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By positioning phase separation between Kirsten rat sarcoma virus oncogene homolog (KRAS) lipidation and membrane signaling, Wang et al. unify distinct aspects of KRAS biology. They show that farnesylation drives cytoplasmic KRAS condensates that promote processing, trafficking, and signaling, establishing condensat formation as a new mechanism for controlling RAS activity.

It remains elusive how various therapeutic approaches, including radiotherapy, chemoradiotherapy, and immunoradiotherapy, reshape malignant cells and the tumor microenvironments (TMEs) during esophageal squamous cell carcinoma (ESCC) progression. A mouse model of ESCC induced by 4-nitroquinoline-1-oxide was constructed and handled by therapeutic regimens including radiotherapy, chemoradiotherapy and immunoradiotherapy, followed by single-cell and spatial transcriptomics sequencing. Besides, ESCC tumors were collected from patients during surgery after chemoradiotherapy or immunoradiotherapy. Immunohistochemical staining or immunofluorescence was applied to detect markers associated with a certain treatment. By combining single-cell and spatial transcriptomics, we have deciphered the aberrant gene expression program in epithelial cells and the cellular compositions in the ESCC mouse model following different therapeutic interventions, where chemoradiotherapy moderated epithelial cells essentially by circumscribing several oncogenes and limiting their crosstalk with Hbegf + macrophages. When radiotherapy, chemoradiotherapy, and immunoradiotherapy all lessened the immunosuppressive TMEs, including regulatory T cells and Col12a1 + cancer-associated fibroblasts, immunoradiotherapy might regulate immune responses, especially as evidenced by the frequencies of Ccl5 + Cd8 + T cells elevated. Here, we mapped a comprehensive single-cell and spatial transcriptional panorama of therapy-related ESCC in mouse models. Discovering these spatiotemporal clues might have clinical implications in establishing and improving effective therapy based on these molecules for ESCC.

Astrocyte-elevated gene-1 (AEG-1), also known as metadherin (MTDH), is a pleiotropic oncogene critically involved in the onset and development of glioblastoma (GBM), other malignant gliomas, and neuroblastoma. Its expression is upregulated under hypoxic conditions and during glucose deprivation, enabling tumor cells to survive severe metabolic stress while sustaining glycolysis. AEG-1 also has emerged as a reliable prognostic and diagnostic biomarker in gliomas, astrocytomas, oligodendrogliomas, and neuroblastomas. High AEG-1 expression correlates with advanced tumor grade, rapid disease progression, metastasis, and poor overall survival, independent of conventional clinical variables. Co-expression of AEG-1 with MDM2 further predicts higher recurrence and reduced survival, highlighting its value in patient stratification and clinical decision-making. Beyond its prognostic relevance, AEG-1 is a promising therapeutic target. Importantly, gene silencing studies demonstrate that AEG-1 knockdown reduces proliferation, promotes apoptosis, and enhances sensitivity to chemotherapeutic agents such as cisplatin, doxorubicin, and temozolomide. Mechanistically, inhibition of AEG-1 disrupts survival pathways including PI3K/Akt, impairs DNA repair, and attenuates immunosuppressive tumor microenvironments. Small-molecule inhibitors, such as DYT-40, synergistically target AEG-1 and NF-κB, reducing tumor growth and invasion in glioblastoma models. Moreover, AEG-1 suppression sensitizes cancer cells to radiotherapy by impairing homologous recombination repair and enhancing DNA damage-induced apoptosis. Collectively, these findings underscore AEG-1 as a central regulator of tumor progression, chemoresistance, and radioresistance, and support its potential as a target for combinatorial therapeutic strategies to improve outcomes in aggressive brain and pediatric tumors.

Alternative polyadenylation (APA) generates mRNA isoforms with distinct 3' untranslated regions (3'UTRs), thereby influencing transcript stability and translation. In cancer, 3'UTR shortening can activate oncogenes by escaping microRNA (miRNA)-mediated repression, but its role in hepatocellular carcinoma (HCC) remains poorly defined. Here, we profiled mRNA length alterations in multistage human HCC transcriptome datasets and investigated their functional consequences. Approximately 77% of mRNAs with altered length exhibited 3'UTR shortening. Glypican-3 (GPC3) was the most prominently upregulated shortened transcript, and high GPC3 expression was associated with poor prognosis in HCC. GPC3 knockdown reduced proliferation and induced apoptosis, whereas GPC3 overexpression promoted cell growth. Among APA regulators, Cleavage Stimulation Factor 2 (CSTF2) was upregulated in HCC, correlated positively with GPC3 expression, and predicted adverse clinical outcomes. Modulation of CSTF2 expression altered GPC3 3'UTR length, with CSTF2 overexpression promoting GPC3 3'UTR shortening, increasing GPC3 protein expression, enhancing proliferation, and suppressing apoptosis. Further analysis revealed that GPC3 3'UTR shortening removed binding sites for miR-96-5p and miR-140-5p, relieving miRNA-mediated translational repression. These findings identify CSTF2-driven APA as a mechanism of oncogenic GPC3 activation in HCC and suggest the CSTF2-GPC3 axis as a potential therapeutic target. Liver cancer is one of the leading causes of cancer-related death worldwide. Glypican-3 (GPC3) is often highly increased in liver cancer and is being studied as a marker and treatment target, but the reason for its increase is not fully understood. In this study, we analyzed patient datasets, liver cancer cells, and tumor samples to investigate how GPC3 is controlled. We found that liver cancer cells often produce a shortened form of GPC3 RNA. This shorter RNA form avoids regulation by small RNA molecules that normally help keep GPC3 levels low. We also identified CSTF2 as an important factor that promotes this shortening process. As a result, GPC3 becomes more stable and more highly expressed, helping cancer cells grow and survive. These findings reveal a new way that liver cancer cells increase GPC3 and may support future strategies to diagnose or treat liver cancer.

Forward genetics screens are routinely employed to perturb thousands of genetic elements in a pooled fashion with the goal of producing large-scale genotype-to-phenotype maps. While often carried out in cell culture systems, accumulating evidence supports that in vivo screens have the power to unveil new biology that cannot be recapitulated in vitro. However, the widespread application of this approach has been limited by two major challenges: a predominant focus on loss-of-function perturbations rather than gene activation and the significant technical hurdles of delivering complex genetic libraries to specific tissues in vivo. To overcome these challenges, we describe a simple and versatile intraductal injection strategy that enables efficient and rapid functional genomic screening in the mouse mammary gland, by generating tens of thousands of discrete epithelial clones. Furthermore, we provide all the details necessary for library generation, intraductal injection, screen deconvolution, and analysis of CRISPR-Knockout and Activation libraries for comprehensive in vivo screens. Using these tools, which we termed CRISPR-KOALA (Knockout and Activation Linked Assay), we have identified new tumor suppressors and oncogenes within the coding and non-coding genome in pooled libraries ranging from 46 loci to one-fifth of the genome. Importantly, this approach and analysis can be applied to other organs to study the biological function of any gene during homeostasis or disease.

Liposomes represent versatile drug delivery shuttles in clinics for cancer therapy. Nevertheless, traditional PEG-modified liposomes encounter difficulties, including (1) poor blood-brain barrier (BBB) transcytosis and tumor targeting without ligand-decoration; (2) accelerated blood clearance (ABC) resulting from anti-PEG antibodies and complement proteins. To overcome these challenges, we employed a ligand-free, BBB-permeable, and glioblastoma (GBM)-targeting zwitterionic polyphosphorylcholine (PMPC)-modified liposomal formulation for siRNA delivery (PMPC-Lipo@siRNA). PMPC-modified formulation leverages interactions with nicotinic acetylcholine receptors (nAChRs) and choline transporters (ChTs) to achieve effective BBB transcytosis and targeted tumor accumulation. Unlike anti-PEG antibodies-induced immunogenicity, PMPC modification successfully circumvents opsonin recognition, which potentially translates into their extended blood circulation and improved therapeutic responses. By targeting the PLK1 oncogene, PMPC-Lipo@siPLK1 effectively induced apoptosis through PLK1 inhibition, significantly extending the median survival of mice in both orthotopic human U87MG and patient-derived CSC2 stem cell xenograft models. Overall, PMPC-modified liposomes provide an effective ligand-free platform for GBM-targeted siRNA delivery by combining prolonged systemic circulation with intrinsic brain-targeting capability, highlighting their potential for RNAi-based therapy against GBM.

To assess immunohistochemically the presence of c-Myc both qualitatively and quantitatively in odontogenic cysts and tumours and to correlate the results with biological behaviour of these lesions. Formalin-fixed, paraffin-embedded blocks of odontogenic cysts and tumours were retrieved from institutional archives. The study sample size was 45 (n = 45), which included 10 cases of odontogenic keratocyst cyst (n = 10), five cases of radicular cyst (n = 5), five cases of dentigerous cyst (n = 5), and 10 cases of solid ameloblastoma of which five cases are follicular (n = 5) and five cases are plexiform (n = 5), 10 cases of Adenomatoid odontogenic tumour (n = 10) and five cases of unicystic ameloblastoma (n = 5). Sections were taken and stained immunohistochemically using c-Myc and evaluated both for quantitative and qualitative analysis. In the current study, the mean number of c-Myc positive cells in the odontogenic tumours was highest in solid Ameloblastoma (78.6 ± 11.59), followed by Adenomatoid odontogenic tumor (AOT) (75.30 ± 39.853) and least in unicystic ameloblastoma (56.6 ± 20.53). Among odontogenic cysts, the mean number of c-Myc positive cells was higher in Odontogenic keratocyst (OKC) (73.2 ± 17.937) compared to dentigerous cyst (28.0 ± 27.9) and radicular cysts (31.0 ± 31.7). The staining intensity varied in odontogenic cysts and tumours. The results and observations of the present study show that c-Myc plays a role in the aggressive biological behaviour of odontogenic lesions like ameloblastoma and OKC. So, it can be used as a proliferative marker. However, additional immunohistochemical and DNA assays are to be carried to determine the role of c-Myc oncogene and to know if any mutations may play a role in the pathogenesis of these odontogenic lesions.

ISA-2011B is a phosphatidylinositol-4-phosphate 5-kinase-α (PIP5K1α) inhibitor that has been reported to be selective in suppressing the growth of prostate, breast and hepatic cancer cells. Here, cell viability of 2-dimensional (2D) cultures and 3-dimensional (3D) spheroids of four colorectal cancer (CRC) cell lines with different mutations were evaluated after treatment with the drug ISA-2011B. The CRC cell lines were investigated for viability in 2D and 3D spheroid cultures. The 3D spheroids were subjected to imaging, and the average volumes were measured. The results show different treatment effects of ISA-2011B on the four CRC cell lines, indicating that mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) and phosphatidylinositol 3-kinase (PI3K) genes can play a role in the outcome of treatment. With additional studies, we suggest that ISA-2011B can be a promising drug target in CRC.

KRAS G12C has emerged as a clinically important therapeutic target in non-small cell lung cancer (NSCLC), representing a major advance in the treatment of KRAS-driven malignancies. The development of covalent inhibitors targeting the switch-Ⅱ pocket of inactive, GDP-bound KRAS has transformed a previously undruggable oncogene into a molecularly actionable target. First-generation KRAS G12C inhibitors, including sotorasib and adagrasib, have demonstrated clinically meaningful activity in previously treated NSCLC; however, their benefit is limited by acquired resistance, which arises through secondary KRAS alterations, bypass pathway activation, and adaptive reactivation of downstream MAPK signaling. In addition, treatment-related hepatotoxicity, particularly in the setting of prior or closely sequenced immune checkpoint inhibitor exposure, has emerged as an important clinical concern. Multiple next-generation KRAS G12C inhibitors, such as divarasib, glecirasib, and olomorasib, are currently under clinical development, with early evidence suggesting improved potency, selectivity, and tolerability. Furthermore, combination strategies incorporating immune checkpoint inhibitors and upstream or downstream pathway-targeted agents, including SHP2, SOS1, and MEK inhibitors, are being actively investigated to enhance the depth and durability of response. More recently, the advent of RAS (ON) inhibitors, exemplified by daraxonrasib (RMC-6236), has introduced a distinct therapeutic paradigm by directly targeting active RAS through a tri-complex mechanism. As the therapeutic landscape continues to evolve, optimal treatment selection will require integrated consideration of molecular heterogeneity, resistance mechanisms, toxicity profiles, and patient-centered shared decision-making.

Growing evidence indicates that lactate and long non-coding RNAs (lincRNAs) exert a crucial influence on tumor development. This study aimed to investigate lactate-induced histone lactylation promotes the roles of lincRNA in lung cancer progression by enhancing proliferation and PD-L1-mediated inhibition of T cell antitumor function. Results showed that both linc00824 and lactate levels were elevated in NSCLC tissues compared to adjacent controls. Lactate upregulated linc00824 expression by regulating histone H3K18 lactylation. Functioning as an oncogene, linc00824 promoted NSCLC cell proliferation and migration. Furthermore, linc00824 upregulated PD-L1 expression through targeting miR-4483 in H1975 cells, thereby suppressing CD8+ T cell activation. MiR-4483 inhibited lung cancer cell proliferation and exhibited synergistic antitumor effects with envafolimab. In summary, lactate-induced histone lactylation drives linc00824 upregulation, facilitating lung cancer progression by enhancing tumor cell proliferation and suppressing T cell antitumor function via regulating miR-4483/PD-L1. We identified an antitumor strategy for lung cancer by using miR-4483.

A-kinase anchoring protein 12 (AKAP12; Gravin/SSeCKS) is a multidomain scaffold that coordinates spatially restricted signaling rather than acting as a single linear effector. By organizing protein kinase A (PKA), protein kinase C (PKC), phosphodiesterases (PDEs), proto-oncogenic non-receptor tyrosine kinase (Src)-related modules, and cytoskeleton- or adhesion-associated proteins within local signaling microdomains, AKAP12 regulates kinase output, PDE-dependent cyclic adenosine monophosphate (cAMP) gradients, cytoskeletal remodeling, cell migration, barrier integrity, inflammatory activation, fibrosis, and tissue repair. However, AKAP12-related evidence remains dispersed across oncology, cardiovascular biology, neurovascular research, and inflammatory disease. Its apparent protective or pathogenic roles are often interpreted without sufficient attention to cell type, isoform usage, post-translational modification, disease stage, or microenvironmental stress. This review integrates mechanistic and translational evidence for AKAP12 across cancer, cardiovascular and cerebrovascular disease, neurological disorders, and inflammation-related conditions. In malignant tumors, AKAP12 most often acts as a tumor suppressor by restraining oncogenic signaling, invasion, cytoskeletal reorganization, and metastatic niche formation; however, emerging studies also reveal pro-tumor functions in hypoxia-adapted melanoma, drug-resistant ovarian cancer, and AKAP12-positive cancer-associated fibroblast niches that drive macrophage-mediated immunosuppression. In the cardiovascular and neurovascular systems, AKAP12 shapes beta-adrenergic cAMP microdomains, PDE-dependent contractile responses, endothelial migration, blood-brain barrier stability, oligodendrocyte differentiation, and injury repair. In inflammatory and fibrotic disorders, AKAP12 links immune polarization, stromal remodeling, metabolic homeostasis, and organ repair. We propose that AKAP12 should be viewed as a dynamic signaling-interface module whose functional output depends on cellular origin, isoform context, and microenvironmental state. Future studies integrating single-cell and spatial omics, interactome proteomics, isoform-specific perturbation, organoid models, and precision delivery strategies will be essential to define when AKAP12 is protective, pathogenic, or therapeutically targetable.

Diffuse large B-cell lymphoma (DLBCL) can be subclassified by phenotype into germinal center B-cell-like and activated B-cell-like (ABC) subtypes and by recurrent potentially oncogenic mutations into 5 to 7 genetic clusters. In ABC-DLBCL, potentially oncogenic mutations frequently occur in genes involved in B-cell receptor (BCR) signaling and NF-κB activation. Autonomous BCR signaling acts as an alternative immunologic driver predominantly in ABC-type DLBCL that cannot be captured by either subclassification system. The relative functional contribution and interdependence of these mechanistically diverse oncogenic drivers have not been completely defined. To directly compare the effects of autonomously signaling BCR and signalosome-activating CARD11 mutations on NF-κB activation and survival of ABC-DLBCL, we reciprocally exchanged these driver mechanisms in the MYD88L265P-mutated ABC-DLBCL cell lines TMD8 and OCI-Ly3. Only CARD11L251P (not CARD11K215N, CARD11D230N, and CARD11R337Q) compensated TMD8 cells for the loss of autonomous BCR signaling, as indicated by survival of BCR knockout and conversion to complete resistance to acalabrutinib. Transduction of the TMD8 BCR rescued OCI-Ly3 cells from replacing the CARD11L215P variant with CARD11WT. The autonomous TMD8 BCR signal provided a slight growth advantage over CARD11L251P-driven cells in both reciprocal systems. Unsupervised clustering of genetically engineered TMD8 and OCI-Ly3 clones demonstrated tight clustering with their parental cells and only minor alterations of cellular pathways. Only the strongest signalosome-activating mutation has functional near-equivalency to an autonomously signaling BCR for NF-κB activation and growth and survival in ABC-DLBCL. Quantifying the effects of co-occurring potential NF-κB-activating mechanisms is essential to predict Bruton tyrosine kinase (BTK) inhibition sensitivity in individual ABC-DLBCL cases.

The high incidence and mortality rates of tumors have resulted in significant social and economic burdens, posing a major global threat to human life and societal development. In recent years, molecular targeted therapy for tumors has become a research hotspot. C-MET, the receptor for hepatocyte growth factor (HGF), plays a crucial role in the HGF/C-MET signaling pathway, which is involved in various processes such as tumor cell growth, invasion, migration, angiogenesis, epithelial-mesenchymal transition, tumor microenvironment remodeling and therapeutic resistance. Several C-MET-targeting strategies have been developed, including small-molecule tyrosine kinase inhibitors (TKIs), monoclonal antibodies (mAbs) against C-MET or HGF, antibody-drug conjugates (ADCs), nucleic acid aptamers, soluble receptors, natural compounds, and proteolysis targeting chimeras (PROTACs) targeting MET. These inhibitors have demonstrated encouraging anti-tumor effects in both preclinical and clinical studies, with several already available on the market. However, further research is still needed on the activation mechanisms of the HGF/C-MET signaling pathway and its interactions with other receptor tyrosine kinases, which will aid in identifying suitable patients for these treatments. This review provides a comprehensive overview of the structure, regulation, signaling pathways, and functions of C-MET, along with recent advances in C-MET inhibitors, offering valuable insights for cancer therapy.

To investigate the molecular mechanism through which secreted protein acidic and rich in cysteine (SPARC) facilitates corneal epithelial wound healing via the β-catenin/c-Met signaling pathway. Wild-type C57BL/6 mice, Sparc-/- mice, and human corneal epithelial cells (HCECs) were used. Corneal epithelial repair was assessed by sodium fluorescein staining, hematoxylin and eosin staining, EdU incorporation, and Cell Counting Kit-8 assays. SPARC- and pathway-related changes were evaluated by quantitative RT-PCR, immunofluorescence, Western blotting, and flow cytometry. β-Catenin-c-Met interaction was analyzed by co-immunoprecipitation. Tandem mass tag-based phosphoproteomics compared phosphorylation profiles between control and exogenous SPARC-treated groups. In vivo and in vitro analyses showed that SPARC promoted corneal epithelial wound healing. SPARC deficiency delayed epithelial closure, reduced epithelial thickness, and impaired epithelial-stromal adhesion, whereas exogenous SPARC partially rescued these defects. In HCECs, SPARC knockdown reduced cell proliferation and migration. Mechanistically, SPARC loss decreased β-catenin expression and nuclear translocation, downregulated c-Myc, and reduced c-Met mRNA expression, total protein abundance, and phosphorylation. Silencing either β-catenin or Met impaired epithelial repair, whereas exogenous SPARC or pathway agonists partially restored these phenotypes. Co-immunoprecipitation further showed that SPARC deficiency weakened the interaction between β-catenin and c-Met. SPARC promotes corneal epithelial wound healing by enhancing β-catenin nuclear translocation and c-Met activation, thereby promoting epithelial proliferation and migration. The SPARC-β-catenin-c-Met axis may represent a therapeutic target for corneal epithelial injury.

To advance next-generation risk assessment of non-genotoxic carcinogens, robust mechanism-based assays are essential. A recognized mode of action for non-genotoxic carcinogens is induction of oxidative stress leading to regenerative proliferation. Most of the currently available New Approach Methodologies (NAMs) rely on simple high-throughput cell models with limited biological complexity and often lack metabolic capacity. In this study, we quantify chemically-induced oxidative stress in zebrafish embryos (ZFE), Danio rerio, to evaluate the added value of a whole-organism model with functional metabolism over a simple high-throughput hepatocyte cell line. Four-day-old ZFE were exposed to a set of 22 chemicals, including fifteen chemicals inducing oxidative stress and seven with another primary mode of action. Following 24hours of exposure, reactive oxygen species (ROS) were quantified in the ZFE using the dichloro-dihydro-fluorescein (DCFH) assay. Using analytically determined internal concentrations, chemicals were ranked based on their ROS-inducing potential. Results were compared with ROS induction in maturated HepG2 cells, where DCFH fluorescence was quantified during the first hour of chemical exposure. Both models identified nine chemicals with ROS-inducing potency, although the identified chemicals did not completely overlap. Of the fifteen chemicals reported to primarily induce oxidative stress, only four were not detected by either model. In ZFE, three of the seven chemicals reported to have another primary mode of action than oxidative stress were flagged for ROS production, whereas none of these seven were flagged in maturated HepG2 cells. We explore potential explanations for discrepancies between the models and discuss their applicability in a regulatory context.

miRNAs are short RNA transcripts that modulate gene expression after transcription and have emerged as pivotal regulators of cancer biology. A subset, termed oncomiRNAs, functions as oncogenes or tumor suppressors, influencing key cellular events such as cell growth, programmed cell death, neovascularization, tissue invasion, and metastatic spread. Dysregulation of these miRNAs drives tumor initiation and progression, underscoring their role in cancer evolution. Traditionally, studies have relied on bulk tissue analyses, overlooking the profound spatiotemporal heterogeneity of oncomiRNA expression, including variations across tumor regions, metastatic sites, disease stages, and during treatment. Advances in spatial transcriptomics, single-cell profiling, and longitudinal liquid biopsy technologies have provided new insights into the dynamic regulation of oncomiRNAs. These approaches reveal significant spatiotemporal variability in miRNA expression and are increasingly implicated in shaping tumor heterogeneity, therapeutic resistance, immune evasion, and divergent clinical outcomes. Emerging evidence underscores the importance of integrating these dynamic molecular patterns into biomarker discovery frameworks and precision oncology strategies. Furthermore, the incorporation of artificial intelligence and multi-omics data integration is enhancing patient stratification and predictive modeling. A comprehensive understanding of the spatiotemporal regulation of oncomiRNAs is essential for advancing next-generation cancer diagnostics and therapeutics. Future efforts should focus on systematic multi-region and longitudinal study designs, as well as their integration into adaptive clinical trials. Leveraging these insights may enable miRNA-guided, stage-adapted precision cancer theranostics in heterogeneous malignancies.

Pediatric sarcomas are a heterogeneous group of rare mesodermal malignancies. These cancers, which affect children from infancy through adolescence and young adulthood, are in general challenging to treat with currently available therapies. Biologically, many are characterized by quiet genomes, fusion oncoproteins, immune "cold" microenvironments, and vast epigenetic deregulation that contributes to diverse and complex mechanistic drivers. Multifaceted advancements in research strategies, including high-throughput screening, new model systems, surfaceome profiling, and study of oncogenic fusion condensates have led to new opportunities for understanding the biology of pediatric sarcomas. To continue to make progress for these difficult to treat cancers, it will be critical to continue to improve access to bioinformatic data, approach patient care using innovative clinical trial frameworks, and foster interdisciplinary partnerships among medicinal chemists, scientists, clinicians, advocates, and industry partners.

The expression of certain genes and proteins in brain tumors, particularly gliomas, presents potential therapeutic targets and biomarkers. One of such genes encodes the protein PINK1 (PTEN-induced Kinase 1), which has been primarily studied due to its mutations being linked to Parkinson's disease (PD). Additionally, epidemiological studies have observed a reduced risk of developing certain types of cancer in patients with neurodegenerative diseases and vice versa. The GPR55 receptor (G protein-coupled receptor 55) exhibits pro-oncogenic properties, and its expression correlates with tumor aggressiveness and the activation of the MAPK/ERK signaling pathway. This review would aim to provide an overview of the current understanding of the relationship between PINK1 and GPR55 proteins in glioma pathophysiology and explore the potential use of plant extracts as a therapeutic alternative to regulate their expression.

Globally, acute ischemic stroke (AIS) continues to be a major contributor to death and long-term functional impairment. The present work investigates the clinical relevance of miR-369-3p in AIS and how it regulates brain microvascular endothelial cells. Quantitative measurements of serum miR-369-3p were conducted in a cohort comprising 138 individuals with AIS and 120 healthy controls. ROC curve analysis and Cox proportional hazards regression were employed to evaluate diagnostic and prognostic performance of miR-369-3p. Human brain microvascular endothelial cells (hCMEC/D3) were exposed to oxygen-glucose deprivation followed by reoxygenation (OGD/R), allowing assessment of how miR-369-3p influences cell viability, inflammatory responses, and the expression of adhesion molecules. Downstream target genes were identified through bioinformatics analysis and validated using a dual-luciferase assay. A statistically significant reduction in serum miR-369-3p levels was observed among AIS patients relative to controls (P&#x2009;<&#x2009;0.001), and this miRNA demonstrated favorable diagnostic accuracy. Lower expression of miR-369-3p emerged as an independent predictor of poorer functional outcomes, as assessed by the modified Rankin Scale (mRS) score at 90 days post&#x2011;stroke. In cellular studies, upregulation of miR-369-3p mitigated the loss of cell viability induced by OGD/R, reduced the production of pro&#x2011;inflammatory cytokines and lowered the levels of ICAM&#x2011;1 and VCAM&#x2011;1. Furthermore, VAV3 was confirmed as a direct target of miR-369-3p; restoring VAV3 expression counteracted the protective effects conferred by miR-369-3p. Serum miR-369-3p may serve as a non-invasive diagnostic and prognostic biomarker for AIS. Mechanistically, miR-369-3p protects against ischemic endothelial injury by targeting VAV3 and mitigating inflammation and adhesion molecule expression.