The RNF43 p.G659fs (RNF43^659mut) mutation occurs in 8% of colorectal cancers (CRCs) and is enriched in microsatellite instability-high (MSI-H) tumors. Although RNF43^659mut promotes tumor growth through phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) activation independent of WNT signaling, its immunologic effects are poorly defined. We show that RNF43^659mut shapes an immunosuppressive natural killer (NK) cell landscape in MSI-H CRC. Single-cell RNA sequencing and multiplex immunohistochemistry revealed increased NK cell infiltration in RNF43^659mut tumors, yet these cells displayed inhibitory phenotypes. Bulk RNA sequencing and flow cytometry of NK cells cocultured with RNF43^659mut isogenic lines and MSI-H patient-derived organoids demonstrated reduced functional NK subsets, decreased activation markers, increased inhibitory receptors, and impaired cytotoxicity. Mechanistically, RNF43^659mut-mediated PI3K/AKT activation induced HLA-E expression, suppressing NK cell function. Pharmacological or small interfering RNA-mediated PI3K/AKT inhibition restored NK cell activity and enhanced tumor cell killing. Spatial analysis of MSI-H patient tumors revealed close proximity between NKG2A⁺NK cells and HLA-E⁺ tumor cells, which were themselves adjacent to PI3K/AKT-activated tumor cells, highlighting a localized immunosuppressive niche. These findings uncover an immune evasion mechanism in MSI-H CRC, implicating the PI3K/AKT-HLA-E/NKG2A axis as a promising therapeutic target to overcome immunotherapy resistance.

Aquaporin-4 (AQP4) water channels support the glymphatic system, a brain-wide pathway that clears cerebral waste products. Here, we use AQP4 gene expression to reconstruct a whole-brain glymphatic-related topography and link it to vascular physiology, glioma, and vulnerability to neurodegenerative diseases. We find that AQP4 expression is highly organized across the brain, peaking in subcortical, ventral, and periventricular territories, consistent with a clearance axis near cerebrospinal fluid reservoirs and perivascular interfaces. Linking AQP4 expression to vascular organization, AQP4-enriched regions show lower normative blood perfusion, but lie close to areas commonly affected by cerebral small vessel disease. Turning to neurodegeneration, we find that atrophy patterns colocalize with AQP4 expression, most strongly for tau and TDP-43 proteinopathies, and high-atrophy regions lie close to AQP4 hotspots in anatomical and structural connectome space. Normative positron emission tomography markers of neuroinflammation strengthen the spatial alignment between AQP4 expression and disease atrophy. Last, we show that glioma is most frequent in AQP4-enriched regions. Collectively, this work highlights how AQP4 expression relates to brain physiology and vulnerability.

Resistance to targeted cancer therapies often arises from drug-tolerant cells, which survive treatment by entering a nonproliferative state. Over time, these cells can acquire mutations that contribute to cell reproliferation, but how nonproliferating drug-tolerant cells accumulate these mutations remains unclear. Here, we show that EGFR inhibition in EGFR-mutated lung cancer transiently down-regulates tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme that resolves abortive topoisomerase I cleavage complexes (TOP1ccs). In drug-tolerant cells, elevated reactive oxygen species promote TOP1cc trapping, while TDP1 down-regulation impairs their repair, driving TOP1cc accumulation, resistance mutation acquisition, and cell reproliferation. We further find that TDP1 expression is absent in ∼25% of EGFR-mutated lung cancers. In TDP1-deficient cells, combining EGFR inhibition with a sublethal concentration of topotecan, which further increases TOP1ccs, abolishes cell reproliferation. Together, these findings establish persistent TOP1cc accumulation as a driver of therapy-induced mutagenesis linking drug tolerance to adaptive resistance and reveal TDP1 loss as a targetable vulnerability in EGFR-mutated lung cancers.

The solute carrier (SLC) family comprises a large group of membrane transport proteins responsible for the transmembrane transport of nutrients, ions, metabolites, and drugs. SLC6A14 (solute carrier family 6 member 14) is a Na⁺ and Cl^--dependent amino acid transporter with broad substrate specificity, capable of transporting a broad spectrum of neutral and cationic amino acids, thereby supporting cellular nutrient uptake and metabolic homeostasis. Altered expression, genetic variation, or dysregulated function of SLC6A14 has been implicated in inflammatory bowel disease, cystic fibrosis-associated gastrointestinal phenotypes, and several digestive system cancers, including gastric, colorectal, and pancreatic cancers. Dysregulation of SLC6A14 has been implicated in intestinal epithelial injury, regulation of intestinal fluid secretion, and tumor cell proliferation and metastasis. Together, these observations support a broad but context-dependent role for SLC6A14 in digestive system diseases. This review summarizes the transport properties of SLC6A14 and current knowledge of its functions in digestive system diseases, with a focus on its potential as a disease biomarker and therapeutic target.

Super-enhancers are clusters of cis-regulatory elements that sustain the expression of cell-identity genes. Their aberrant activation or dysfunction constitutes a hallmark of malignant cellular transformation, which frequently rewires oncogenic transcriptional programs to support uncontrolled cell proliferation and metastatic potential. However, the functions and epigenetic regulation mechanisms of colorectal cancer specific super-enhancers remain poorly understood, and few studies have focused on dissecting how tumor enriched super-enhancers mediate downstream oncogenic signaling in CRC. By integrating multi-omics sequencing data, we identified a highly active super-enhancer in colorectal cancer, termed DCBLD2-SE. Through luciferase reporter assays, the SE3-2 subregion was identified as the minimal functional core of this super-enhancer. Mechanistic studies confirmed that transcription factors of the activator protein-1 family (FOSL2 and JUND) can bind directly to the SE3-2 cis-regulatory element, synergistically regulating local chromatin remodeling and strongly driving the upregulation of the target gene DCBLD2. Following knockout of the DCBLD2-SE core region, the malignant proliferative capacity of colorectal cancer cells decreased significantly, and the growth of xenograft tumors in vivo was markedly inhibited. Functionally, DCBLD2-SE facilitates tumor progression through a DCBLD2-dependent CD146/AKT/TNFRSF6B signaling axis. Clinically, high expression of DCBLD2 correlates with malignant metastasis and poor overall survival in patients with colorectal cancer. In summary, this study uncovers a previously undescribed DCBLD2-centered regulatory cascade that promotes colorectal cancer initiation and progression. DCBLD2-SE and its binding transcription factor activator protein-1 represent promising prognostic biomarkers and actionable therapeutic targets for colorectal cancer.

The epitranscriptomic regulation of cancer represents one of the most rapidly expanding frontiers in oncology. Among the newly characterized epigenetic axes, the Methyltransferase-like protein 5-Microsomal Glutathione S-Transferase 1 (METTL5-MGST1) signaling axis has emerged as a mechanistically compelling circuit implicated in tumor progression, ferroptosis resistance, immune evasion, and treatment-refractory behavior, most directly established in hepatocellular carcinoma and increasingly recognized, though through varying and not always MGST1-dependent mechanisms, across other cancer types. METTL5, a ribosomal 18S rRNA N6-methyladenosine (m6A) methyltransferase stabilized by its obligate cofactor tRNA methyltransferase activator subunit 11-2 (TRMT112), orchestrates oncogenic mRNA translation by methylating adenosine 1832 (A1832) in the 18S ribosomal RNA decoding center. Among its downstream effectors, Microsomal Glutathione S-Transferase 1 (MGST1) has been identified as a key mediator of ferroptosis suppression and redox homeostasis, enabling cancer cells to resist lipid peroxidation-driven cell death and conventional therapies. This review comprehensively examines the structural biology, expression patterns, molecular mechanisms, and cancer-type-specific functions of both METTL5 and MGST1, with particular emphasis on their functional interdependence. We further discuss downstream signaling cascades including c-Myc/FBXW7, TGF-β/SMAD, Akt/GSK-3β, Nrf2/SLC7A11, and the ATF4/ferroptosis axis. The therapeutic implications of targeting this axis mainly through small-molecule inhibitors, RNA interference, CRISPR strategies, and immunotherapy combinations are critically evaluated. Understanding the METTL5-MGST1 axis provides a compelling rationale for novel combination strategies against therapy-resistant cancers.

STAM-binding protein-like 1 (STAMBPL1, also termed AMSH-LP) is a conserved zinc-dependent metalloprotease deubiquitinase of the JAMM family, distinguished by its exquisite specificity for Lys63-linked polyubiquitin chains. Its unique bipartite structural recognition mode underpins this linkage selectivity, enabling it to orchestrate diverse physiological processes spanning endosomal trafficking, apoptosis regulation, metabolic homeostasis, immune signaling, and epithelial-mesenchymal plasticity. Aberrant STAMBPL1 upregulation is widely documented across multiple human malignancies, consistently correlating with advanced clinicopathological features and unfavorable patient survival. Mechanistically, it drives the malignant phenotype through both catalytic and noncatalytic mechanisms: it stabilizes multiple oncogenic substrates and thereby hyperactivates core pathways, including JAK2/STAT3, mTORC1, and NF-κB, to promote tumor proliferation, metastasis, chemotherapy resistance, and immune escape. Preclinical studies have validated the remarkable antitumor efficacy of STAMBPL1-targeting strategies ranging from natural-product modulators to peptide inhibitors and engineered ubiquitin variants. This review systematically integrates advances in STAMBPL1 biology from structural to translational studies, highlighting its promise as a therapeutic target for precision cancer therapy.

Uterine leiomyosarcoma (uLMS) is the most common subtype of uterine sarcomas characterized by high recurrence, metastasis rates, and limited responsiveness to conventional therapies. Zerumbone has been proven that have chemotherapeutic effects on cancer by modulating many molecular targets. The present study aimed to evaluate, for the first time, the antiproliferative potential of zerumbone against SK-UT-1 human uterine leiomyosarcoma cells.

Cell viability was assessed by CCK-8 assay. To evaluate the effect of zerumbone on apoptosis and cell cycle progression in SK-UT-1 cells, Annexin V and PI staining apoptosis assay and the PI staining assay were performed, respectively. To determine the cell cycle regulation and apoptosis-related gene expression changes, total RNA was isolated from SK-UT-1 cells treated with zerumbone and untreated control cells. The cDNAs were synthesized by Reverse transcription assay, and gene expressions were analysed using qRT-PCR. Zerumbone significantly decreased the viability of SK-UT-1 cells in a dose- and time-dependent manner. Flow cytometry analysis revealed that zerumbone induced G0/G1-phase arrest, followed by apoptosis and suppressed cell proliferation in SK-UT-1 cells.

Thus, our data indicate that zerumbone may represent a promising candidate for further investigation as potential therapeutic agents for uLMS, including its possible use in combination therapy.

The RapGEF Epac1 has emerged as an important modulator of pro-angiogenic signalling pathways, including VEGF/VEGFR2. However, its specific role in tumor angiogenesis has remained unexplored. Here, we identify endothelial Epac1 as a critical driver of melanoma angiogenesis. Analysis of patient-derived melanomas revealed that Epac1 is markedly upregulated in tumor endothelial cells. Using both global and endothelial-specific Epac1 knockout mouse models, we demonstrate that Epac1 deletion reduced melanoma growth and vascularization following subcutaneous melanoma cell inoculation. Transcriptome profiling of tumor-associated endothelial cells from Epac1-deficient mice showed broad downregulation of pro-angiogenic and YAP/TAZ target genes. This was corroborated in vitro using an Epac1 knockout endothelial cell line, where VEGFR2 expression, YAP/TAZ nuclear translocation, and YAP/TAZ target gene transcription were all suppressed. Consistently, Epac1 deletion impaired VE-cadherin/VEGFR2 interaction, VEGF-dependent nuclear YAP/TAZ and transcriptional activity, and abolished endothelial cell alignment in response to shear stress. Collectively, our results reveal Epac1 as a central modulator of VEGFR2 and YAP/TAZ signalling, integrating angiogenic and mechanosensory cues during melanoma vascularization.

BACKGROUND Vaccine hesitancy remains an important public health challenge, particularly in settings where vaccine uptake may vary according to sociodemographic and contextual factors. This study aimed to assess sociodemographic and lifestyle factors associated with coronavirus disease 2019 (COVID-19) vaccination uptake among healthy individuals and patients with chronic comorbidities attending a primary health care clinic in Siedlce, Eastern Poland. MATERIAL AND METHODS A cross-sectional survey was conducted between November 2, 2022, and January 3, 2023, in a convenience sample of 458 adult primary care patients. Lifestyle was assessed using the Lifestyle Screening Questionnaire (LSQ)-Cavendish Diagnostic Questionnaire. RESULTS Full COVID-19 vaccination was mainly associated with older age, higher educational attainment, and retirement status. In the adjusted model, age remained a strong predictor of vaccination uptake; participants with higher education had greater odds of full vaccination relative to those with primary or lower secondary education. Rural residence was independently associated with higher odds of full vaccination, despite a borderline association in unadjusted analyses. Several lifestyle domains differed between vaccination groups in descriptive analyses; the overall pattern did not indicate a clear independent association between lifestyle and vaccination uptake. CONCLUSIONS In this primary care sample from Eastern Poland, COVID-19 vaccination uptake was mainly associated with age, education, retirement status, and place of residence rather than a consistent lifestyle profile. The finding of higher vaccination uptake among rural participants contrasts with international literature and may reflect the local health care context. Vaccination strategies should consider regional and primary care-based differences in access, trust, and patient engagement.