficial genera during the juvenile-to-adult transition (p < 0.05). Metabolomic profiling identified ILA as a signature metabolite consistently elevated by probiotic supplementation. Conclusions: These findings provide evidence that early-life compound probiotic intervention is associated with improved intestinal barrier maturation, with ILA identified as a key candidate metabolite that may mediate this effect, as supported by functional validation in murine and cellular models. This provides a mechanistic rationale for probiotic-based strategies to support intestinal health in human infants during critical developmental windows. Full article

Salinity is a major constraint to crop productivity. Beneficial plant–fungus interactions represent a promising strategy to enhance stress resilience. Here, we investigated fungal endophytes isolated from the roots of Oryza sativa cultivated in saline-prone marshlands of the Guadalquivir River, Spain. From a collection of 38 isolates, five salt-tolerant strains exhibiting plant growth-promoting activity were identified, including a previously uncharacterized Reticulascus sp. strain S5. Co-cultivation assays with the non-native host plant Arabidopsis thaliana demonstrated that S5 increased the root and shoot biomass under salt stress. To elucidate the underlying molecular mechanisms, a comprehensive RNA-Seq analysis of the roots and shoots under control and saline conditions was performed. Fungal colonization induced pronounced transcriptomic changes, particularly in the shoots, including rewiring of the auxin- and abscisic acid-related pathways and the induction of genes associated with cell wall remodeling. Concurrently, defense-related processes, including glucosinolate biosynthesis and ethylene signaling, were broadly repressed, suggesting attenuated stress perception in colonized plants. In the roots, S5 inoculation suppressed the expression of genes involved in root hair development and cell wall organization, indicating a fungus-driven reconfiguration of root development. Moreover, comparative analysis with Fusarium sp. K-23, a fungus that has previously been demonstrated to promote plant growth under salinity stress, revealed distinct root-associated mechanisms but convergence on a shared regulatory module in shoots involving ABA-responsive transcription factors and osmotic stress regulators. Collectively, our findings demonstrate that Reticulascus sp. S5 enhances plant salt stress tolerance through the coordinated transcriptional reprogramming of growth, hormone signaling, and stress responses, highlighting a possible potential of habitat-adapted endophytes for sustainable crop improvement. Full article

Tendinopathy is a prevalent musculoskeletal condition characterised by chronic inflammatory and degenerative changes. Pulsed electromagnetic fields (PEMFs) represent a promising biophysical therapeutic modality, yet their effects across different inflammatory states of tendinopathy remain poorly characterised. To evaluate PEMF biological effects on human tenocytes, three in vitro models differing in IL-1β dose and duration were tested: acute low-dose (0.1 ng/mL, 96 h), acute high-dose (1 ng/mL, 96 h), and prolonged (0.1 ng/mL, 9 days). At the transcriptional level, PEMFs significantly reduced IL-6 and IL-8 mRNA overexpression in the acute low-dose model and CCL2 upregulation in the prolonged model. At the secretome level, PEMFs reduced GM-CSF and IL-8 secretion in the acute high-dose model, and suppressed CCL2 and CCL5 protein secretion in the prolonged model. MMP activity was not modulated by PEMFs in any condition. PEMFs consistently increased tenocyte proliferation across both the acute models. Finally, in wound healing assays, non-inflamed tenocytes exposed to PEMFs showed significantly enhanced wound closure compared to IL-1β-treated cells across all models; in the acute low-dose model, PEMFs also significantly improved wound closure in IL-1β-treated cells at an early timepoint, whereas no such effect was observed in cells exposed to high-dose or prolonged inflammation. PEMFs exert context-dependent effects, promoting healing primarily during acute or mild inflammation. These findings suggest that the inflammatory stage of tenocytes may influence PEMF responsiveness in vitro, highlighting the importance of considering this variable in the design of future clinical studies evaluating PEMF therapy for tendinopathy. Full article

Background: Dengue has expanded rapidly beyond traditional tropical and subtropical regions, driven by climate change, urbanization, population mobility, and the spread of competent Aedes vectors. Vaccination is an increasingly important component of dengue prevention, but development has been complicated by four viral serotypes, antibody-dependent enhancement, variable baseline serostatus, and the need for balanced and durable tetravalent immunity. Methods: We conducted a narrative review of PubMed/MEDLINE, Google Scholar, ClinicalTrials.gov, and relevant public health and regulatory sources. Evidence on dengue epidemiology, immunopathogenesis, licensed vaccines, advanced candidates, efficacy, immunogenicity, safety, durability, and implementation was critically evaluated. Priority was given to randomized trials, long-term follow-up studies, regulatory assessments, and surveillance data. Evidence was synthesized descriptively without formal meta-analysis or risk-of-bias assessment. Results: CYD-TDV was the first licensed dengue vaccine but is restricted to individuals with documented previous infection because seronegative recipients may experience an increased risk of severe dengue. TAK-003 has demonstrated overall efficacy against virologically confirmed dengue and dengue-related hospitalization in both baseline-seropositive and baseline-seronegative populations. However, protection is heterogeneous by serotype, and evidence remains limited or uncertain for some serotype-by-serostatus strata. Butantan-DV offers a promising single-dose strategy, but broader use requires additional long-term safety, effectiveness, and serotype-specific data. Inactivated, DNA, viral-vectored, virus-like particle, and mRNA vaccines remain investigational. Conclusions: Dengue vaccination should be integrated with surveillance, vector control, clinical preparedness, and risk communication. Population-based vaccination is most appropriate in high-transmission settings, whereas selective, risk-based strategies are preferable in temperate regions. Continued pharmacovigilance and effectiveness monitoring are essential to guide safe and equitable implementation. Full article

Background/Objectives: Cerebral ischemia–reperfusion injury (CIRI) poses therapeutic challenges because of oxidative stress, blood–brain barrier disruption, and neuronal apoptosis, limiting current treatments. Paeoniflorin (PF) from Paeonia lactiflora has neuroprotective potential, but its multi-target mechanisms remain unclear. This study investigated the role and mechanisms of PF in CIRI, focusing on neuron–endothelial crosstalk. Methods: Oxygen–glucose deprivation/reoxygenation (OGD/R) models were established using SH-SY5Y (human neuroblastoma) and HCMEC/D3 cells (human cerebral microvascular endothelial). Network pharmacology was used to predict potential PF targets and pathways. RNA sequencing, molecular docking, and molecular dynamics simulation were performed to screen and evaluate PF binding characteristics with key targets, and MTT, flow cytometry, Western blotting, and co-cultures were employed to detect paracrine interactions. Results: Network pharmacology and transcriptomics identified VEGF/PI3K-AKT/mTOR pathway enrichment. Molecular docking confirmed stable PF binding to VEGF-A (−8.4 kcal/mol), AKT (−5.5 kcal/mol), and mTOR (−9.6 kcal/mol). PF (10–80 μM) showed no cytotoxicity and reduced OGD/R injury in a concentration-dependent manner (maximal at 40 μM). PF activated VEGF/PI3K-AKT/mTOR signaling, reducing apoptosis by 57% (SH-SY5Y) and 33% (HCMEC/D3); PI3K inhibitor LY294002 abolished these effects. PF-treated HCMEC/D3-conditioned media enhanced OGD/R neuronal viability, verifying paracrine crosstalk. Conclusions: PF alleviated CIRI by directly protecting neurons and indirectly modulating neuron–endothelial crosstalk through VEGF/PI3K-AKT/mTOR activation, supporting its multi-target therapeutic potential. Full article

The application of biochar and bioorganic fertilizer (BOF) in agricultural systems has garnered increasing attention in recent years. Nevertheless, research remains scarce on the impacts of biochar and BOF on the rhizosphere microecological characteristics of saline-alkali soils. This research involved the execution and analysis of 16S rRNA sequencing using Illumina technology to explore how biochar, whether used alone or in conjunction with BOF, along with varying application rates, impacts the microbial community in the saline-alkali rhizosphere soil during quinoa cultivation. In the conducted field trial, sole BOF application, sole biochar application, and their combined application (referred to as BOFB) led to a substantial enhancement of 23.88%, 74.08–97.00%, and 188.88–220.59% in quinoa aerial biomass, respectively. Meanwhile, sole biochar application or biochar combined with BOF reduced soil electrical conductivity (EC) by 26.42–39.81%. Biochar and BOF significantly improved most soil parameters, with the exception of total phosphorus (TP). In comparison to the control (CK), the relative abundances of Pseudomonas, Arthrobacter, Skermanella, and Bacillus were elevated in the biochar and BOFB treatments, while Sphingomonas was more abundant in the BOF treatment. In addition, Skermanella exhibited a significant positive correlation with EC and available potassium (AK). Biochar exerted a stronger effect on soil bacterial community structure than BOF. Furthermore, the complexity of the bacterial community in biochar and BOFB treatments far exceeded that in the BOF and CK treatments. Overall, the application of biochar effectively reduced soil EC and improved soil fertility, enhanced bacterial community stability, and optimized bacterial community structure, thereby increasing quinoa aerial biomass. Under the conditions of this study, the optimal application rate for biochar was 15 t/ha, and the combined application of biochar and BOF produced superior effects relative to either amendment alone. Full article

Ankylosing spondylitis (AS) is a chronic inflammatory disease strongly associated with human leukocyte antigen B27 (HLA-B27). However, the incomplete penetrance of HLA-B27 suggests that additional molecular mechanisms contribute to AS pathogenesis. Circular RNAs (circRNAs) have emerged as important regulators of immune responses, but their roles in AS pathogenesis remain incompletely understood. In this study, circRNA expression profiles were examined by high-throughput RNA sequencing and selected circRNAs were validated by quantitative RT-PCR in T cells from AS patients and healthy controls. Among the validated circRNAs, circRNPS1 was significantly up-regulated in T cells from AS patients. Overexpression of circRNPS1 in activated Jurkat cells increased IL-2, IL-17A, and interferon-γ expression and enhanced JAK2/STAT1 and MEK1/2-ERK signaling. RNA pull-down followed by proteomic analysis identified heterogeneous nuclear ribonucleoprotein K (hnRNPK) that binds to the back-splicing junction region of circRNPS1. CircRNPS1 increased the stability of hnRNPK and VAV1, whereas hnRNPK knockdown attenuated circRNPS1-mediated MEK1/2-ERK activation and inflammatory cytokine expression. Furthermore, an antisense RNA fragment targeting the back-splicing junction region of circRNPS1 suppressed IL-2, IL-17A, and interferon-γ expression in activated circRNPS1-overexpressing Jurkat cells and T cells from AS patients. Disrupting the interaction between circRNPS1 and hnRNPK therefore warrants further investigation as a potential therapeutic strategy for AS. Full article

The tea tree (Melaleuca alternifolia) essential oil (TTEO) exhibited in vitro antioxidant activities with an inhibition concentration (IC50) of 29.02 ± 0.57 µg/mL. This is due to its content of bioactive compounds; practically α-pinene (1.52%), eucalyptol (9.05%), 2-bornanone (57.94%), 1-dotriacontanol (1.82%), 1-decanol, 2-hexyl- (1.99%), and 1-heptatriacotanol (4.90%). Therefore, this research aimed to determine changes in growth, antioxidant capacity, immune functions, and disease resistance in Nile tilapia (Oreochromis niloticus) when fed on a low-fishmeal (FM) diet enriched with TTEO. Nile tilapia juveniles (14.6–15.9 g) were fed on a low-FM diet containing 0.0 (the control), 0.1, 0.15, 0.2, and 0.25 g TTEO/kg feed up to apparent satiety three times a day for 70 days. Following the feeding trial, fish were intraperitoneally injected with Aeromonas hydrophila, and fish mortality was recorded for an additional 10 days. It is noted that feeding the fish on 0.2 g TTEO/kg feed increased the feed intake as well as the growth indices. Marked declines in FCR values were seen in fish fed on 0.15–0.25 g TTEO/kg feed. However, fish fed on a diet with 0.2 g TTEO/kg feed exhibited highest enhancements in intestinal villi width/length and absorption area compared with other TTEO levels. No statistical (p > 0.05) differences were observed in glucose and cortisol levels among TTEO-fed groups, indicating no stress effects on fish. Conversely, ALT and AST activities in Nile tilapia declined significantly (p < 0.05), especially at 0.20 and 0.25 g TTEO/kg feed, with no difference (p > 0.05) between the two treatments. It is noted that high TTEO levels (0.2–0.25 g/kg feed) increased hepatic superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities as well as the mRNA expression of hepatic SOD, CAT, and GPx genes. Compared with other TTEO groups, feeding the fish with 0.2 g TTEO/kg feed showed higher alkaline phosphatase, lysozyme, complement C3, and ACH50 levels, along with marked increases in IL-8 and IL-10 genes expression and declines in the expression TNF-α, IL-1ß, HSP70, Caspase-3, and Caspase-9 genes. After A. hydrophila infection, fish fed on the control diet exhibited the highest mortality (76.7%), whereas fish fed on 0.2 and 0.25 g TTEO/kg feed were more resistant to bacterial infection, with mortality rates of 23.3% and 26.7%, respectively, with no difference (p > 0.05) between them. The results confirmed that dietary TTEO enhanced growth, antioxidant capacity, immunological biomarkers, and disease resistance in Nile tilapia when added to low-FM diets, with an optimum dose of 0.2 g TTEO/kg feed. Full article

Kidney cystic epithelium primarily comprises proliferating A-intercalated (A-IC) cells in humans and mouse models of TSC. These studies explored the expression of transcription factors (TF) that drive the development of A-IC cells and the downregulation of B-intercalated (B-IC) cells, as well as the status and localization of Tsc1 and Tsc2 in epithelial cells lining the cysts. Transcriptome studies indicated enhanced expression of the following TFs: DMRT2, FOXI1, and FOXP1 in young TSC mice, and DMRT2 and FOXI1 in aged mice. The expression of Hmx2 decreased in TSC mice of all ages. Our studies further demonstrated: (1) distinct and predominant DMRT2 and FOXP1 localization in the cystic epithelium of in TSC mouse models; and (2) expression of Foxi1, Tsc1, and Tsc2 in epithelial cells lining the kidney cysts. Expression of DMRT2, FOXI1, and FOXP1 is enhanced in the A-IC cells lining the kidney cysts of TSC mouse models. In the same models, the expression of Hmx2 mRNA is decreased and is accompanied by the loss of B-IC cells in cyst epithelia. Both DMRT2 and FOXP1 localized to the nucleus of A-IC cells of the renal cysts, suggesting that TSC kidney cystogenesis is driven by factors that exclusively promote A-IC expansion. Full article

Differences in the composition, microstructure, infrared spectral characteristics, and enzymatic hydrolysis properties of rice bran protein extracted by four methods were investigated, and the antioxidant and anti-photoaging activities of peptides derived from the resulting hydrolysates were further evaluated. Rice bran protein obtained via ultrasonic pretreatment combined with alkaline solublilization and acid precipitation (URP) exhibited relatively high purity (59.17%) and extraction yield (47.61%), together with increased surface porosity, enhanced hydration capacity, and improved enzymatic hydrolysis performance. The URP hydrolysate (URPP) showed a protein content of 81.00%, a degree of hydrolysis of 33.57%, and marked antioxidant activity (ABTS, 684.21; ORAC, 2016.15 μmol TE/g sample). The identified peptides were predominantly short and enriched in hydrophobic amino acids. Structural analysis suggested that the indole N-H group of tryptophan may play an important role in the antioxidant activity of these peptides. Moreover, these peptides alleviated UVB-induced photoaging in HaCaT cells by reducing oxidative stress and inflammatory responses and downregulating the mRNA expressions of AP-1, MMP-1 and MMP-3. Overall, these findings reveal an association between the extraction method, structural characteristics, and enzymatic hydrolysis properties of rice bran protein and the biological activities of its derived peptides, providing a basis for the high-value utilization of rice bran protein and the development of antioxidant and anti-photoaging functional ingredients. Full article

Background: High-altitude hypobaric hypoxia (HH) is a major environmental stressor that impairs cognitive function, yet effective and widely available therapeutics remain limited. Although Rhodiola rosea has shown neuroprotective effects, its resource scarcity restricts large-scale application. Cistanche tubulosa (Schrenk) Wight, a traditional Chinese functional food, has been increasingly used in health supplements due to its anti-fatigue, anti-dementia, and memory-enhancing properties, suggesting potential benefits against hypoxia-induced cognitive impairment. Objective: This study aimed to investigate the effects of C. tubulosa ethanol extract (CTE) on hippocampal tissue and gut microbiota upon chronic HH exposure using SPF male Sprague–Dawley (SD) rats. Methods: A total of 60 male SD rats were randomly assigned to six experimental groups (n = 10 per group): normoxic control, untreated HH model, positive control (R. rosea), and low-, medium-, high-dose CTE treatment groups. Behavioral tests (Morris water maze), hippocampal histopathology, serum and hippocampal oxidative stress markers (SOD, GSH-Px, MDA), expression of PI3K/Akt/mTOR-HIF-1α signaling pathway proteins (by immunohistochemistry), and gut microbiota composition (by 16S rRNA sequencing) were evaluated. Results: The results demonstrated that CTE significantly improved cognitive function, enhanced SOD and GSH activities, and reduced MDA levels in both hippocampus and serum. CTE also modulated the expression of PI3K/Akt/mTOR-HIF-1α pathway proteins in the hippocampus. Furthermore, CTE altered gut microbial diversity and abundance, increasing the proportion of beneficial bacteria, which may further influence hippocampal function via the gut–brain axis. Conclusion: These findings provide scientific evidence for the application of C. tubulosa as a potential health supplement for high-altitude adaptation and lay a foundation for subsequent research. Full article

Background/Objectives: Mosquito-borne viruses cause substantial global morbidity and mortality. Mosquito saliva, secreted during biting, facilitates blood feeding and can enhance virus infection. Here, we evaluated whether combining virus-specific antigens with mosquito salivary protein-derived peptides improves protection in Zika virus (ZIKV) and chikungunya virus (CHIKV) mouse models. Methods: Peptides from Aedes and Culex salivary proteins were selected based on conservation, predicted T-cell reactivity, and cellular and humoral immunogenicity in mice. Mice were immunised subcutaneously with a prime and boost two weeks apart using adjuvanted salivary peptides (SAL), commercial ZIKV- or CHIKV-like particles (VLPs), or salivary peptides combined with the relevant VLPs. Vaccine doses contained 0.5 µg VLPs and/or 10 nmol of each salivary peptide, formulated with Montanide ISA-51; when combined, VLPs and SAL were administered on opposite flanks. Two weeks after boosting, mice were challenged with ZIKV or CHIKV plus Aedes aegypti saliva. Challenge teams were blinded to group allocation until data analyses were complete. Results: SAL enhanced the protective effect of VLP vaccination compared with VLPs alone. In the CHIKV model, CHIKV VLP + SAL prevented joint swelling and reduced infectious virus in the inoculated ankle and viral RNA in the contralateral ankle. In the ZIKV model, ZIKV VLP + SAL reduced viral RNA in skin and brain tissue and improved survival. Conclusions: Mosquito salivary peptide antigens improved the protective efficacy of VLP vaccines against ZIKV and CHIKV in mouse models. Salivary antigens may provide a complementary vaccine component for multiple arboviruses transmitted by Aedes and Culex mosquitoes. 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