Search Results (22,795)

The activator protein-1 (AP-1) transcription factor is a regulatory dimeric transcription factor complex, that responds to a wide range of intracellular and extracellular stimuli and controls gene expression involved in tumor initiation and progression. Comprised primarily of members of Jun and Fos protein subfamilies, AP-1 is activated downstream of major oncogenic signaling pathways such as the mitogen-activated protein kinase (MAPK) pathway and controls cellular processes including differentiation, invasion, proliferation and apoptosis. In various cancer types, AP-1 contributes to tumor growth by promoting tumor-like phenotypes and facilitating metastatic behavior. Furthermore, AP-1 can affect the tumor microenvironment by modulating inflammation and interaction with immune cells. AP-1 deregulation is linked to tumor heterogeneity and resistance to chemotherapy and radiation. Therefore, AP-1 has emerged as a potential therapeutic target. In preclinical models, direct and indirect targeting via upstream pathways of AP-1 components has demonstrated encouraging results. In addition, combinatorial approaches targeting AP-1 and other regulators may improve the effectiveness of treatment and overcome therapy resistance. In this review, we highlight the AP-1’s role as a critical hub in tumorigenesis that links oncogenic signaling to transcriptional regulation. We also focus on its regulation, function in the tumor microenvironment, and therapeutic potential in combating tumors. Full article

Background and Objectives: Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is an emerging minimally invasive therapeutic option for pancreatic and selected extra-pancreatic lesions. However, its clinical adoption is limited by heterogeneous indications, non-standardized techniques, and variable quality of evidence. This systematic review assessed the published literature on EUS-RFA and classified available evidence according to the Oxford Centre for Evidence-Based Medicine levels of evidence. Materials and Methods: A systematic search was performed to identify peer-reviewed studies reporting clinical or translational data on EUS-RFA. Studies were grouped by indication, including pancreatic insulinoma, non-functioning pancreatic neuroendocrine neoplasms, branch-duct intraductal papillary mucinous neoplasms and other pancreatic cystic neoplasms, pancreatic ductal adenocarcinoma, pancreatic metastases, adrenal adenoma, and miscellaneous indications. Each study was categorized according to Oxford level of evidence based on study design. Results: Thirty-seven records were included in the final evidence map, comprising 36 clinical studies classifiable according to Oxford levels of evidence and one translational record not classifiable as clinical therapeutic evidence. Among the 36 clinically classifiable studies, one provided Level 1b evidence, consisting of a randomized trial evaluating EUS-guided celiac ganglion RFA for pancreatic cancer-related pain palliation, and three provided Level 2b evidence, including non-randomized comparative cohorts in pancreatic insulinoma and unresectable pancreatic ductal adenocarcinoma. Most clinically classifiable studies were Level 4 evidence (32/36), mainly uncontrolled prospective or retrospective cohorts and case series. One preclinical/translational study was not classifiable within clinical therapeutic evidence levels. Pancreatic insulinoma was the most evidence-supported tumor-ablation indication, with comparative data suggesting efficacy comparable to surgery and a more favorable safety profile. For non-functioning pancreatic neuroendocrine neoplasms, branch-duct IPMN, renal cell carcinoma pancreatic metastases, and adrenal adenomas, available data suggest feasibility and encouraging short-term outcomes but remain predominantly non-comparative. In pancreatic ductal adenocarcinoma, EUS-RFA remains investigational as an adjunct to systemic therapy. Conclusions: EUS-RFA is a promising therapeutic platform, but evidence remains highly indication-dependent and dominated by low-level observational studies. Standardized protocols, indication-specific outcomes, prospective registries, and comparative trials are needed. Full article

DNA double-strand breaks (DSBs), caused by various endogenous and exogenous factors, pose a significant threat to genomic stability. Several conserved repair pathways address DSBs, with homologous recombination (HR) being the only mechanism capable of accurately restoring the original DNA sequence. The BRCA1 gene plays a critical role in HR and is involved in maintaining genomic stability, cell cycle regulation, transcription, and tumor angiogenesis. Germline mutations in BRCA1 are strongly associated with increased risks of breast, ovarian, and other cancers. Dysfunction of BRCA1 leads to homologous recombination deficiency (HRD), forcing cells to rely on error-prone repair pathways, which promotes genomic instability and tumorigenesis. Besides hereditary mutations, HRD can also arise in sporadic cancers through epigenetic mechanisms such as promoter hypermethylation and reduced BRCA1 expression. Although BRCA1 deficiency is uncommon in lung cancer, BRCA1 status is considered a potential biomarker for sensitivity to platinum-based chemotherapy and other cytotoxic agents used in lung cancer treatment. However, the impact of BRCA1 on treatment response and prognosis in lung cancer remains controversial and not fully understood. This review summarizes current evidence on the role of BRCA1 in modulating chemotherapy response and disease outcomes in lung cancer patients, highlighting its potential as a biomarker for personalized therapy selection. Thus, in this context, the key unresolved issues critical for the development of personalized treatment strategies for lung cancer associated with BRCA1 alterations include the identification of molecular biomarkers most reliably associated with tumor sensitivity to chemotherapy. In addition, the development of methods for identifying patients with homologous recombination deficiency specifically in lung tumors appears to be of considerable importance, as does a better understanding of how the biological and therapeutic implications of BRCA1-related parameters in lung cancer differ from those observed in other tumor types. Addressing these challenges could substantially improve the efficacy of chemotherapy and patient outcomes, while also expanding the opportunities for a personalized approach to treatment selection in patients with lung cancer. Full article

Objectives: Pancreatic cancer remains one of the most aggressive malignancies, characterized by late diagnosis, limited therapeutic options, and poor survival outcomes. Increasing evidence indicates that systemic inflammation and tumor microenvironment interactions play a crucial role in disease progression and patient prognosis. This review aims to summarize current evidence on the clinical utility of inflammation-based hematological indices derived from complete blood count (CBC), including the neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR), in pancreatic cancer. Content: Available data consistently demonstrate that elevated NLR and PLR, as well as decreased LMR, are associated with poorer overall survival, more aggressive disease phenotype, and reduced response to therapy. Among these indices, NLR appears to be the most robust and widely validated prognostic marker. Its clinical value is enhanced when combined with markers such as CA 19-9. LMR reflects the balance between host immune response and monocyte-derived tumor-promoting activity, while PLR highlights the role of platelets in tumor progression, angiogenesis, and immune evasion. Despite their potential, the routine clinical implementation of these indices is limited by the lack of standardized cut-off values, variability between patient populations, and susceptibility to confounding factors such as inflammatory conditions. Summary and outlook: In this article we show that inflammation-based hematological indices represent inexpensive, accessible, and promising tools for laboratory diagnostics and prognostic assessment in pancreatic cancer. Their integration with clinical, biochemical, and molecular data may improve risk stratification and support personalized therapeutic strategies; however, further large-scale prospective studies are required to establish their standardized clinical use. Full article

Melanoma is an aggressive skin cancer that has the potential to metastasize to the lymph nodes, lungs, liver, and brain. Therefore, the prevention and treatment of this condition are essential for achieving lower incidence rates and improving patient outcomes. Traditional treatment methods like surgery, radiation therapy, and chemotherapy have shown limited efficacy in the treatment of metastatic melanoma, and hence new treatment strategies have been developed. These recently developed treatment options include combining targeted therapies with immunotherapies to reduce drug resistance and improve overall effectiveness in preventing melanoma progression. Moreover, BRAF mutations are found in approximately 40–50% of cutaneous melanomas, and NRAS mutations in 15–25%, making these the two most common oncogenic drivers in the MAPK pathway. While alterations in other genes such as KRAS (~1.7%), HRAS (~1%), and MET (~2–4%) are relatively rare in melanoma, they still remain important to disease biology and are under investigation as potential therapeutic targets. These alterations may contribute to tumor progression, metastasis, and therapeutic resistance, highlighting the importance of continued investigation of targeted strategies in melanoma. This review aims to explore the role of each of these genes in melanoma, discusses their resistance mechanism, and summarizes preclinical and clinical trials involving drug combinations. By integrating current evidence on melanoma-associated genomic alterations with available targeted and immune approaches, this review aims to define molecular and clinical contexts that suggest potential treatment selections for melanoma patients. Full article

Colorectal cancer (CRC) remains a leading cause of cancer morbidity worldwide, highlighting the need for improved therapies. Metformin, a widely used antihyperglycemic agent, has gained attention for its potential antitumor properties. In this study, we evaluated the effects of the tumor suppressor genes TP53 and CDKN1A on metformin responsiveness in a KRAS-mutant CRC in vitro model using HCT116 cells harboring a G13D mutation in KRAS. Using parental (p53^+/+, p21^+/+) and isogenic knockout cell lines, we assessed cell-cycle distribution and transcriptomic responses following metformin treatment. In parental wild-type cells, metformin exposure was associated with a dose- and time-dependent reduction in cell viability and an increased proportion of cells in the G0/G1 phase, with significance levels across treatment conditions ranging from p = 0.03 to p < 0.0001. Loss of p53 or p21 was associated with attenuated cellular responses to metformin, with p21-deficient cells responding primarily at higher doses and prolonged exposure (72 h). Transcriptomic profiling revealed extensive differential gene expression in parental cells (1399 DEGs), compared with more limited responses in p53^−/− (270 DEGs) and p21^−/− cells (32 DEGs). Differentially expressed genes associated with MAPK signaling (DUSP5) and inflammatory regulation (TNFAIP3) were observed across genotypes, whereas pathway enrichment of DNA replication and chromatin organization was specific to p53-deficient cells. These findings provide a transcriptomic and phenotypic characterization of genotype-dependent cellular responses to metformin and establish a basis for future mechanistic and functional validation studies. Full article

Background/Objectives: Triple-negative breast cancer (TNBC) is an aggressive subtype in which neoadjuvant chemotherapy plays an important role in initial treatment. Pathological complete response (pCR) following neoadjuvant therapy can serve as a surrogate marker for long-term survival. Our study aimed to evaluate the value of the Pan-Immune-Inflammation Value (PIV), Neutrophil-to-Lymphocyte Ratio (NLR), and Platelet-to-Lymphocyte Ratio (PLR), measured at multiple time points, in predicting pCR. Methods: We retrospectively included 89 patients with non-metastatic TNBC treated with neoadjuvant chemotherapy with or without immunotherapy, followed by surgery. Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Pan-Immune-Inflammation Value (PIV) were calculated at baseline, before the second treatment cycle, and at the pragmatic pre-transition assessment before a subsequent treatment phase, when applicable. The primary endpoint was pCR, defined as ypT0N0. Multivariable logistic regression models included age, Ki-67, clinical T stage, and tumor grade. Biomarker-extended models were compared with the clinical model on identical complete-case samples. Model performance was assessed using the area under the receiver operating characteristic curve (AUC), likelihood ratio testing, calibration measures, Brier scores, and bootstrap internal validation with 2000 resamples. Results: pCR was achieved in 25 of 89 patients (28.1%). Baseline platelet counts were lower in patients with pCR than in those without pCR (median 246 × 10³/µL vs. 272 × 10³/µL; p = 0.021). At the pre-transition assessment, patients with pCR had lower monocyte counts (0.20 × 10³/µL vs. 0.57 × 10³/µL; p = 0.048) and lower PIVs (378.9 vs. 746.0; p = 0.011). Baseline PIV did not improve the clinical model. On the same 83-patient sample, adding baseline platelet count increased the apparent AUC from 0.751 to 0.807; however, the bootstrap 95% confidence interval (CI) for the AUC difference included zero (−0.003 to 0.128). On the same 75-patient sample, adding pre-transition PIV increased the apparent AUC from 0.735 to 0.798, with a bootstrap 95% confidence interval for the AUC difference of 0.005 to 0.142. The optimism-corrected AUC for the overall clinical model was 0.716, indicating lower internally validated performance than suggested by the apparent AUC. A smaller absolute increase in PIV from baseline to the pre-transition assessment was associated with pCR, but this finding was definition-dependent and remained exploratory. Conclusions: Standalone baseline markers have limited utility in predicting pCR in non-metastatic TNBC. Pre-transition PIV showed the most consistent incremental association with pCR beyond conventional clinical variables, whereas the added value of baseline platelet count was uncertain and baseline PIV provided no incremental benefit. Because of the retrospective design, limited sample size, treatment heterogeneity, and evidence of model optimism, these findings should be regarded as hypothesis-generating and require external validation. Full article

Background & Objectives: Endovascular embolization has matured into a sophisticated, precision-guided discipline that is central to the management of complex neurovascular pathologies. This review synthesizes contemporary treatment strategies, evaluating the advanced material characteristics of conventional inert liquid polymers, specifically non-adhesive ethylene vinyl alcohol (EVOH) copolymers and adhesive cyanoacrylates, alongside their targeted clinical applications in brain arteriovenous malformations (bAVMs), dural arteriovenous fistulas (dAVFs), hypervascular intracranial tumors, and chronic subdural hematomas (CSDHs). Furthermore, it examines the critical material and hemodynamic constraints that limit these agents in cerebral aneurysm repair. Methods: A comprehensive literature synthesis through 3 July 2026 was integrated with peer-reviewed clinical illustrations to evaluate both procedural mechanics and the necessity of post-procedural physiological management. Review Findings: Embolization serves a critical dual role: as a definitive curative therapy and as an essential preoperative or radiosurgical adjunct. As demonstrated by recent clinical validations, technical angiographic success must be closely coupled with vigilant neurocritical oversight to manage profound, localized hemodynamic shifts. While these conventional methods represent established clinical practice, the field is evolving away from inert mechanical occlusion toward a highly integrated approach. The convergence of stimuli-responsive “smart” hydrogels and endovascular robotics is being evaluated for potential roles in transforming these interventions into dynamic, bioactive platforms capable of modulating disease-specific mechanisms, such as Rat Sarcoma-Mitogen-Activated Protein Kinase (RAS-MAPK) and Bone Morphogenetic Protein (BMP) signaling in bAVMs or the Von Hippel-Lindau/Vascular Endothelial Growth Factor (VHL/VEGF) axis in hypervascular tumors. This review further analyzes landmark data, including the Squid Trial For the Embolization of the Middle Meningeal Artery for Treatment of Chronic Subdural Hematoma (STEM) trial for CSDH, providing a synthesis for translating these advanced material sciences into standardized, multidisciplinary neurointerventional care. Full article

Background: Natural products with unique mechanisms remain of great interest because targeted cancer therapies frequently fail due to toxicity or resistance. Cardiac glycosides have demonstrated antitumor activity, but whether their effects involve microRNA regulation remains largely unexplored. This study investigates whether ouabain derived from Strophanthus gratus (Wall. & Hook. ex Benth.) Baill. (SGO) exerts its antitumor effects through miR-145-5p, a known tumor suppressor, using both colorectal and breast cancer models. Methods: We performed transcriptomic profiling in HCT116 colorectal cancer cells treated with SGO, followed by in vitro assays—including cell viability, caspase 3/7 activity, flow cytometry, and colony formation—in HCT116 and MCF-7 breast cancer cells. In vivo efficacy was evaluated using HCT116 xenograft models in BALB/c-nu/nu mice. miR-145-5p gain- and loss-of-function approaches were employed to determine its functional requirement. Results: SGO dose-dependently suppressed proliferation, induced apoptosis, and inhibited colony formation in both colorectal (HCT116) and breast (MCF-7) cancer cells, and significantly upregulated miR-145-5p levels in both cell types. Transcriptomic analysis identified miR-145-5p as a highly differentially expressed miRNA. In HCT116 xenograft models, SGO inhibited tumor growth by approximately 60% and elevated intratumoral miR-145-5p levels. Importantly, inhibition of miR-145-5p significantly attenuated these effects both in vitro and in vivo, establishing that the antitumor activity of SGO depends on the upregulation/activation of miR-145-5p in both cancer types. Conclusions: We have found that SGO inhibits colorectal and breast cancer growth through a miR-145-5p-dependent mechanism, revealing a previously unrecognized regulatory axis for cardiac glycosides. These findings position SGO as a promising candidate for further preclinical studies and suggest that pharmacologic re-expression of miR-145-5p may represent a viable therapeutic strategy in targeted therapy. Full article

Background: The highly heterogeneous and dynamically evolving tumor microenvironment leads to the development of drug resistance and recurrence in traditional therapies. Although immunotherapy demonstrates unique advantages, its clinical utility remains constrained by the suboptimal immunogenicity and the limited effect of monotherapy. Herein, a hybrid drug delivery system based on a spatiotemporal hierarchical controlled-release strategy was proposed to achieve dual immunotherapy with immune checkpoint blockade (ICB) and immunogenic cell death (ICD) to promote synergistic anti-tumor therapy. Methods: A liposome–micelle hybrid drug delivery system (RUT-RPP-LP) was constructed using a lipid bilayer composed of dioleoyl phosphatidylethanolamine/hemisuccinyl cholesterol to encapsulate rutin (RUT) and to form an inner cavity-encapsulated resveratrol micelle (RPP). RUT-RPP-LP was characterized, and its pH sensitivity and release behavior were investigated. Subsequently, a colon cancer tumor-bearing mouse model was constructed to evaluate the in vivo targeted anti-tumor effect and biological safety. On this basis, the combined mechanism of ICB and ICD was preliminarily explored. Results: RUT-RPP-LP possessed excellent formulation characteristics, stability, and biocompatibility, achieving graded controlled release of drugs via responding to the TME and lysosomal acidity, respectively. Obviously, RUT-RPP-LP could specifically target the tumor site, induce the occurrence of ICD, and simultaneously block the PD-1/PD-L1 immune checkpoint signaling pathway, thereby enhancing the function of T cells and inducing apoptosis of tumor cells. Conclusions: The RUT-RPP-LP based on the hierarchical controlled-release strategy exerted a spatiotemporally coordinated enhancement of anti-tumor immunity, and may provide a novel combinatorial approach to overcome the low response of immunotherapy in solid tumors. Full article

Background: Drug repurposing offers a cost-effective strategy to accelerate therapeutic discovery, but most computational approaches do not model noncoding genetic variation. Because over 90% of genome-wide association study (GWAS) risk variants reside in noncoding regions, linking regulatory variation to therapeutic hypotheses remains a major challenge. Methods: We developed an integrative deep learning framework that links allele-specific enhancer prediction to candidate therapeutics through two complementary prioritization strategies, a transcription factor (TF)-based and a gene-based approach. We used MCF7-breast cancer context as a proof-of-concept system. Results: GWAS heritability was significantly enriched in MCF7 enhancers. Allele-specific variant scoring identified 1537 breast cancer risk variants with strong predicted regulatory effects, and attribution-based motif discovery revealed enrichment of FOXA1-associated motif features, consistent with FOXA1 upregulation in primary tumors. TF-based prioritization, integrating FOXA1 knockdown-induced and drug-induced gene expression profiles, identified 63 candidate compounds, including 18 approved drugs, and recovered fulvestrant, an established breast cancer therapy. Gene-based prioritization, mapping candidate regulatory variants to 347 target genes, identified 140 candidate compounds, including approved breast cancer drugs toremifene and raloxifene. Both strategies identified compounds with anti-correlated transcriptional signatures across core breast cancer hallmark pathways, and integration of pathway anti-correlation, drug-gene interactions, and supporting experimental or clinical evidence yielded 15 high-confidence repurposing candidates. Conclusions: Recovery of approved breast cancer therapeutics supports the biological relevance of deep learning-predicted regulatory variants. This study establishes a regulatory variant-guided drug repurposing framework that connects noncoding genetic variation to candidate therapeutics and provides a scalable strategy for generating pharmacologically relevant hypotheses from the noncoding genome. Full article

Boron neutron capture therapy (BNCT) is a radiotherapeutic modality that enables tumor-targeted cell killing. The nuclear capture reaction between boron-10 (¹⁰B) and low-energy thermal neutrons produces high linear energy transfer (LET) particles (α-particles and recoiling lithium nuclei), each of which have short path lengths within the diameter of a single mammalian cell. The deposited energy creates clustered DNA double-strand breaks that are cytotoxic in these tumor cells while sparing the surrounding healthy tissues. This advantage makes BNCT a highly attractive treatment modality compared to conventional radiotherapy. Nevertheless, despite its theoretical precision, the clinical translation of BNCT remains constrained by suboptimal tumor-selective boron delivery; insufficient intracellular accumulation; and heterogeneous biodistribution profiles associated with conventional small-molecule-based boron agents, such as boronophenylalanine (BPA) and sodium borocaptate (BSH). While the development of new accelerator-based neutron sources (ABNSs) has renewed interest in BNCT, effective ¹⁰B delivery remains a major challenge. To address this, nanomedicine has been steadily on the rise in cancer research. In recent years, nanocarrier-based delivery systems have emerged as a transformative alternative delivery strategy. Nanodrugs offer several advantages over conventional small-molecule drugs, such as improved solubility, increased plasma half-life, enhanced permeability and retention in tumors, and active targeting, as well as decreased systemic toxicity and drug resistance. In recent years, nanocarrier-based delivery systems have emerged as a transformative strategy for ¹⁰B delivery. In this focused review, we will discuss various types of nanocarriers used for boron drug delivery that enhance boron loading efficiency and evaluate what enables their selective delivery to and accumulation within tumor cells. Full article

Since decades, surgery of pancreatic adenocarcinoma is confronted with two major challenges. First, the prognosis of pancreatic adenocarcinoma is the worst of all gastrointestinal malignancies, characterized by late diagnosis and aggressive tumor biology. Second, postoperative mortality and morbidity have been exceptionally high, giving pancreatic resection a reputation of being one of the most dangerous procedures. This narrative review concentrates on the progress in decreasing postoperative mortality by centralization and standardization, the exertion of extended resections for local tumor clearance and multimodal strategies to improve oncologic survival. Research regarding surgical techniques, especially robotic assistance, indicated further progress in minimizing the perioperative trauma. Multimodal treatment concepts have been implemented with adjuvant therapy in resectable and neoadjuvant regimen in borderline and locally advanced cancer. However, significant problems have to be solved. Postoperative morbidity remains high, hindering the administration of adjuvant therapy, and toxicity is an essential factor in neoadjuvant strategies. Despite neoadjuvant therapies, resection rates of locally advanced carcinoma are modest and tumor progression hinders resection of borderline and resectable carcinomas. Obviously, deficits in understanding tumor biology are a central obstacle in improving resection rates and overall survival. Hence, improvement in selection of patients for surgical resection apart from using preoperative anatomical findings is mandatory. The progression of current standards, future developments and the status of surgery in multimodal concepts to treat pancreatic adenocarcinoma are delineated using historical and recent reports, registry data, meta-analysis and randomized controlled trials. Full article

Background: Uveal melanoma (UM) represents the most prevalent primary intraocular malignancy in adults, yet patients harboring GNAQ/GNA11 mutations face particularly poor prognoses with median survival of merely 6–12 months following metastasis. Multi-targeted combination therapy offers a promising strategy to circumvent drug resistance. The present study investigated the synergistic anti-tumor efficacy and mechanistic basis of Isoliquiritigenin (ISL), Quercetin (Que) and Methylnissolin (Meth), three bioactive constituents from Astragalus membranaceus (Huangqi, a widely used traditional Chinese medicinal herb) against UM. Methods: Molecular docking and 100 ns molecular dynamics simulations assessed binding stability between the compounds and their respective targets (Gαq, MEK and YAP). Synergistic interactions were quantified using the Zero Interaction Potency (ZIP) model, a reference synergy model that compares observed combination effects to predicted non-interaction baselines across full dose–response matrices, based on CCK-8 assays. Cell cycle distribution, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry. Western blotting detected target proteins and apoptotic markers. A male BALB/c nude mouse xenograft model validated therapeutic efficacy and systemic safety. Results: Molecular docking revealed binding energies <−7.0 kcal·mol⁻¹ for all three drug–target pairs, with molecular dynamics trajectories confirming stable complex conformations (RMSD < 3 Å). In vitro, the ISL-Que-Meth (IQM) combination exhibited strong synergism (ZIP scores > 10), significantly increasing apoptotic rates, collapsing mitochondrial membrane potential and upregulating cleaved-caspase 9 expression compared with monotherapy, and a modest G2/M phase accumulation was also observed, although the magnitude was limited relative to apoptotic induction. In vivo, the triple combination achieved approximately 50% reduction in tumor growth compared with the control group, with effects comparable to or exceeding those of the clinical reference agent Trametinib, and reduced Ki67 proliferation indices while elevating cleaved-caspase 9 levels, without eliciting hepatorenal toxicity. While these data demonstrate therapeutic efficacy, they do not establish in vivo synergy, as single-agent and dual-combination arms were not included in the xenograft design. Conclusions: These findings demonstrate that IQM synergistically suppresses UM growth in association with coordinated modulation of Gαq/MEK/YAP axis components and caspase 9-dependent apoptosis via the intrinsic mitochondrial pathway, providing preclinical evidence for natural product-based multi-targeted therapy against UM. Full article

Background: Bone metastasis is a frequent and debilitating complication of advanced cancer, particularly in breast and prostate cancer, and is driven by complex interactions among tumor cells, bone-resident cells, immune populations, vascular components, and the extracellular matrix. Within this specialized microenvironment, proteoglycans have emerged as key molecular regulators of tumor–bone crosstalk, matrix remodeling, metastatic niche formation, dormancy, and therapeutic resistance. Methods: We conducted a narrative review using targeted searches of PubMed and Google Scholar for studies published through 31 May 2026. Search terms included combinations of proteoglycan- and glycosaminoglycan-related concepts, including “proteoglycans,” “glycosaminoglycans,” “heparan sulfate proteoglycans,” “hyaluronan,” “heparanase,” “syndecans,” “glypicans,” “perlecan/HSPG2,” “versican,” and “decorin,” with disease- and process-related terms such as “bone metastasis,” “extracellular matrix,” “tumor–bone crosstalk,” “breast cancer,” “prostate cancer,” “metastatic niche,” “osteolytic metastasis,” “osteoblastic metastasis,” “dormancy,” “reactivation,” “immune regulation,” and “therapy resistance.” Original studies, reviews, and translational reports were selected according to their relevance to cell-surface, pericellular, and extracellular proteoglycans in bone metastatic progression. Results: Proteoglycans and associated GAG/ECM axes are implicated in multiple processes involved in skeletal metastasis, including growth factor availability, extracellular matrix organization, osteolytic and osteoblastic niche formation, angiogenesis, immune evasion, metastatic dormancy, reactivation, and therapy resistance. These functions are highly context-dependent and are influenced by proteoglycan localization, core protein structure, glycosaminoglycan composition, sulfation patterns, proteolytic processing, and cellular source. Conclusions: Proteoglycans represent critical molecular nodes in the bone metastatic microenvironment and hold potential as biomarkers, therapeutic targets, and tools for stratifying metastatic niche heterogeneity. Their clinical translation will require validation in human bone metastasis samples, improved models that reproduce the mineralized and immune-rich bone niche, and a clearer distinction between causal mechanisms and correlative associations. Future studies should integrate matrisome profiling, spatial proteomics, single-cell and spatial transcriptomics, glycosaminoglycan omics, degradomics, and three-dimensional bone niche models to define actionable proteoglycan-dependent mechanisms and improve therapeutic targeting of metastatic bone disease. Full article