Search Results (309)

Philadelphia-negative (Ph-negative) myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), which are clonal hematopoietic disorders caused by somatic gene mutations in the JAK2, CALR, or MPL genes. Mutations activate the JAK–STAT pathway and disrupt NF-κB signaling, leading to a chronic inflammatory state caused by pro-inflammatory cytokines and reactive oxygen species (ROS). This altered microenvironment causes serious clinical features of the disease, such as bone marrow fibrosis, splenomegaly, vascular niche remodeling, and a greater probability of thrombosis or secondary leukemic transformation. Concurrently, MPNs cause both severe immune dysregulation and tumor evasion, as evidenced by progressive lymphopenia, T and B cell exhaustion, Natural Killer cell maturation arrest, and the accumulation of myeloid-derived suppressor cells. Although FDA-approved JAK1/JAK2 inhibitors ruxolitinib, fedratinib pacritinib and momelotinib effectively reduce splenomegaly and symptom burden and have demonstrated survival benefits in clinical trials, their ability to eliminate malignant clones or induce durable disease modification remains limited, and disease progression continues to occur in most patients. Finally, this review assesses the complex immunological dysfunction and chronic inflammatory dysregulation that characterize Ph-negative MPNs, as well as emerging therapeutic strategies, emphasizing the importance of fully understanding these intricate microenvironmental mechanisms for the identification and development of novel precision treatment targets. Full article

The bone marrow stromal microenvironment is damaged in patients with acute leukemia. The aim of this study was to analyze changes associated with the extracellular matrix, mitochondrial function, and vesicular transport in the proteome of multipotent mesenchymal stromal cells (MSCs) in patients at the onset, in remission, before, and 1–3 months after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The study included paired MSCs samples from the bone marrow of 12 patients at the onset and in remission of acute leukemia (4 ALL, 8 AML) and eight patients before and after allo-HSCT (4 ALL, 4 AML). MSCs from eight healthy donors were used as a control. The growth characteristics and the proteome subsets describing extracellular matrix, mitochondria, and vesicular formation were studied. The proteome of the patients’ MSCs differed significantly from that of the donor MSCs, both at the onset and in remission. Changes noted in the composition of extracellular matrix proteins may affect cell adhesion and access to growth factors. Significant changes were revealed in proteins affecting mitochondrial function. Vesicular transport proteins also differed between the donor and patient groups. Unexpectedly, no differences were found between the MSCs of donors and patients before and after allo-HSCT. Full article

Diffusion-weighted imaging (DWI) has evolved from a niche research sequence into an increasingly valuable adjunct to conventional magnetic resonance imaging (MRI) in musculoskeletal (MSK) radiology. By providing qualitative and quantitative information on tissue microstructure through assessment of water diffusion and apparent diffusion coefficient (ADC) mapping, DWI offers functional insights beyond conventional morphological imaging. We aim to present the current evidence for DWI in MSK imaging organised around established applications and emerging applications, with particular emphasis on composition-related interpretive pitfalls relevant to differentiating tumours and other pathologies, and to review the technique’s evolving role in routine practice. This narrative review synthesises the current literature on the clinical utility of DWI in MSK imaging. It is structured in four parts: foundations and the tissue composition signal framework, including the basis of qualitative and quantitative assessment; established applications; emerging applications; and assessment of tissue composition-related interpretive as well as technical pitfalls, including those arising due to myxoid matrix, chondroid matrix, blood degradation products, organising thrombus, crystalline or mineralised material, keratinaceous debris, purulent content, cellular haematopoietic marrow, by using original cases from the authors’ institution, which have been confirmed either histologically or surgically. Applications are stratified by strength of evidence. Established applications of DWI include soft tissue abscess detection, differentiation of malignant from benign soft tissue tumours, differentiation of malignant from benign vertebral compression fractures, and myeloma staging and response assessment, as well as treatment response in soft tissue and bone sarcomas. Whole-body MRI with DWI for staging and response assessment in multiple myeloma is guideline-endorsed and supported by prospective multicentre data. Soft tissue abscess detection, soft tissue and bone tumour characterisation, and characterisation of vertebral compression fractures are supported by consistent evidence from multiple independent cohorts, although no universally transferable ADC threshold exists. The emerging applications, which are promising adjuncts supported by small, single-centre or heterogeneous studies with thresholds that have not been externally validated, include ADC ghost sign in osteomyelitis (high specificity but sensitivity of only 20%), peripheral nerve sheath tumour characterisation and surveillance in NF1 patients, peripheral neuropathy and plexopathy, predisposing conditions such as Li Fraumeni syndrome in paediatric cancers, inflammatory myopathy, and postsurgical assessment of residual disease, as well as opportunistic detection of venous thrombosis. Radiomics and machine learning approaches remain experimental. Recent technical advances, including reduced field-of-view imaging, multi-shot acquisition and improved fat suppression, have mitigated but not eliminated historical limitations of susceptibility artefacts and limited spatial resolution. DWI has become an important functional imaging technique that complements conventional MRI across a broad range of musculoskeletal disorders. Understanding the relationship between tissue composition and the diffusion signal is central to both interpreting DWI correctly and avoiding its characteristic pitfalls. DWI is best regarded not as a stand-alone technique but as one component of a multiparametric assessment, in which its functional information is integrated with conventional morphological imaging. Ongoing technical improvement and expanding clinical evidence are expected to further support its integration into routine MSK imaging and its development as a quantitative biomarker for diagnosis, prognostication, and treatment monitoring. Full article

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts and the persistence of leukemic stem cells (LSCs) within a profoundly remodeled bone marrow (BM) microenvironment. Despite advances in molecular stratification and the introduction of targeted agents, long-term outcomes remain unsatisfactory, particularly in older and high-risk patients. Increasing evidence indicates that leukemogenesis and treatment resistance are critically sustained by a permissive immune milieu, in which LSCs, myeloid-derived suppressor cells, leukemia-associated macrophages, and dysfunctional T and NK cells shape an immunosuppressive “leukemic niche.” This evolving understanding has renewed interest in immune-based strategies capable of restoring effective antitumor immunity. Bispecific antibodies (bsAbs) are engineered molecules designed to engage AML-associated antigens while simultaneously recruiting and activating immune effector cells, most commonly T cells or NK cells. By promoting immune synapse formation independently of major histocompatibility complex expression and conventional co-stimulatory pathways, bsAbs can overcome several mechanisms of immune escape. In this review, we summarize the biological rationale for immunotherapy in AML, with a focus on the role of the BM microenvironment and immune dysregulation. We then discuss the structural and functional properties of IgG-like and non-IgG-like bsAbs, key antigenic targets such as CD33, CD123, CD70 and others, and the main T-cell- and NK-cell-engaging platforms under clinical investigation. Finally, we highlight emerging clinical data, principal toxicities, and the challenges of integrating bsAbs into existing treatment algorithms, including combinations with hypomethylating agents, BCL-2 inhibitors, and allogeneic stem cell transplantation. A deeper understanding of AML immune biology and antigen expression patterns will be essential to optimize bsAb design, maximize therapeutic benefit, and minimize on-target off-tumor toxicity. Full article

Bone remodeling is increasingly recognized as an immunologically regulated process in which inflammatory signaling governs the balance between bone formation and resorption. While extensive efforts have focused on pathways that promote osteoclastogenesis, endogenous mechanisms that restrain inflammatory bone destruction remain less well defined. Here, we propose NLRP12 as a previously underappreciated osteoimmune checkpoint that integrates innate immune regulation with skeletal homeostasis. Emerging evidence demonstrates that NLRP12 suppresses NF-κB and MAPK signaling, antagonizes NLRP3 inflammasome activation, and limits the production of osteoclastogenic cytokines, thereby constraining pathological bone resorption. Beyond its direct effects on osteoclast precursors, NLRP12 may shape the broader bone marrow immune niche through regulation of macrophages, dendritic cells, neutrophils, immunometabolic pathways, and host–microbiota interactions. We synthesize current knowledge linking NLRP12 to osteoclast differentiation, inflammatory bone diseases, and osteoimmune communication, and highlight key unanswered questions regarding its functions in osteoblasts, osteocytes, and skeletal aging. By framing NLRP12 as an important regulator of inflammatory tone within the skeletal microenvironment, we introduce an osteoimmune checkpoint paradigm that provides new conceptual insights into the pathogenesis of osteolytic disorders and identifies opportunities for therapeutic intervention. Full article

Acute myeloid leukemia (AML) develops within a bone marrow environment that influences leukemic stem cell behavior, residual disease, and response to therapy. This review examines evidence that the marrow microenvironment is not only a site of leukemic growth, but can actively shape AML initiation, maintenance, and treatment resistance. Clinical observations such as donor cell leukemia after allogeneic transplantation, together with experimental models in which stromal or osteolineage abnormalities induce myeloid disease, suggest that altered niches may contribute to leukemogenesis in selected settings. In established AML, vascular and endosteal compartments provide adhesive, chemokine, inflammatory, and metabolic signals that promote leukemic-cell retention, quiescence, survival, and chemotherapy tolerance. AML cells also remodel the surrounding marrow, suppressing normal hematopoiesis and generating stromal, endothelial, osteoblastic, adipocytic, and immune-cell programs that favor leukemic persistence. These interactions are especially relevant to drug resistance, including resistance to venetoclax-based therapy, where cytokine-mediated changes in apoptotic dependence, fatty-acid metabolism, mitochondrial adaptation, and stromal support may all contribute. Several therapeutic approaches have attempted to disrupt niche-mediated protection, including targeting CXCL12/CXCR4 signaling, adhesion pathways, inflammatory circuits, Hedgehog signaling, and metabolic dependencies. Although early-phase studies have shown activity in some AML subsets, randomized evidence remains limited and results have been inconsistent. We discuss how a better understanding of microenvironmental biology may help define when niche-directed therapy is most likely to complement conventional and molecularly targeted AML treatment. Full article

Background/Objectives: Colorectal liver metastases (CRLMs) are a major contributor to recurrence and mortality in colorectal cancer (CRC), with approximately a quarter of patients developing liver metastases over the course of the disease. Bone-marrow-derived myeloid lineages are sent into the circulatory system and colonize pre-metastatic niches, yet the transcriptional programs by which they establish a pro-metastatic microenvironment remain incompletely defined. Methods: Using an MC38 splenic-injection CRLM mouse model, we generated single-cell RNA sequencing (scRNA-seq) profiles of FACS-sorted CD11b⁺Gr1⁺ bone marrow myeloid cells, together with bulk RNA sequencing profiles of bone marrow and peripheral blood. Downstream analyses were performed in silico, including clustering and annotation, trajectory inference, cell–cell communication analysis, weighted gene co-expression network analysis (WGCNA), and pathway enrichment, with subset specificity examined against a public dataset of E. coli (Escherichia coli)-infected mice. Results: Within the CD11b⁺Gr1⁺ compartment, a CCR2⁺ neutrophil-like population (Ly6g⁺S100a8/9⁺) emerging during terminal differentiation was identified, which was enriched in CRLM mice but nearly absent in controls. Communication inference revealed an FN1-CD44 interaction involving mature neutrophils, which was associated with an epithelial–mesenchymal transition signature and upregulation of Tgfb1 and Il1b. This subpopulation was not recovered in the infection dataset, suggesting relative specificity to CRLMs. Conclusions: Within the constraints of a splenectomized hepatic colonization model, integrated transcriptomic analysis highlighted a CCR2⁺ bone marrow neutrophil-like population as a candidate contributor to CRLM, challenging the view that CCR2⁺ pro-metastatic myeloid cells are exclusively monocytic and suggesting candidate biomarkers and therapeutic targets for further study. Full article

Restoration of the osteochondral unit remains a major challenge in regenerative orthopaedics, largely due to the limited intrinsic healing capacity of articular cartilage and the complex, multilayered nature of the cartilage–bone interface. Osteochondral regeneration must accommodate differences in cellular composition, vascularization, metabolic demand, and mechanical properties between cartilage and bone, while simultaneously recreating a stable, functional interface. While exogenous mesenchymal stem cell (MSC) therapies have dominated the field, their clinical translation has been hindered by donor variability, phenotypic instability, logistical complexity, and inconsistent long-term outcomes. Resident stem cells from sources such as articular cartilage, bone marrow, periosteum, synovium, synovial fluid, and adipose tissue (infrapatellar fat pad) can act as potential targets for in situ osteochondral regenerative therapies. Joint-resident MSCs are adapted to the biomechanical and biochemical environment of the joint and may therefore represent a promising cell source for osteochondral regeneration; however, much of the supporting evidence remains preclinical. Effective osteochondral repair depends on the precise orchestration of stem cell recruitment, maintenance of chondrogenic phenotypes, induction of osteogenic differentiation in the subchondral compartment, and modulation of local immune responses. Patient-specific factors, including age, inflammatory status, and the severity of osteoarthritis, can significantly influence the regenerative potential of resident MSC populations and should therefore guide biomaterial design strategies. The proposed niche-by-design framework integrates stem cell biology with advanced biomaterial engineering, offering a rational roadmap for developing next-generation therapies that promote endogenous osteochondral regeneration through targeted activation of joint-resident progenitor cells. Full article

Megakaryocytes (MKs) and platelets are increasingly recognized as active regulators of the bone marrow (BM) microenvironment rather than passive effectors of thrombopoiesis and hemostasis. Recent single-cell and lineage-tracing studies have established that megakaryopoiesis generates functionally heterogeneous populations, including immune-biased and niche-supporting subsets that shape hematopoietic stem cell (HSC) behavior, inflammatory tone, and vascular homeostasis. In leukemia, these regulatory circuits are systematically rewired to establish a marrow niche that suppresses normal hematopoiesis while sustaining leukemic stem cell (LSC) fitness through cytokine gradients, stromal remodeling, and direct cell-to-cell communication. In this focused review, we propose that the immune MK (iMK)–platelet axis is a central driver of leukemic niche remodeling. We discuss how iMK states arise under leukemic pressure, how MK heterogeneity encodes distinct niche instructions, and how platelet-derived extracellular vesicles (EVs) distribute inflammatory signals across the marrow and systemic circulation. Within this framework, we position mitochondrial stress outputs—such as reactive oxygen species (mtROS), mitochondrial DNA (mtDNA) release, metabolic rewiring, and mitochondria-containing EV secretion—not as isolated phenomena, but as mechanistic amplifiers embedded within the broader inflammatory and niche-regulatory programs of MKs and platelets. We further highlight preleukemic inflammatory states as an underappreciated entry point for therapeutic intervention, and propose three clinically actionable axes: inflammatory niche interruption, mitochondrial stress modulation, and platelet–leukemia communication blockade. This framework aligns with emerging concepts in MK heterogeneity, innate immune sensing, endothelial remodeling, and preleukemic signaling, and positions the MK–platelet axis as a promising therapeutic framework in leukemia-associated niche remodeling. Full article

Multiple myeloma (MM) is a genetically and clinically heterogeneous plasma cell malignancy characterised by clonal expansion of differentiated B cells within the bone marrow (BM). Patients start with monoclonal gammopathy of undetermined significance (MGUS) and progress to an intermediate stage called smouldering multiple myeloma (SMM), characterised by several genetic alterations that represent the genomic backbone of the malignant clone. Immune checkpoint pathways play a central role in shaping an immunosuppressive BM niche, contributing to T-cell dysfunction, immune evasion, and therapeutic resistance. Key inhibitory receptors such as PD-1, CTLA-4, TIM-3, LAG-3, and CD47 are frequently dysregulated, promoting T-cell exhaustion, anergy, and senescence. Emerging evidence highlights extracellular vesicles (EVs) as critical mediators of intercellular communication in MM. MM-derived EVs carry bioactive cargo, including proteins and miRNAs, that reprogram immune and stromal cells, enhancing tumour progression and immune escape. Notably, EV-associated immune checkpoint molecules contribute to the establishment of a permissive microenvironment. This review provides an integrated overview of immune checkpoint dysregulation and EV-mediated immunomodulation in MM, emphasising their role in disease pathogenesis and progression. Furthermore, we discuss the therapeutic potential of targeting immune checkpoints and exploiting EVs as novel biomarkers and drug delivery systems, highlighting their promise for improving precision medicine approaches in MM. Full article

Bone marrow aspirate concentrate (BMAC) is widely used as a source of mesenchymal stromal/stem cells (MSCs) for musculoskeletal regeneration; however, BMAC lacks essential bone marrow extracellular matrix (ECM) components, a critical component of the stem cell niche that regulates MSC survival, paracrine signaling, and regenerative capacity. We previously demonstrated that an ECM-retaining micronized bone marrow product (BMAX™) preserves pro-regenerative MSC phenotypes in vitro. Human bone marrow from a single donor was processed into conventional BMAC or BMAX™. Post-traumatic osteoarthritis was induced in immunodeficient rats using destabilization of the medial meniscus (DMM). Four weeks after surgery, animals were randomly assigned to receive intra-articular injections of BMAX™, BMAC, or phosphate-buffered saline (n = 10–12 in each group). Pain-related behavior (n = 5–6/group), histological assessment (n = 3–6/group), and micro-computed tomography (n = 4–6/group) were evaluated for up to 8 weeks after treatment. At 4 weeks after treatment, BMAC significantly increased the paw withdrawal threshold compared with PBS (p = 0.0068), whereas BMAX™ significantly reduced knee joint swelling compared with both PBS (p = 0.0235) and BMAC (p = 0.0039), and BMAX™ significantly improved knee bend scores compared with PBS (p = 0.0011). Neither treatment significantly improved OARSI histological scores at this time point. At 8 weeks after treatment, BMAX™ significantly increased the paw withdrawal threshold compared with PBS (p = 0.0305), whereas BMAC showed a non-significant trend (p = 0.0517); both treatments significantly reduced knee bend scores compared with PBS (p = 0.0027 and p = 0.0255), and BMAX™ demonstrated significantly lower knee bend scores than BMAC (p = 0.0090). BMAX™ significantly reduced knee swelling compared with PBS (p = 0.0196). Histologically, BMAX™ significantly improved OARSI scores in both the femoral condyle and tibial plateau compared with PBS (p = 0.0020 and p = 0.0003, respectively), whereas BMAC significantly improved only tibial plateau OARSI scores (p = 0.0014). Furthermore, BMAX™ demonstrated significantly lower femoral condyle OARSI scores than BMAC (p = 0.0243). Micro-computed tomography revealed that both BMAX™ and BMAC significantly reduced medial subchondral trabecular separation compared with PBS (p = 0.0340 and p = 0.0426, respectively), whereas no significant differences were observed between the two treatment groups for other bone structural parameters. In conclusion, preservation of the native bone marrow ECM was associated with improved functional outcomes and greater cartilage regeneration compared with conventional BMAC in this preclinical rat model of post-traumatic osteoarthritis. These findings support the concept that maintaining the native stem cell niche may enhance the therapeutic potential of bone marrow-derived cell therapies for osteoarthritis. Full article

Chronic lymphocytic leukemia (CLL) is characterised by the dependence of malignant cells on specialised tissue microenvironments within the bone marrow (BM) and secondary lymphoid organs (SLOs), which provide essential survival and proliferative signals. The CXCR4/CXCL12 and CXCR5/CXCL13 chemokine axes direct the trafficking of CLL cells into these anatomically distinct compartments, where stromal-derived survival signals protect them from both spontaneous and therapy-induced apoptosis. Although each chemokine axis has been extensively studied individually, no previous review has integrated both pathways into a unified mechanistic framework. This review proposes that the signal transducer and activator of transcription 3 (STAT3) function as a shared molecular hub that integrates niche-derived cytokine signals, including interleukin-6 (IL-6), IL-10, and IL-21, and may transcriptionally upregulate both CXCR4 and CXCR5, and reinforce tissue homing through a positive feedback loop. This review seeks to evaluate the expression, signalling, and clinical significance of each axis, their points of convergence and divergence and the therapeutic strategies that disrupt these parallel homing pathways. Complementing this framework, recent clinical evidence indicates that circulating CXCL13 serves as a robust prognostic biomarker in CLL, and that STAT3 inhibition may overcome bone marrow stromal-mediated cytoprotection. The CXCL12-CXCR4-STAT3-IL-10 immunosuppressive axis further drives T-cell exhaustion. Together, these pathways form an integrated oncogenic network that supports CLL cell survival, drives immune dysfunction, and promotes therapy resistance. Several important knowledge gaps remain. These include the lack of direct validation of the STAT3-CXCR5 transcriptional axis in primary CLL cells and uncertainty regarding whether CXCR4/CXCR5 dominance represents a stable transcriptional programme or a dynamic, microenvironment-driven process. Addressing these questions through single-cell transcriptomics, spatial transcriptomics, proteomics, and functional validation studies will be essential for developing rational combination therapies capable of simultaneously disrupting both homing axes. Full article

Bone metastasis develops within a specialized marrow ecosystem where hematopoiesis, immune regulation, vascular trafficking, and skeletal remodeling intersect. Neutrophil-lineage cells occupy a unique position in this setting because they are generated, retained, mobilized, aged, and reprogrammed within the same bone marrow niches that disseminated tumor cells exploit for homing and survival. This review examines how neutrophils, tumor-associated neutrophils, immature neutrophils, low-density neutrophils, and PMN-MDSCs shape skeletal colonization. We discuss tumor-to-marrow signaling, CXCR2-dependent recruitment, CXCR4/CXCL12-mediated marrow retention, neutrophil–circulating tumor cell interactions, vascular arrest, dormancy escape, NET-mediated matrix remodeling, immune suppression, and effects on osteoclast–osteoblast coupling. Evidence is strongest in breast and prostate cancer models, where pathways such as CXCL5/CXCR2, CTNND1–CXCR4/CXCL12, PR3–RAGE, and DKK1–CKAP4–STAT6–CHI3L3 link neutrophil-lineage cells to skeletal progression and immunotherapy resistance. However, several mechanisms, including CTC–neutrophil clustering and NET-driven dormancy awakening, remain partly extrapolated from non-skeletal models. We therefore emphasize evidence hierarchy, methodological limitations, and therapeutic opportunities, arguing that selective reprogramming or functional inhibition of pro-metastatic neutrophil states may be more promising than indiscriminate neutrophil depletion in metastatic bone disease. A clearer understanding of these context-dependent neutrophil programs may help refine biomarker development and guide combination therapies for patients with skeletal metastases. Full article

Osteoporosis (OP) and osteoarthritis (OA) are two common degenerative musculoskeletal disorders associated with aging and are traditionally classified and managed as distinct disease entities. Emerging evidence suggests that OP and OA may share bidirectional associations and common biological mechanisms, and that under specific pathological conditions they may develop into a mutually reinforcing comorbid state. The comorbidity of osteoporosis and osteoarthritis (OP–OA) is not a simple superimposition of bone loss and cartilage degeneration; rather, it represents a disorder of the osteochondral unit centered on disruption of the subchondral bone microenvironment. Alterations in the structural strength, remodeling dynamics, vascular and neural status, and bone marrow lesions of subchondral bone collectively reshape the local microenvironment, thereby directly affecting mechanical signal transmission and cellular behavior within the joint. Focusing on the subchondral bone microenvironment as the central pathological nexus, this review systematically summarizes how mechanical imbalance, aberrant bone remodeling, inflammatory activation, metabolic dysregulation, and cellular senescence jointly remodel the local niche in OP–OA comorbidity. These microenvironmental changes further induce phenotypic remodeling and fate deviation of bone marrow mesenchymal stem cells, bone remodeling-related cells, osteoimmune cells, and chondrocytes. On this basis, we integrate the regulatory roles of developmental signaling, mechanotransduction pathways, and inflammatory–immune signaling networks, and propose that microenvironment-driven cell fate plasticity may serve as a key mechanistic hub promoting the initiation and progression of OP–OA comorbidity as well as the persistent destabilization of the osteochondral unit. This perspective may help overcome the limitations of current studies that address OP and OA separately, and may provide a theoretical framework for early identification and stratification, biomarker discovery, and combined precision-targeted interventions for this comorbid condition. Full article

Background: Cytarabine (Ara-C) remains the cornerstone of remission-induction and consolidation chemotherapy for acute myeloid leukemia (AML) and related hematological malignancies. Despite more than six decades of clinical use, its multi-organ toxicity continues to be managed almost exclusively through dose attenuation and supportive care, with no approved upstream pharmacological prevention strategy available. Objectives: This scoping review aimed to systematically map the breadth and nature of pharmacological agents tested in vivo for their capacity to mitigate cytarabine-induced multi-organ toxicity, to characterize their mechanisms of action and organ targets, and to identify evidence gaps and agents with translational potential. Methods: The review was designed and reported in accordance with the PRISMA-ScR checklist. A structured electronic search was conducted across PubMed/MEDLINE, Scopus, Cochrane Library and Embase, and Web of Science from database inception to 15 July 2025. Eligible studies were restricted to full-text, peer-reviewed, English-language research involving in vivo mammalian models administered cytarabine as the principal toxin, with at least one pharmacological co-intervention and at least one quantitative or histopathological organ-injury outcome. Results: From 5701 retrieved records, 36 eligible in vivo mammalian studies (spanning 1964–2024) were identified. Included studies addressed neurotoxicity (n = 6), gastrointestinal mucositis (n = 9), ocular toxicity (n = 3), hepatotoxicity (n = 3), bone marrow suppression (n = 4), chemotherapy-induced alopecia (n = 5), and reproductive and developmental toxicity (n = 4). Five recurring mechanistic strategies were identified across the heterogeneous agents tested: redox buffering (N-acetylcysteine, α-lipoic acid, rutin, swertiamarin, α-tocopherol), mitochondrial preservation (betanin, thymoquinone, vitamin D, sodium zinc dihydrolipoylhistidinate [DHLHZn]), tissue-microenvironment reprogramming (apraglutide, BADGE, plerixafor, short-chain fatty acids, β-glucan), molecular antagonism (deoxycytidine, dCMP), and immunomodulation (lienal peptide, IL-1β, AHCC). Conclusions: This scoping review provides the first systematic cartography of pharmacological mitigation strategies for cytarabine-induced multi-organ toxicity. Five mechanistic pathways converge across eight organ systems, with apraglutide and N-acetylcysteine representing the most clinically translatable candidates. Plerixafor and PPARγ blockade by BADGE constitute high-priority candidates for bone marrow niche protection, while the deoxycytidine antagonism principle warrants formal pharmacokinetic evaluation. The complete absence of cardiotoxicity mitigation data defines the most critical gap for future research. Full article