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Parabiotics (also termed paraprobiotics) are defined as non-viable microbial cells or their components, including peptidoglycans, teichoic acids, surface proteins, that confer health benefits without requiring viability which distinguishes them from traditional probiotics. Their non-viable nature eliminates risks such as microbial translocation, bacteremia, and sepsis, making them suitable for vulnerable populations including immunocompromised, critically ill, paediatric and elderly individuals. In addition, parabiotic exhibit improved thermal stability, extended shelf life, and easier incorporation into functional foods, nutraceuticals, and pharmaceutical formulations without cold-chain requirements. Mechanistically, parabiotics retain immunomodulatory, anti-inflammatory and have barrier-enhancing activities through interactions with host pattern recognition receptors, including Toll-like receptors, modulation of cytokine responses, and reinforcement of gut epithelial integrity. Preclinical and clinical studies support their therapeutic potential such as in case of heat-killed Lactobacillus acidophilus LB (L. acidophilus) has shown efficiency in managing acute paediatric diarrhoea, while heat-inactivated Lacticaseibacillus paracasei PS23 (Lcb. paracasei) has demonstrated improvements in muscle strength and inflammatory markers, including reduced C-reactive protein and interleukin-6 and increased interlukin-10 in elderly individuals. Similarly, inactivated Lactiplantibacillus plantarum (Lpb. plantarum) and Bifidobacterium strains have been associated with benefits in irritable bowel syndrome, atopic dermatitis, respiratory infections, visceral fat reduction, and antibiotic-associated dysbiosis. Synergistic combinations with prebiotics, postbiotics and related bioactives further enhance therapeutic outcomes in inflammatory, metabolic and infectious conditions. Advances in metagenomics, next-generation sequencing, proteomics, metabolomics, CRISPR-Cas systems, and synthetic biology are accelerating strain characterization, functional evaluation, and scalable production. Despite ongoing challenges in standardization and regulated harmonization, parabiotics represent a safe and effective approach for microbiome-targeted interventions. This review synthesizes current evidence on their therapeutic applications, technological advancements, and translational potential, highlighting their role in precision health and next-generation functional nutrition.
To interpret and transmit biological signals, proteins use correlated motions. Experimental determination of these dynamics and the structural distributions they generate remains a key challenge. Here, using 1146 crystal structures of the main protease (Mpro) from SARS-CoV-2, we were able to infer a model of the enzyme's structural fluctuations. Mpro is regulated by concentration, becoming enzymatically active after forming a homodimer. To understand the structural changes that enable dimerization to activate catalysis, we employed our model, predicting which regions of the dimerization domain are structurally correlated with the active site. Mutations at these positions, expected to disrupt catalysis, resulted in a dramatic reduction in activity in one case, a mild effect in the second, and none in the third. Additional crystallography and biophysical experiments provide a mechanistic explanation for these results. Our work suggests that a statistical crystallography, in which numerous crystallographic datasets are analyzed, can reveal the structural fluctuations of protein native states and help uncover their biological function.
Renal Fanconi syndrome (RFS) refers to a generalized dysfunction of the proximal tubule, including impaired 1-α hydroxylation of vitamin D. Consequently, rickets is a typical complication. Clinical observations in children with severe nutritional vitamin D deficiency sometimes include proximal tubular dysfunction, raising the possibility that lack of vitamin D could not only be a consequence of RFS but also a cause of it, although this has never been confirmed. Observations in Mendelian disorders with their genetically defined pathophysiology can provide clearer insights. We performed a retrospective review of 2 cases with vitamin D deficiency due to loss-of-function variants in CYP27B1. Additionally, we performed an in silico search for vitamin D-responsive elements (VDRE) in the promoter region of genes encoding proximal tubular transporters. Both cases presented with clinical rickets that had been resistant to supplementation with cholecalciferol. Biochemistries at presentation showed a non-anion gap metabolic acidosis, generalized aminoaciduria and urinary phosphate wasting consistent with proximal tubular dysfunction. Symptoms resolved upon treatment with active vitamin D. VDRE motifs were identified in the promoters of SLC34A1 and SLC34A3. Our observations support the notion of vitamin D deficiency as a cause of RFS and suggest that unresolved cases of RFS should be actively investigated for it.
Ectonucleotidases, including NTPDases and ecto-5'-nucleotidase (e-5'NT/CD73), regulate extracellular purinergic signaling by converting ATP to adenosine, a pathway critically involved in immune response, inflammation, and cancer progression. In this study, a novel library of 22 N-propylsulfonyl-substituted indole-based hydrazinecarbothioamides (5a-5v) was synthesized and structurally characterized. Biological evaluation against human e-5'NT and NTPDase1, -2, -3, and - 8 revealed that several compounds exhibited low micromolar inhibitory activity, with 5n (IC50 = 1.7 µM), 5o (IC50 = 1.7 µM), 5f (IC50 = 1.0 µM), and 5i (IC50 = 1.6 µM) emerging as the most promising derivatives, showing strong potency and isoform selectivity. Structure-activity relationship analysis indicated that both electronic and steric features of substituents significantly influence activity and enzyme preference. Molecular docking studies performed on e-5'NT demonstrated that active compounds adopt consistent binding modes within the catalytic pocket, stabilized by key residues such as Asp-506, Phe-500, Phe-417 and Arg-395. Binding free energy calculations (MM-GBSA) supported strong ligand-protein interactions ( ~ - 70 kcal/mol). The docking protocol was validated by redocking, yielding an RMSD value well below the accepted threshold. Molecular dynamics simulations (500 ns) confirmed stable complex formation, with low RMSD values (~ 1-3 Å), limited residue fluctuations, and persistent interactions with catalytic residues. Surface and compactness parameters (rGyr, SASA) remained stable, indicating consistent ligand accommodation. In silico ADME analysis suggested favorable drug-like properties for most compounds, particularly for the lead candidates. Overall, these findings identify 5n and 5o as the most promising lead compounds, supported by both experimental and computational results, and highlight this scaffold as a valuable platform for the development of selective ectonucleotidase inhibitors.
The practical application of Fe-N-C catalysts in proton exchange membrane fuel cells is fundamentally constrained by the inherent activity-stability trade-off. Here, we propose a "repair-and-upgrade" engineering strategy that not only repairs pyrolysis-induced defects through carbon and nitrogen supplementation but also evolves conventional FeN4 moieties into stabilized FeN5 configurations via an in situ constructed carbon bilayer. The axial nitrogen modulates the electronic structure of Fe center to enhance catalytic activity, while the adaptive interlayer spacing of the N-linked carbon bilayer compensates for fluctuations in the axial Fe─N bond length during catalysis, therefore anchoring the Fe active sites. When integrated into membrane electrode assemblies, the catalyst delivers a high peak power density of 1221 mW cm-2 and exhibits exceptional durability, retaining over 85% of its initial power density after 10,000 cycles in H2-O2 and showing negligible decay over 45 h at 0.6 V in H2-air tests. This work presents a novel design strategy for stable single-atom catalysts, centered on creating an adaptive local environment that ensures exceptional electrocatalytic stability.
Tanzania has adopted artificial intelligence (AI)-assisted chest X-ray screening for tuberculosis (TB), including the use of CAD4TB version 6, which is registered by the Tanzania Medicines and Medical Devices Authority (TMDA). While GeneXpert, practical reference standard used in routine practice, remains the primary bacteriological confirmatory test in routine practice, there is currently no established national threshold for CAD4TB use in either active case finding (ACF) or passive case finding (PCF) settings. This study evaluates the implementation and operational use of CAD4TB version 6 within mobile TB screening units in Tanzania and highlights challenges affecting its effective use. We conducted a retrospective analysis of screening data from 11,923 individuals collected from mobile clinics equipped with digital X-ray, CAD4TB version 6, and GeneXpert systems. Comparisons were made between manual chest X-ray interpretation, CAD4TB scores, and GeneXpert results within the subset of individuals who underwent confirmatory testing. The findings reveal substantial inconsistencies in screening workflows, including non-uniform use of CAD4TB prior to GeneXpert testing, missing radiological records, and deviations from intended protocols across sites. Descriptive analysis showed that CAD4TB scores generally aligned with GeneXpert-positive cases within the tested subset; however, due to selective application of GeneXpert and incomplete data, these observations cannot be interpreted as measures of diagnostic accuracy. This study should be interpreted as an implementation and operational assessment of AI-assisted TB screening rather than a diagnostic accuracy or threshold-setting study. The findings highlight important gaps in protocol adherence, data completeness, and workflow standardization, underscoring the need for prospective, protocol-driven studies to establish validated national thresholds for CAD4TB use in Tanzania.
This study aimed to prepare and evaluate a novel monoammonium glycyrrhizinate (MAG) controlled-porosity osmotic pump (CPOP) with controlled-release properties. Capsule shells were prepared by the dip-coating method method, and the key variables affecting in vitro release were optimized using a Box-Behnken design-response surface methodology. In vitro release behavior was evaluated, and scanning electron microscopy (SEM) was used to examine shell morphology before and after dissolution. Pharmacokinetic behavior in rabbits, molecular docking, and solid-state characterization by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were also performed. The optimized formulation exhibited a near zero-order release profile of MAG over 12 h in vitro, and the release curve closely matched the target profile. In rabbits, the self-prepared capsules reduced the peak plasma concentrations of MAG and its active metabolite glycyrrhetinic acid (GA) and significantly prolonged mean residence time compared with the reference formulation, indicating marked controlled-release behavior in vivo. Molecular docking confirmed stable binding of GA to nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor gamma (PPARγ), providing a mechanistic basis for the pharmacological benefits associated with prolonged in vivo exposure. DSC and XRD further showed that MAG remained in a stable crystalline state, with no crystal-form transition or incompatibility with the excipients during preparation. This study provides a promising advanced drug-delivery system for MAG, enhances understanding of its pharmacological advantages, and offers useful guidance for the development of controlled-release formulations.
Incorporating redox active ligands into coordination cages offers a direct way to reach architectures whose structure or composition can be modulated in response to changes in the oxidation state. An exTTF-based ditopic ligand L affords a M2L4 cage in presence of a palladium(II) salt (M). The resulting M2L4 cavity exhibits selective binding properties for medium length α,ω-dinitrile alkanes. Modifying the coordination geometry of the ligand by oxidation to its Lox state redirects the self-assembly process toward a M2Lox 2 structure. The oxidized ligand can also be combined with a dibenzothiophene linker (L') to afford a heteroleptic M2LoxL'2 structure whose vacant coordination sites enable subsequent dimerization into an unprecedented M4L4L'4 architecture. Key intermediates and products were structurally authenticated by single-crystal x-ray diffraction. Notably, these processes are reversible. Reduction converts the M2LoxL'2 assembly back to the homoleptic M2L4 cage. This sequence illustrates how changes of oxidation state can reshape nuclearity and composition in metal organic assemblies.
Controlling peroxymonosulfate (PMS) activation at the atomic scale is crucial for steering reactive oxygen species (ROS) pathways, yet design principles that selectively bias PMS chemistry toward interfacial radical states remain elusive. Herein, we report an asymmetric Fe-Te dual-atom pair (FeTe DAs/NC), in which a p-block metalloid electronically modulates an Fe center through pronounced p-d hybridization. This atomic asymmetry reconstructs the local electronic structure, strengthens PMS binding, and directs PMS activation toward the generation and retention of surface-bound hydroxyl radicals. Mechanistic studies reveal surface-bound hydroxyl radicals (•OH) as the dominant ROS, while singlet oxygen (1O2) plays a secondary role. As a result, FeTe DAs/NC achieves complete degradation of carbamazepine within 60 min, markedly outperforming Fe or Te single-atom analogs, together with excellent reactivity and cycling stability across different water matrices and pollutant systems. This work establishes atomic-scale asymmetry and metal-metalloid p-d coupling as an effective strategy for steering PMS activation chemistry toward long-lived interfacial radical states.
Plant cells are connected to their neighbors via plasmodesmata facilitating the exchange of nutrients and signaling molecules. During immune responses, plasmodesmata close, but how this contributes towards a full immune response is unknown. To investigate this, we develop two transgenic lines which allow to induce plasmodesmal closure independently of immune elicitors, using the over-active CALLOSE SYNTHASE3 allele icals3m and the C-terminus of PDLP1 to drive callose deposition at plasmodesmata. Induction of plasmodesmal closure increases the expression of stress responsive genes, salicylic acid accumulation and resistance to Pseudomonas syringae DC3000. More homogeneous plasmodesmal closure using icals3m also leads to the accumulation of starch and sugars, decreases leaf growth, as well as hypersusceptibility to Botrytis cinerea. Based on the profile of responses, we conclude that plasmodesmal closure activates stress signaling, raising questions about the signals mediating this response and whether these responses occur in all circumstances when plasmodesmata close.
Chitin is the second most abundant polysaccharide in nature, and its degradation by marine microorganisms plays a critical role in the global carbon and nitrogen cycles. This study investigated the marine bacterium Microbulbifer harenosus CGMCC 1.13584T to elucidate its chitin metabolic pathway through genomic and transcriptomic analyses. When cultured with chitin as the carbon source, the strain exhibited an extended lag phase and enhanced extracellular chitinase activity. Genome sequencing revealed the presence of genes involved in both hydrolytic and oxidative chitin degradation pathways. Transcriptomic analysis showed that genes associated with the hydrolytic pathway were significantly upregulated upon chitin induction. In contrast, within the oxidative degradation pathway, only early-stage response genes (such as those encoding LPMOs) were markedly upregulated, while genes involved in subsequent metabolic steps (converting GlcNAc1A to KDG-6-P) did not show significant upregulation. Furthermore, a gene encoding a GH10 domain-containing protein was found to be substantially upregulated during growth on chitin. These findings indicate that Microbulbifer harenosus CGMCC 1.13584T utilizes a coordinated chitin degradation mechanism, where the hydrolytic pathway dominates carbon flux during active growth, while the oxidative pathway (via LPMOs) likely provides critical initial structural disruption.
Population-based organized prostate-specific antigen (PSA) screening is implemented in 80% of Japanese municipalities; however, Shiga Prefecture remains a unique exception without such a systematic program. This study characterized the longitudinal clinical features and treatment patterns in this opportunistic testing environment using data from 1716 patients diagnosed via prostate biopsy in 2012, 2017, and 2022. While median PSA levels remained stable (10.40-11.43 ng/mL), median age at diagnosis increased from 72 to 74 years. Over the decade, the incidence of International Society of Urological Pathology Grade Group 1 and cT1c stages decreased significantly (p < 0.001), with nearly 90% of cases being cT2 or higher in 2022. Risk classification showed a decrease in low-risk cases and a rise in high-risk cases. Regarding treatment, radical prostatectomy rates remained stable at approximately 25%, whereas the overall use of active surveillance (AS) increased from 1 to 9%. Notably, among low-risk patients, AS adoption rose markedly from 2.3% in 2012 to 68% in 2022. While clinical practices have evolved to successfully minimize unnecessary invasive intervention, these findings suggest that clinical progress alone cannot fully compensate for the lack of organized efforts to improve early detection.
Soft skills correspond to intrapersonal and interpersonal abilities related to how individuals interact, make decisions, and manage their activities. In the context of undergraduate nursing education, their development is fundamental to the preparation of professionals capable of acting in an ethical, critical, and relational manner, making it relevant to understand how these competencies are incorporated into the teaching and learning process. In this context, the objective of this study is to understand how faculty members in undergraduate nursing programs incorporate soft skills into their pedagogical approaches and practices, identifying the competencies considered essential and the challenges to their implementation. A qualitative study was conducted with 26 nursing faculty members from four federal public universities in southern Brazil. Data were collected between June and September 2025 through semi-structured interviews, following the criteria of the Consolidated Criteria for Reporting Qualitative Research checklist. The interviews were processed using IRaMuTeQ software and analyzed in light of Discursive Textual Analysis. Three analytical categories emerged: faculty understanding of soft skills in nursing education; pedagogical approaches and strategies for the development of these competencies; and perceived difficulties in their promotion within teaching. The faculty members recognize the relevance of soft skills and report the use of active methodologies and reflective strategies for their development. However, most had not received specific training, and the teaching of these competencies occurs predominantly in an implicit manner. The findings demonstrate that, although soft skills are widely valued in nursing education, their promotion still lacks pedagogical systematization and institutional support. Challenges such as the subjectivity of these competencies, the prioritization of technical skills by students, and distractions associated with the use of technologies limit their intentional development. These results contribute to the international literature in nursing education by highlighting the need for structured institutional strategies for faculty development and for the explicit integration of soft skills into nursing curricula.
Up to 80% of diffuse midline gliomas (DMGs) are characterized by a lysine to methionine driver mutation (K27M) in the tail of histone variant H3.3, pointing to likely roles for epigenetic mechanisms in K27M-driven tumorigenesis. Understanding the effects of mutant histone H3.3 on the complex patterns of histone modifications and interactions with chromatin structure and modifying enzymes is essential to developing effective combination treatment therapies for K27M DMG such as targeting multiple epigenetic enzymes at once. Here, using a genomics approach, we identified combinatorial patterns of epigenetic modifications that are affected by mutant H3.3 in DMG. We also characterized a strong association between H3.3 and the structural chromatin regulator CTCF, finding that mutant H3.3 leads to ectopic binding of CTCF at many additional sites across the genome in DMG. Notably, a number of these ectopic CTCF binding events occur within the HOX gene loci and are associated with an increase in H3K27me3 levels at bivalent domains and a decrease in HOX gene expression. We also find an association of H3.3 and CTCF at genomic sites adjacent to regions with active or repressive modifications, suggesting a potential role for these two factors in segmenting the chromatin and regulating, perhaps insulating, different types of domains. Together our data suggest that H3.3 K27M both affects epigenetic marks and chromatin organization in part through interaction with CTCF and point to a potentially novel contributory role for CTCF in promoting oncogenesis in DMG. These findings could have potential implications for designing therapy regimens to more effectively target the chromatin changes and genomic instability observed in H3.3K27M glioma cells.
Lung cancer is one of the most common malignancies and the leading cause of cancer-related mortality worldwide, posing a major public health challenge. Flavonoids, a large and diverse group of plant metabolites, exhibit various anticancer properties, making them promising candidates for therapeutic applications. This study evaluated the anticancer efficacy of methoxy flavonoids and elucidated their underlying mechanisms of action in A549 lung cancer cells. A549 cells were treated with various flavonoids (AKC1-AKC5), and their effects were analyzed using an MTT assay, DAPI staining, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production, colony formation, and wound scratch tests. Molecular docking was also performed to confirm the binding of AKC1 and AKC3 to EGFR, BCL-2, and CDK-2 proteins. AKC1 and AKC3 prevented the growth of A549 lung cancer cells with IC50 of 64.57 and 19.80 μM among 5 methoxy flavonoids. AKC1 and AKC3 triggered notable alterations in the shape and reduced the colony-forming potential of A549 cells. The DAPI staining experiment demonstrated that AKC1 and AKC3 impede the growth of cancer cells through activation of apoptotic cell death. Moreover, the anticancer properties of AKC1 and AKC3 were attributed to significant inhibition of MMP and a notable ROS enhancement in a dose-related pattern. The wound scratch assay demonstrated that AKC1 and AKC3 suppressed A549 lung cancer cell migration, suggesting their anti-metastatic properties. Molecular docking studies confirmed that AKC-1 and AKC-3 bind strongly to EGFR, BCL-2, and CDK2, suggesting a multi-target mechanism that underlies their anti-proliferative and pro-apoptotic effects in A549 cells. AKC1 and AKC3 exhibited significant anticancer activity against A549 cells and may serve as promising therapeutic drugs for lung cancer treatment.
Therapeutic resistance to chemotherapy or radiotherapy is a significant issue in several cancers, including head and neck squamous cell carcinoma (HNSCC). One pathway associated with therapeutic resistance is the NFκB pathway, which promotes survival in response to the cytokine TNFα, a key mediator of chemotherapy and radiotherapy-induced cytotoxicity. However, direct targeting of the NFκB pathway is associated with significant toxicity and thus targeting the regulation of this pathway is a promising therapeutic target. We recently demonstrated that the USP14/UCHL5 inhibitor b-AP15 inhibits NFκB activity, inhibiting proliferation and inducing apoptosis in HNSCC cells. Furthermore, b-AP15 treatment sensitised HNSCC cells to the cytotoxic effects of TNFα, as well as TNF-inducing radiation treatment. Here, we investigated if b-AP15 sensitised HNSCC cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a cancer selective member of the TNF family. b-AP15 treatment sensitised HNSCC cells to TRAIL treatment. Mechanistically, we show that b-AP15 induced expression of the TRAIL receptor Death Receptor 5 (DR5)/TRAIL Receptor 2 (TRAILR2), which was required for b-AP15-mediated TRAIL sensitisation. b-AP15 induced reactive oxygen species (ROS) and activated the JNK signalling pathway and both ROS and JNK signalling were required for the induction of DR5 expression and TRAIL sensitisation. We further show that b-AP15-mediated reduction of the NFκB-dependent gene XIAP induced DR5 expression and TRAIL sensitisation and that combination between b-AP15 and IAP antagonists was synergistic in HNSCC cells in vitro. Our data further define the mechanism of b-AP15-mediated cytotoxicity and highlight potential combination treatments that warrant further exploration in pre-clinical studies in HNSCC.
Clinical empathy refers to a healthcare professional's ability to understand a patient's experiences and emotions through cognitive and affective perspective taking, and to communicate that understanding through compassionate and appropriate professional behaviors. Aging simulation suits are experiential educational tools designed to replicate the sensory and physical limitations associated with aging. However, evidence regarding their effectiveness in enhancing clinical empathy among active healthcare professionals remains limited. This study aimed to evaluate the effects of an aging simulation suit on clinical empathy among healthcare professionals working in long-term care settings. A randomized controlled trial was conducted with 82 healthcare professionals from four nursing homes in Madrid and Asturias (Spain). Participants were randomly assigned to an experimental group (EG) (n=41) or a control group (CG) (n=41). Both groups received the same structured educational session on empathy and aging. The experimental group additionally participated in an immersive experience using the GERT aging simulation suit, whereas the control group did not receive the simulation component. Self-reported empathy were measured pre- and post-intervention using the Interpersonal Reactivity Index (IRI) and the Jefferson Scale of Empathy-Health Professions version (JSPE-HPS). No significant differences were found between groups in IRI scores. However, the experimental group showed significant improvements in total JSPE-HPS scores and in the subscales Perspective Taking and Compassionate Care (p < 0.05), compared with the control group. These findings suggest that the immersive intervention enhanced both cognitive and affective components of clinical empathy. The use of an aging simulation suit was associated with improvements in specific dimensions of clinical empathy among healthcare professionals working in long-term care. This educational tool offers a valuable experiential approach that enhances understanding and compassion toward older adults. However, these findings are limited to short-term, self-reported measures, and no behavioral or patient outcome data were collected. Further longitudinal studies are needed to determine the long-term sustainability of these effects and their translation into clinical practice. ClinicalTrials.gov, Unique Protocol ID: 2711201916919; ClinicalTrials.gov ID: NCT07280689. Date of registration: 10/10/2025. Retrospectively registered.
IL-11, a novel target for drug development, has been associated with several fibroinflammatory diseases including thyroid eye disease (TED), where it plays an important role in signaling to stromal cells activating multiple intracellular pathways. In TED patient tissue, IL-11 is elevated and stimulates multiple effects important in disease progression, including the production of proinflammatory cytokines, hyaluronic acid (HA) and fibrotic markers. LASN01, a potent antibody to IL-11 receptor, inhibits these effects and is a potential therapeutic agent for TED. Teprotumumab, an antibody to IGF-1 receptor, inhibits HA production and adipogenesis and is effective in reduction of proptosis. Activation of the IGF-1 and IL-11 pathways in TED tissue induces the expression of fibroinflammatory genes regulated by LASN01 and lipid biosynthetic genes regulated by Teprotumumab. Clinical studies show that LASN01 is well tolerated and in a placebo-controlled phase II trial in TED, LASN01 resulted in a statistically significant resolution of clinical activity score (CAS) in 88% of treated patients (p = 0.028), but had lesser effects on proptosis. The data supports the importance of IL-11 biology in fibroinflammatory disease and that IL-11 receptor is a pharmacologically active target for drug development.
Bone remodelling is essential for maintaining skeletal integrity by preserving the balance between bone formation and resorption, with excessive osteoclast activity contributing to osteoporosis. Osteocytes act as central regulators of osteoclastogenesis through mechanically sensitive paracrine signals, yet the influence of osteoblasts and their mesenchymal precursors remains less defined. Extracellular vesicles (EVs) have recently emerged as mediators of bone cell communication, although their role in osteoclast regulation are still underexplored. This study demonstrates that mesenchymal-derived bone cells inhibit osteoclastogenesis through an EV-dependent mechanism shaped by their differentiation stage and mechanical environment. Mechanically stimulated osteocyte-derived EVs showed the strongest anti-catabolic response. Notably, we identify miR-150-5p as a mechano-responsive miRNA enriched within osteocyte EVs, capable of inducing a dose-dependent reduction in osteoclastogenesis. Transcriptomic analyses reveal that EV treatment and miR-150-5p delivery induce substantial transcriptional changes in osteoclast precursors, including downregulation of shared target genes linked to bone remodelling. Overall, we highlight mechanically activated osteocytes as key regulators of osteoclastogenesis through an EV-mediated mechanism, in which miR-150-5p represents a promising candidate contributor within the broader EV cargo landscape, highlighting their potential for future cell-free therapeutic strategies.