Search Results (2,473)

Background/Objectives: To describe the demographic, clinical, and epidemiological characteristics of a cohort of patients diagnosed with Multiple Sclerosis (MS) in Lima, Peru. Methods: A descriptive, retrospective cohort study conducted across three major hospitals in Lima. We included adult patients diagnosed with MS in any of its clinical phenotypes—Clinically Isolated Syndrome (CIS), Relapsing-Remitting MS (RRMS), Secondary Progressive MS (SPMS), and Primary Progressive MS (PPMS)—who were followed between 2007 and 2017. Results: A total of 103 patients were identified. The majority were women (58.3%), with a median age at onset of 38.4 years (Interquartile Range [IQR]: 28.9–46.5). The most common clinical phenotype at onset was RRMS (90.3%), which remained the most prevalent phenotype at the current evaluation (79.6%). Twelve patients (12.9%) progressed from RRMS to SPMS by their last control visit. The most frequent symptoms at onset were limb weakness (72.8%), sensory symptoms (72.8%), and blurred vision (42.0%). At the last evaluation, the most frequent symptoms were limb weakness (78.6%), sensory symptoms (71.8%), and spasticity (40.2%). The most common initial treatment was interferon-beta (44.7%), while two patients (1.9%) initiated therapy with a highly effective disease-modifying drug (DMD), Ocrelizumab. The most recent treatment reported remained interferon-beta (33.9%), but 12 patients (11.7%) were currently receiving Ocrelizumab. Conclusions: This study describes clinical characteristics at onset and during follow-up that are largely similar to those reported in international series. However, we found no evidence of improved disease evolution, a finding potentially attributable to the heterogeneity of treatment and management strategies employed across the cohort. Full article

Osteoarthritis (OA) is increasingly recognized as a mechanically driven whole-joint disease in which abnormal mechanotransduction initiates a cascade of mitochondrial dysfunction, chronic inflammation, and progressive cartilage degeneration. Among the mechanosensitive molecules identified to date, Piezo1 has emerged as a key mechanosensitive regulator linking pathological mechanical loading to intracellular calcium signaling and downstream cellular responses. Growing evidence indicates that persistent Piezo1 activation promotes mitochondrial calcium overload, excessive reactive oxygen species production, ATP depletion, mitochondrial membrane depolarization, and impaired mitophagy, ultimately amplifying chondrocyte dysfunction and extracellular matrix degradation. In parallel, mitochondrial damage triggers immunometabolic reprogramming through activation of the cGAS–STING pathway and the NLRP3 inflammasome. It also promotes pro-inflammatory cytokines, including interleukin-1β, tumor necrosis factor-α, and interleukin-6. Together, these responses may contribute to a self-perpetuating cycle of inflammation and tissue destruction. This review provides a comprehensive synthesis of recent advances regarding the role of Piezo1 in OA, focusing on the mechanistic links between mechanotransduction, mitochondrial dysfunction, mitophagy, and immunometabolic dysregulation. We further discuss the contribution of mitochondrial quality-control pathways, including PINK1/Parkin-, BNIP3-, and FUNDC1-mediated mitophagy, as well as alterations in mitochondrial dynamics involving DRP1, MFN1, MFN2, and OPA1. Emerging experimental models are discussed as valuable tools for accelerating therapeutic discovery. Finally, we critically evaluate current therapeutic strategies targeting the Piezo1–mitochondria axis, including mechanosensitive channel modulation, mitochondrial protection, mitophagy enhancement, gene therapy, biomaterial-assisted delivery, and nanomedicine. Collectively, current evidence supports the Piezo1–mitochondria–immune axis as an important mechanistic framework contributing to OA pathogenesis and as a potential therapeutic target. Integrating mechanobiology, mitochondrial medicine, and precision-engineered experimental models may facilitate the development of next-generation disease-modifying therapies capable of slowing or preventing osteoarthritis progression. Full article

Background/Objectives: Enteral nutrition (EN), delivered either exclusively (EEN) or partially (PEN) in combination with the Crohn’s Disease Exclusion Diet (CDED), represents an evidence-based dietary therapy for active Crohn’s Disease (CD), recommended in clinical guidelines. However, adherence to this therapy remains suboptimal among adult patients. This study aimed to explore the intention to repeat CDED & PEN alongside perceived factors affecting adherence to CDED & PEN in CD adult patients. Methods: A single-center, cross-sectional qualitative study was conducted between October 2025 and March 2026 at a private dietetic practice in Larissa, Greece. Semi-structured interviews were undertaken and analyzed using thematic analysis. Results: Out of the 88 patients screened, 15 adults with CD participated in semi-structured interviews. Four overarching themes emerged: (1) intention to repeat CDED & PEN, with all participants reporting willingness to repeat CDED & PEN in the event of future relapse; (2) barriers to CDED & PEN adherence, including challenges in social situations involving food; (3) facilitators of CDED & PEN adherence, such as improved symptom control and increased sense of security; and (4) dual factors affecting CDED & PEN adherence, whereby meal preparation demands, taste and variety, and social and environmental support acted as either facilitators or barriers against adherence depending on individual circumstances. Conclusions: Greek adults with CD showed strong willingness to reinitiate CDED & PEN during relapse. Addressing modifiable barriers, particularly dietary monotony and financial burden, alongside strengthening structured dietitian support and personalized dietary guidance, may help optimize adherence in clinical practice. Full article

Background/Objectives: Surgical indications for spondylodiscitis are controversial, particularly when epidural extension and evolving neurological compromise are present. This study aimed to describe the clinical, neurological, pain-related, and inflammatory outcomes of patients with spondylodiscitis treated with decompressive laminectomy without spinal stabilization, at a single tertiary center. Methods: We retrospectively reviewed 15 consecutive patients with spondylodiscitis who underwent decompressive laminectomy at the University Hospital of Trieste between January 2017 and December 2023. Inclusion required at least 6 months of clinical and laboratory follow-up. Patients treated with acute vertebral stabilization were excluded. Collected data included spinal level, timing from diagnosis to surgery, visual analog scale (VAS) pain score, Cooper Scale grade, modified Japanese Orthopedic Association score (mJOA), white blood cell count, and C-reactive protein (CRP). Assessments were performed preoperatively (T0), 1 week after surgery (T1), and at 6 months (T2). Imaging findings from representative cases were reviewed to illustrate the radiographic evolution after decompression combined with antibiotic therapy and orthotic support. Results: The cohort included 8 women and 7 men with a mean age of 57.33 years. Twelve patients (80%) underwent surgery within 48 h because of neurological deterioration or urgent compressive findings. Thoracic involvement was predominant (11 cases, 73%), whereas cervical and lumbar disease accounted for 1 and 3 cases, respectively. Intraoperative cultures were positive in 9 patients (60%), and Staphylococcus aureus was isolated in 7 of these 9 cases (77.8%). Mean VAS pain score improved from 6.3 at T0 to 4.3 at T1 and 1.4 at T2. Mean lower-extremity Cooper Scale grade improved from 2.7 to 2.1 to 0.6; mean upper-extremity Cooper Scale grade improved from 1.3 to 1.0 to 0. Mean mJOA improved from 10.3 to 11.4 to 16.0. Mean white blood cell count declined from 11.58 to 8.35 to 6.14 × 10³/µL, and mean CRP declined from 123.9 to 72.81 to 19.44 mg/L. No patient worsened neurologically after surgery. No patient required acute stabilization or delayed arthrodesis during follow-up. Conclusions: In our case series of patients with compressive or progressive neurological spondylodiscitis, decompressive laminectomy combined with antibiotic treatment, bracing, and rehabilitation was associated with early neurological stabilization, substantial pain relief, and marked reduction in inflammatory markers, without subsequent need for instrumented stabilization. These data support the role of spinal decompression as part of a personalized, effective treatment strategy in patients with neurological decline. Full article

Background/Objectives: High-risk prostate cancer is a biologically heterogeneous group of tumors carrying a substantial risk of progression to lethal, castration-resistant disease. Although androgen deprivation therapy (ADT) remains the therapeutic backbone, nearly all advanced disease eventually progresses to castration-resistant prostate cancer (CRPC) through Darwinian clonal evolution under sustained therapeutic pressure. This narrative review reframes high-risk prostate cancer management as an effort to reprogram the evolutionary trajectory and delay castration resistance, addressing current risk stratification, androgen receptor (AR)-dependent and AR-independent mechanisms of resistance, and multidisciplinary strategies that modify selective pressure. Methods: A narrative review of the literature was conducted, including peer-reviewed studies, pivotal phase III trial reports, and current clinical practice guidelines indexed in PubMed, Scopus, and Web of Science up to 2026. Sources on high-risk and castration-resistant prostate cancer, the biology of treatment resistance, and multidisciplinary treatment intensification were selected and synthesized. Results: Treatment intensification has been extended to high-risk biochemical recurrence (EMBARK), directed by biomarkers in PTEN-deficient disease (CAPItello-281), and moved earlier through prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PSMAfore, PSMAddition). In localized disease, effective AR-pathway intensification with abiraterone (STAMPEDE) contrasts with the failure of chemotherapy (PEACE-2) and enzalutamide (ENZARAD). Emerging therapies targeting lineage plasticity exploit its dynamic and potentially reversible biology, raising the prospect of reversing established resistance rather than merely delaying it. CAPItello-281 and PSMAddition have immature overall survival data and are not yet standard of care. Conclusions: Coordinated multidisciplinary care, matched to the disease stage and molecular context, offers a realistic path to delay castration resistance and improve survival. 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

Autoimmune rheumatic diseases are still treated predominantly through broad or targeted suppression of inflammatory pathways, yet durable restoration of self-tolerance remains a central unmet therapeutic goal. This narrative review examines restoration of immune tolerance as an emerging translational framework in rheumatology, integrating checkpoint agonism, antigen-specific immunotherapy, regulatory cell-based strategies, and immune-reset approaches within a unified therapeutic perspective. Rather than treating these strategies as isolated innovations, the review evaluates how each attempts to restore, reinforce, or reconfigure immune restraint at distinct biological levels, spanning inhibitory receptor signaling, antigen-selective non-responsiveness, dominant regulatory control, and deeper reconfiguration of pathogenic immune architecture. Their relevance is considered across rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s disease, and systemic sclerosis, with emphasis on mechanistic rationale, translational maturity, disease-specific therapeutic fit, biomarkers, therapeutic timing, and major barriers to clinical implementation. Collectively, these approaches suggest a shift in rheumatology from repeated control of inflammatory consequences toward more selective and potentially durable recalibration of autoreactive immunity. Although the field remains biologically and clinically immature, restoration of immune tolerance is emerging as an important organizing principle for the development of more precise and potentially disease-modifying therapies in autoimmune rheumatic disease. Full article

Dominant pathogenic mutations in tyrosyl-tRNA synthetase (YARS1) are associated with Charcot–Marie–Tooth disease (CMT), a progressive peripheral neuropathy for which no disease-modifying therapies currently exist. While recent advances in amino acid supplementation therapies suggest potential benefit for recessive aminoacyl-tRNA synthetase disorders, their applicability to dominant YARS1-associated neuropathies remains unclear. Here, we investigated the pathogenic mechanisms underlying the dominant YARS1 variants G41R, D81I, and E196Q. Using biochemical and functional analyses, we identified increased structural rigidity for G41R and E196Q proteins, while D81I is more susceptible to tryptic digestion. Furthermore, expression of the YARS1 variants in a humanized yeast model produced a dominant negative growth defect that is exacerbated at elevated temperatures, supporting disruption of canonical YARS1 function as a contributor to disease pathogenesis. Notably, tyrosine supplementation significantly rescued the observed growth defects across variants. These findings demonstrate that impaired tyrosine utilization contributes to the pathogenic effects of dominant YARS1 variants and provide proof-of-concept evidence that tyrosine supplementation may represent a potential therapeutic strategy for patients with YARS1-associated CMT. Full article

Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy caused by extracellular deposition of misfolded proteins, most commonly immunoglobulin light chains (AL) or transthyretin (ATTR). Once considered a rare disease, CA is increasingly recognised due to improved diagnostic strategies and the availability of disease-modifying therapies. Early diagnosis is crucial, as treatment efficacy and clinical outcomes are strongly influenced by the stage of cardiac involvement. Multimodality cardiac imaging plays a central role in the diagnostic pathway, risk stratification, and evaluation of therapeutic response in CA. Echocardiography represents the first-line imaging modality and is essential for raising clinical suspicion through the identification of characteristic structural and functional abnormalities, including ventricular wall thickening, diastolic dysfunction, and distinctive strain patterns. Bone scintigraphy has revolutionised the non-invasive diagnosis of ATTR-CA, allowing accurate identification of transthyretin-related disease in the absence of monoclonal gammopathy, which needs to be excluded via serum and urinary immunofixation. Cardiovascular magnetic resonance provides advanced tissue characterisation through late gadolinium enhancement and quantitative mapping techniques, enabling detection of early myocardial involvement and robust prognostic stratification. Emerging imaging modalities, including dual-energy (spectral) computed tomography and positron emission tomography tracers, show promise in myocardial amyloid quantification and subtype differentiation, although their role is still evolving. Integration of imaging findings with clinical and laboratory parameters allows comprehensive disease assessment, facilitating early diagnosis, guiding therapeutic decisions, and improving risk stratification. This review summarises the current role of multimodality imaging in CA, highlighting its contribution from early detection to prognostic evaluation and monitoring of treatment efficacy, with particular emphasis on the emerging role of quantitative imaging in monitoring treatment response. Full article

Background/Objectives: Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) are a rare subgroup of GISTs and respond poorly to conventional systemic therapies. This study describes long-term outcomes after yttrium-90 (Y-90) selective internal radiation therapy (SIRT) for progression of unresectable SDH-deficient GIST hepatic metastases. Methods: We performed a retrospective review of consecutive patients treated with SIRT at three tertiary referral centers in Europe and the United States. Data collection included demographics, tumor profiling, prior therapies, Y-90 dosimetry approach, imaging response, adverse events, and long-term outcomes. Results: Twelve patients (66.7% female) with a median age of 27 years (range, 17–57 years) were included. One patient had a complete response (8.3%) and seven had partial responses (58.3%) by modified Response Evaluation Criteria in Solid Tumors. Four patients (33.3%) had tumor shrinkage that did not meet partial response criteria. The objective response rate was 66.7%, with a disease control rate of 100%. One grade 3 or higher adverse event was observed (cholecystitis requiring cholecystectomy). At a median follow-up of 32 months (range, 3–77 months), two patients experienced disease progression. Median overall survival was not reached, with one death during follow-up. Conclusions: SIRT appears safe and effective for patients with progressive, unresectable SDH-deficient GIST hepatic metastases, with durable responses and limited serious toxicity. These findings suggest that SDH-deficient GIST may be more sensitive to radiation than previously appreciated and that SIRT may be a useful liver-directed approach for patients with limited systemic options. Full article

Background: The growing awareness of breast cancer’s molecular diversity has not changed the technical foundations of surgery itself, but it has profoundly reshaped how surgeons think about surgery. Rather than molecular biology prescribing specific surgery, it is the surgeon’s interpretation of biological behavior—tumor subtype, genomic risk, treatment responsiveness—that influences surgical timing, extent, and feasibility. This is particularly important in the developing world, where mastectomy continues to be the default surgery, not always because it is required, but because biological nuance is underutilized in surgical planning. This review integrates existing evidence, guidelines, and real-world clinical experience to show how a surgeon who understands tumor biology can meaningfully expand safe breast conservation, de-escalate axillary surgery, and align operative choices with systemic therapy. In essence, molecular biology becomes a lens through which surgeons can practice more personalized, precise, and less invasive surgery, without compromising oncologic safety. Recent findings: We present evidence-based algorithms focusing on Luminal A, Luminal B, HER2-positive, and triple-negative subtypes, while discussing the nuances of multifocal and multicentric disease, metaplastic histologies, and discordant lesion management. The review addresses axillary management in the molecular era, specifying the appropriateness of sentinel lymph node biopsy, targeted axillary dissection, or completion axillary dissection, and how subtype-specific nodal responses to neoadjuvant therapy can guide de-escalation strategies. Through clinical vignettes, we exemplify how molecular integration into surgical planning can modify clinical courses, enabling oncoplastic conservation in downstaged tumors and justifying definitive resection in chemo-resistant cases. We examine the implications of germline and somatic genetic testing on surgical decision-making, particularly in relation to BRCA1/2 and PALB2 mutation carriers, alongside ethical and practical counseling considerations. Additionally, we review emerging biomarkers—such as circulating tumor DNA and immune and radiomic signatures—and propose research priorities for their incorporation into surgical trials. Conclusions: Effective implementation necessitates enhanced surgeon education, standardized assays, and multidisciplinary coordination to promote equitable access, consistent utilization of biology-driven algorithms, and rigorous quality oversight. This review furnishes breast surgeons with a pragmatic framework for translating molecular knowledge into multidisciplinary, patient-centered care pathways that optimize oncological safety, aesthetic outcomes, and overall quality of life. Full article

Glioblastoma (GBM) recurs predominantly from infiltrative disease that persists beyond the contrast-enhancing tumor (CET). This structured narrative review aims to define the invasive margin and peritumoral brain zone (PBZ) as a spatially organized molecular ecosystem, summarize the approaches used to interrogate this compartment, and evaluate how malignant-cell plasticity, host niches, and treatment-induced remodeling contribute to minimal residual disease and recurrence. A structured literature search of PubMed/MEDLINE, Scopus, and Web of Science identified the clinical, translational, preclinical, and review literature available through July 2026; evidence was synthesized qualitatively, with priority given to human tissue studies and single-cell or spatially resolved analyses. Across studies, the margin differs from both tumor core and normal brain and contains heterogeneous malignant states interacting with neural, vascular, immune, hypoxic, and extracellular-matrix-supported niches. Surgery, radiotherapy, and systemic treatment further reshape these interactions through inflammation, vascular injury, senescence, hypoxia, and fibrosis. The main translational challenge is therefore not simply to control the CET, but to identify biologically high-risk non-enhancing tissue and demonstrate that therapy reaches and modifies it. We propose three priorities: image-registered characterization of residual compartments, regional measurement of drug exposure and target engagement, and integration of local margin control with distributed and niche-directed treatment. Prospective validation is required before spatial PBZ biomarkers can guide routine care. Full article

The liver is an immunologically distinctive organ. Portal blood continuously delivers gut-derived antigens and microbial products, requiring hepatic immunity to balance surveillance with restraint. In hepatocellular carcinoma (HCC), this physiology is commonly overlaid by chronic injury, inflammation, and fibrosis, so the background liver forms part of the disease context in which the tumor microenvironment (TME) develops. This review synthesizes how cellular architecture, tumor-intrinsic programs, and structural, metabolic, and microbial conditions interact to shape immune evasion and heterogeneity. HCC provides the principal evidence base, with intrahepatic cholangiocarcinoma (iCCA) used as a structured, biologically distinct comparator. We organize therapies by the microenvironmental barriers they are intended to modify and distinguish established clinical efficacy from evidence that the proposed mechanisms mediate treatment benefit. Single-cell and spatial studies have resolved cellular states and spatial arrangements, including onco-fetal endothelial–myeloid neighborhoods and a macrophage–fibroblast boundary band separating lymphocyte-rich stroma from malignant tissue. These patterns operate within fibrotic and metabolically altered tissue and vary by etiology, spatial context, and tumor type. Vascular endothelial growth factor blockade with immune checkpoint inhibition and dual checkpoint blockade are established first-line options in advanced HCC. Chemo-immunotherapy is established in biliary tract cancer, and IDH1 inhibition has established efficacy in IDH1-mutant cholangiocarcinoma. Myeloid- and stroma-directed strategies, natural-product approaches, and engineered-cell therapies remain preclinical or early clinical. None of the pivotal trials tested whether the proposed microenvironmental mechanism mediated treatment benefit. The liver TME informs treatment selection without yet determining it. Full article

Radiation-free treatment for early-stage classic Hodgkin lymphoma (eHL) has been shown to be less effective than standard combined-modality treatment (CMT; chemotherapy plus involved-node radiotherapy (INRT)), which achieves long-term disease control of 94–95%. Approximately 70% of patients can be cured with chemotherapy alone, whereas about 5% fail CMT. Identifying patients who can safely receive chemotherapy alone and those requiring intensified CMT could enable a risk-adapted treatment strategy. The RAFTING trial (NCT04866654; EudraCT 2020-002382-33) is an international, prospective, phase 2, non-inferiority study enrolling patients 18–70 years, stage I–IIA eHL without bulky disease, B symptoms, or extranodal involvement. Low-risk (LR) patients are defined by total metabolic tumor volume (TMTV) <84 mL and negative PET-2. Those with at least one modified EORTC (mEORTC) risk factor, in which bulky disease is replaced by a large nodal mass (5–10 cm), receive four ABVD cycles, while those without risk factors receive two ABVD cycles alone. High-risk (HR) patients, defined by TMTV ≥84 mL and/or positive PET-2, receive “triple therapy”: 4 ABVD cycles, INRT (20/30 Gy), and nivolumab (240 mg q2w, ≤doses). LR patients are monitored using cfDNA. Limited relapse is treated with INRT (36 Gy) and nivolumab. The RAFTING trial is the first prospective eHL study to personalize treatment using TMTV and PET-2. It aims to omit radiotherapy in LR patients, intensify treatment in HR patients, and spare relapsed LR patients high-dose chemotherapy and autologous transplantation. CfDNA is being evaluated as a relapse marker. Despite the protocol’s complexity, this study exemplifies personalized medicine and could transform treatment practices. Full article

Background: Population aging is driving a convergent rise in three disorders historically managed in isolation: cardiovascular disease, neurocognitive decline, and osteoporotic bone loss. Mechanistic data indicate that these systems are coupled through shared regulators of calcium trafficking, inflammation resolution, vascular integrity, and inflammaging. On this basis, a “Heart–Brain–Bone” axis has been proposed; it should be understood as an integrative conceptual framework that organizes evidence drawn from three separate studies, not as a validated physiological entity with agreed diagnostic criteria or demonstrated modifiability. Three lipid-soluble nutrients—long-chain omega-3 polyunsaturated fatty acids (EPA/DHA), vitamin D3 (cholecalciferol), and vitamin K2 (menaquinone-7 [MK-7])—act on overlapping nodes of this network. Methods: We performed a structured narrative review. PubMed/MEDLINE, Embase, the Cochrane Library, and Web of Science were searched from database inception to 25 June 2026 using predefined term blocks for each nutrient, each organ domain, and each candidate mechanism, and the search was updated on 7 August 2026. Records were screened against prespecified inclusion and exclusion criteria by two authors independently, with disagreements resolved by a third. The strength of evidence for each nutrient–organ relationship was graded with an explicitly defined four-level scheme ((−) to (+++)) applied separately to preclinical, observational, randomized and meta-analytic evidence. Results: Vitamin K2-dependent gamma-carboxylation of matrix Gla protein (MGP) and osteocalcin has been proposed to influence whether calcium is incorporated into the bone matrix or deposited in the arterial wall, offering a candidate mechanistic account of the “calcium paradox” associated with isolated vitamin D3 supplementation; EPA/DHA-derived specialized pro-resolving mediators may support resolution of endothelial and neuronal inflammation; and bone-, vascular- and brain-derived signals (osteocalcin, FGF23, the neurovascular unit) interconnect the three organs. These mechanisms are biologically plausible but remain insufficiently confirmed in humans. The clinical evidence is heterogeneous, formulation- and population-dependent, and comprises positive, neutral and null results: cardiovascular omega-3 trials are discordant (REDUCE-IT, which used icosapent ethyl [an EPA ethyl ester], positive; VITAL/STRENGTH/ASCEND null, predominantly in lower-risk or replete cohorts); cognitive trials are largely null or subgroup-dependent (MAPT, DO-HEALTH, VITAL); and MK-7 improves surrogate bone and calcification biomarkers and slowed coronary artery calcification in one recent randomized imaging trial (VitaK-CAC), whereas combined MK-7 plus vitamin D3 did not slow aortic valve or coronary calcification in AVADEC and MK-7 did not reduce bone loss in early menopausal women. Recognized safety signals include a dose-dependent increase in atrial fibrillation with high-dose omega-3, adverse skeletal effects of high-dose or bolus vitamin D, and clinically relevant interference of even low-dose MK-7 with vitamin K antagonist therapy. Conclusions: No adequately powered randomized trial has demonstrated that the combination of long-chain omega-3, vitamin D3 and MK-7 is superior to its individual components or to placebo for any clinical endpoint. The combined regimen is therefore mechanistically rational and hypothesis-generating rather than clinically established; benefit appears most plausible in individuals with elevated risk or demonstrable nutritional insufficiency, and least in replete, low-risk populations. Findings should be interpreted within a broader healthy-aging context that includes lifestyle and psychosocial factors. Adequately powered factorial randomized controlled trials stratified by baseline Omega-3 index, 25(OH)D and vitamin K status, with prespecified mechanistic biomarkers and hard endpoints, are required. Full article