Tumor necrosis factor receptor-associated factor interacting protein (TRAIP) has emerged as a critical regulator of multiple oncogenic processes across various malignancies. However, its specific functional role and underlying mechanisms in breast cancer pathogenesis remain to be fully elucidated. Integrated bioinformatics analysis of TCGA and GTEx datasets was performed to assess TRAIP expression patterns. Complementary experimental validation was conducted using immunohistochemistry, qRT-PCR, and western blot in clinical specimens. Functional characterization of TRAIP in breast cancer cells was achieved through CCK-8 proliferation assays, colony formation analysis, transwell migration/invasion tests, wound healing experiments, and flow cytometric apoptosis detection. Mechanistic investigations employed co-immunoprecipitation and ubiquitination assays to delineate the TRAIP-PLSCR4 interaction, supplemented by rescue experiments to confirm functional interdependence. Consistent overexpression of TRAIP was observed in breast cancer tissues compared to normal controls. Genetic knockdown of TRAIP significantly attenuated malignant phenotypes, including: (1) reduction in cellular proliferation, (2) decrease in colony-forming capacity, (3) reduction in migratory/invasive potential, and (4) increase in apoptosis rates (Annexin V staining). Mechanistically, TRAIP functioned as an E3 ubiquitin ligase mediating proteasomal degradation of PLSCR4 through K48-linked polyubiquitination (co-IP validation). Notably, PLSCR4 silencing effectively rescued the tumor-suppressive effects of TRAIP knockdown. This study identifies a novel TRAIP/PLSCR4 regulatory axis in breast cancer pathogenesis, wherein TRAIP exerts its oncogenic function via ubiquitination-dependent degradation of tumor-suppressive PLSCR4. These findings position TRAIP as a promising therapeutic target for precision breast cancer interventions.

Helicobacter pylori (H. pylori) has been identified as a pathogenic factor in gastric cancer (GC). Building on our previous findings that VacA upregulates TRAF1, which in turn transcriptionally activates OASL, we explored the role of this TRAF1-OASL-PANoptosis axis in GC using clinical samples, cell lines, and mouse models. Functional assays (CCK-8, colony formation, migration, invasion, TUNEL) demonstrated that TRAF1 promotes GC cell proliferation, migration, and invasion via OASL, while suppressing apoptosis. RNA-seq revealed that upregulation of TRAF1 and OASL, combined with H. pylori infection in gastric epithelial cells, enriched pathways associated with PANoptosis. Rescue experiments showed that TRAF1 knockdown increased PANoptosis, and this increase was attenuated by the pan-caspase inhibitor Z-VAD-FMK, whereas subsequent OASL overexpression reversed the suppression of PANoptosis caused by TRAF1 knockdown, whereas LPS further induced PANoptosis. Both in vitro and in vivo models confirmed that H. pylori infection triggers PANoptosis. Co-Immunoprecipitation assays uncovered a protein interaction between OASL and the ZBP1-PANoptosome. Critically, under H. pylori infection conditions, OASL overexpression rescued the PANoptosis suppressed by TRAF1 knockdown in gastric epithelial cells. This study demonstrates that H. pylori infection induces PANoptosis, and defines a pathway wherein TRAF1 promotes PANoptosis by regulating OASL-mediated activation of the ZBP1-PANoptosome. Our findings reveal a novel, context-dependent duality of the TRAF1/OASL axis: it promotes PANoptosis, contributing to mucosal damage during the precancerous inflammatory stage, yet in established GC, this axis appears to suppress PANoptosis, facilitating tumor progression. These insights provide a theoretical foundation for targeting this pathway in treating H. pylori-associated gastritis-cancer progression.

Cancer-associated fibroblasts (CAFs) are central to the pancreatic ductal adenocarcinoma (PDAC) microenvironment, promoting tumor progression and therapeutic resistance. However, the expression landscape of CAF membrane proteins in PDAC remains poorly defined. We integrated scRNA-seq (n = 33; 87,949 cells), spatial transcriptomics (n = 2; 7,011 spots), and bulk RNA-seq (n = 7; 642 samples) to systematically identify PDAC-specific CAF membrane genes. A LASSO-based Cox model was developed to construct a prognostic signature, PaFMS, and evaluated through multi-cohort validation. Functional enrichment, immune infiltration, drug sensitivity, and immunotherapy response analyses were further conducted. Validation was performed using multiple database-driven analyses. We identified a PDAC-enriched myoCAF-c1 cluster closely associated with epithelial-mesenchymal transition (EMT) and angiogenesis. From this cluster, 33 candidate CAF membrane genes were defined, whose protein-protein interactions were predominantly linked to extracellular matrix organization and collagen remodeling, and spatially colocalized with myoCAF-c1 and EMT regions. An 11-gene prognostic signature, PaFMS that robustly stratified patients across six independent cohorts, achieving high predictive accuracy for overall survival. High-risk patients exhibited proliferative signaling activation, immune suppression, and reduced T/B-cell infiltration. PaFMS was associated with responses to 33 anticancer agents and predicted enhanced benefit from anti-PD-L1 immunotherapy in the low-risk group. Multi-cohort validation confirmed the expression specificity of PaFMS genes, including PLAU, TMEM158, and TRIM59. Together, these findings reveal that myoCAF-c1 promotes angiogenesis and tumor progression, and establish PaFMS as a robust CAF membrane-based prognostic model in PDAC with potential utility for precision prognosis and therapeutic decision-making. KEY MESSAGES: Integrated single-cell, spatial, and bulk RNA-seq analyses identified PDAC-specific CAF membrane genes. Discovered a PDAC-enriched myoCAF-c1 subtype linked to EMT and angiogenesis. Developed an 11-gene CAF membrane-based prognostic model (PaFMS) validated across six cohorts. PaFMS predicts patient survival, drug sensitivity, and immunotherapy response in PDAC.

The tumor suppressor gene TP53 is the most frequently mutated gene in human cancers and has been a popular area of research in the field of oncology. The p53 protein, encoded by the TP53 gene, not only binds to many targeted genes but also regulates apoptosis, autophagy, cell cycle arrest, metabolism, senescence and the tumor immune microenvironment to suppress tumorigenesis. In recent years, an increasing number of new functions of p53 have been discovered, and p53-mediated tumor suppressor functions have been greatly expanded. Mutations in TP53 not only abolish its ability to suppress tumorigenesis but also confer carcinogenic properties to p53-mutant cells. Because of the prevalence of p53 dysfunction in various disease types, p53 has long been considered an attractive target for new anticancer drugs. However, drugs targeting p53 are still under investigation in early clinical trials and have not been approved for clinical use. This finding is consistent with the speculation that p53 is widely regarded as "undruggable." Surprisingly, several novel therapeutic approaches targeting p53, including MDM2/4 antagonists, compounds that target specific p53 mutants or restore the wild-type function of the mutated p53 protein, p53-based genetic therapies and p53-based tumor immunotherapy, have been developed in recent years. Here, we present a review of the structure, inactivation, and roles of p53 in diseases. In addition, this review discusses the efforts to target diseases associated with p53 dysfunction and the challenges encountered in the clinical development of these approaches.

Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies, exhibits a 5-year survival rate below 10% and extremely poor clinical prognosis. Over 90% of PDAC patients harbor KRAS gene driver mutations, which promote tumor proliferation, invasion, and immunosuppression of the tumor microenvironment through constitutive activation of downstream RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways. Although the therapeutic potential of targeting KRAS has been recognized for decades, its smooth protein structure and lack of traditional drug-binding pockets led to its long-standing classification as an "undruggable" target, resulting in limited efficacy of early targeted agents. Recent breakthroughs with next-generation KRAS inhibitors have transformed the therapeutic landscape for pancreatic cancer. This review synthesizes evidence from basic research and clinical translation to provide a theoretical foundation and practical guidance for the precision treatment of KRAS-mutant pancreatic cancer. Cite this article as: Li W, Lin X, Liu P, et al. Emerging therapeutic landscapes for KRAS-mutant pancreatic ductal adenocarcinoma: beyond the "undruggable" paradigm. Turk J Gastroenterol. Published online January 30, 2026. doi: 10.5152/tjg.2026.25595.

Patient-derived cells (PDCs) and patient-derived organoids (PDOs) are complementary preclinical models widely used in translational cancer research. However, their molecular and functional differences have not been systematically characterized. This study established and analyzed paired PDC and PDO models derived from the same gastric cancer ascites to delineate platform-dependent molecular and functional profiles.

Although gastric cancer (GC) exhibits significant genomic heterogeneity, the clinical implications of its immune microenvironment remain poorly understood.

Immune checkpoint inhibitor plus chemotherapy is the standard first-line treatment for advanced gastric cancer; however, predictive biomarkers for optimal patient selection remain unsatisfactory. This study was aimed at evaluating the predictive value of tumor mutational burden (TMB) and insertion/deletion (Indel) rate in patients with gastric cancer treated with nivolumab plus chemotherapy.

The gastrointestinal stromal tumor (GIST) is one of the most common mesenchymal tumors of the gastrointestinal tract. Between the 1990s and early 2000s, GIST was identified as a tumor characterized by KIT or PDGFRA mutations, resulting in imatinib being established as an effective targeted therapy. However, with advances in molecular diagnostics, approximately 10%-15% of GISTs have been reported to harbor alternative mutations, such as those in the succinate dehydrogenase subunit genes and BRAF, leading to the development of additional targeted therapies. GISTs exhibit a wide spectrum of clinical behaviors, ranging from indolent to highly aggressive, prompting the development of diverse risk classification systems. However, multiple systems remain in use, leading to inconsistent pathologic reports. Moreover, the mitotic counting method-a key factor in risk stratification-has become a major source of confusion among pathologists owing to the adoption of digital pathology and discrepancies between updated international guidelines and outdated reimbursement requirements. These inconsistencies have hindered pathologic reporting and communication between pathologists and clinicians. This review comprehensively overviews the historical background, molecular subtypes, and risk classification systems of GIST, focusing on evolving issues in mitotic rate evaluation and the application of risk classification systems in clinical practice.

Plasma cell-free DNA (cfDNA), originating from multiple organs, holds significant potential for noninvasive diagnostics and prognostics. Current cfDNA methylation assays primarily focus on single clinical indications by targeting specific genomic loci. In contrast, comprehensive profiling of cfDNA methylome can enable simultaneous detection of multiple diseases by capturing organ-specific methylation signatures, thereby offering a holistic view of health, when disease etiology is unclear or when conventional biochemical diagnostics are unavailable. However, deep sequencing required for sensitive detection of methylation abnormalities remains prohibitively expensive, limiting widespread clinical use. To overcome this barrier, we developed MethylScan, a highly cost-effective approach for cfDNA methylome sequencing. We demonstrated its broad clinical utility in a cohort of 1,061 individuals across diverse applications, including multicancer detection in general population, liver cancer surveillance in high-risk individuals, liver disease classification, identification of organ abnormalities, and race prediction from cfDNA. In multicancer detection (liver, lung, ovarian, and stomach cancers), MethylScan achieved an area under the receiver operating characteristic curve (AUROC) of 0.938 (95% CI: 0.920 to 0.954), with a sensitivity of 63.3% (95% CI: 58.9 to 67.9%) at 98.0% specificity for all cancer stages. For early-stage cancers, the AUROC was 0.916 (95% CI: 0.890 to 0.940), with 55.3% sensitivity (95% CI: 49.1 to 62.1%) at the same specificity. In liver cancer surveillance, MethylScan achieved an AUROC of 0.927 (95% CI: 0.889 to 0.959), with 79.6% sensitivity (95% CI: 70.6 to 87.8%) at 90.4% specificity. The assay also demonstrated strong performance in additional diagnostic tasks, supporting its potential as a versatile platform for comprehensive cfDNA-based health monitoring.

Risk-reducing mastectomy substantially reduces breast cancer risk in women at increased genetic or familial risk; however, it may have an impact on quality-of-life. The aim of this longitudinal study was to analyze differences in quality-of-life over time in women at increased risk of breast cancer who underwent risk-reducing mastectomy. A total of 55 cisgender women at increased risk of breast cancer, due to BRCA1/2 pathogenic variants or a significant family history, participated in the study. Some of them had a prior diagnosis of breast cancer. Quality-of-life was assessed using EORTC Quality-of-Life Questionnaire Core 30 (QLQ-C30) and the Breast Cancer-Specific Module (BR23). Assessments were conducted 15-30 days immediately before and 15-30 days immediately after the risk-reducing mastectomy, and at long-term follow-up. The follow-up assessment ranged from 1 to 15 years post-surgery (mean = 5.24 years). Changes over time were analyzed using repeated measures General Linear Models (GLM). Results indicated decreases in functional scales of quality-of-life and worsening of symptom scales following the risk-reducing mastectomy. However, quality-of-life scores returned to baseline levels at long-term follow-up. Worries regarding future perspective decreased following surgery and continued to improve over time. Although risk-reducing mastectomy was associated with short-term deterioration in selected domains, findings indicate recovery and long-term stabilization of quality-of-life. Additionally, risk-reducing mastectomy appears to alleviate future-oriented cancer concerns. This longitudinal evidence strengthens the basis for anticipatory guidance in genetic counseling and supports more balanced, evidence-informed decision-making.

We have previously defined the constitutive photomorphogenic protein 1 (COP1) gene as a therapeutic target in hepatocellular carcinoma (HCC). A recent study demonstrated that COP1 induces non-alcoholic fatty liver disease (NAFLD), a precursor to HCC, in normal hepatocytes and that reducing COP1 expression significantly improves high-fat diet-induced hepatic steatosis. Thus, in this study, we investigated if the function of COP1 was associated with HCC metabolism and evolution. Silencing of COP1 expression by a target siRNA significantly suppressed long-term colony formation in Huh7, HepG2, Huh1, and PLC/PRF/5 HCC cell lines. RNA sequencing of COP1-silenced Huh7 and HepG2 cells revealed the same directional regulation of 24 (14 up- and 10 down-regulated) genes. Notable molecular alterations were upregulation of AKR1D1 and downregulation of TMEM65, which involves negative regulation of lipid metabolism and promotion of metastasis, respectively. Correlation analysis using GEPIA2 supported inverse relationship between COP1 and AKR1D1 expression and positive relationship between COP1 and TMEM65 expression in HCC clinical samples. Targeting of COP1 reduced fat accumulation and metastatic potential in both HCC parental cells and CD133+ liver cancer stem cells. Overexpression of COP1 reversed the phenotypic changes. Collectively, our findings indicate that the COP1 is functionally correlated with HCC lipid metabolism and stemness.

We present a case of diffuse hemispheric glioma (DHG), H3 G34-mutant, NEC. Postoperative histological examination and DNA sequencing detected some features consistent with DHG, H3 G34-mutant; however, no canonical H3 alterations or ATRX variants were detected. The diagnosis could only be established based on the DNA methylation profiling result. In light of these distinctive molecular findings, we propose some insights into the current WHO diagnostic criteria for DHG H3-G34 and emphasise the value of comprehensive molecular diagnosis.

Kinesin family member 23 (KIF23) is recognised as an important tumour promoter involved in the pathogenesis of various cancers. However, its role and underlying molecular mechanisms in regulating cervical cancer (CC) growth and primary chemoresistance remain to be fully elucidated.

Accurate risk stratification and early detection of colorectal cancer (CRC) are critical for improving patient outcomes and optimizing the use of colonoscopy; however, the diagnostic performance of existing biomarkers remains suboptimal. This study aimed to develop and evaluate machine learning (ML)-based models to facilitate individualized risk assessment and clinical decision-making for colorectal lesions.

T cell-based immunotherapies have improved outcomes in lung adenocarcinoma (LUAD), yet many patients develop primary or acquired resistance. Tumor-intrinsic mechanisms that suppress CD8+ T cell function remain incompletely understood.

Gliomas are the most common primary malignant tumors of the adult central nervous system, characterized by rapid growth, high recurrence rates, and limited response to standard treatments, with median survival under 15 months. The SIX transcription factor family has been implicated in tumor development, but the role and regulatory mechanism of SIX5 in glioblastoma (GBM) remain unclear. This study systematically investigates the biological function of SIX5 and its regulatory network in GBM. Differential expression and weighted gene co-expression network analyses of GSE4290 and GSE50161 datasets, combined with machine learning algorithms including LASSO, identified SIX5 as a core candidate gene. Functional enrichment analyses and evaluation using TCGA and UALCAN databases revealed that SIX5 is highly expressed in GBM and associated with poor prognosis. Single-cell RNA sequencing and spatial transcriptomics showed enrichment of SIX5 in the tumor core and in astrocyte-like and stem cell-like subsets at the invasion front. In vitro, U87 and U251 cells with lentivirus-mediated SIX5 knockdown or overexpression were assessed for proliferation, migration, invasion, apoptosis, and colony formation. SIX5 knockdown significantly inhibited proliferation, migration, invasion, epithelial-mesenchymal transition, and tumorigenicity, while promoting apoptosis. Mechanistically, KDM5C positively regulates SIX5, which directly binds the UBE2C promoter to activate its transcription, enhancing AKT/mTOR signaling and promoting aerobic glycolysis via upregulation of GLUT1, HK2, PGK1, and LDHA. Rescue experiments showed that UBE2C overexpression partially restored malignant phenotypes under SIX5 downregulation. In vivo xenograft studies confirmed that the KDM5C-SIX5-UBE2C axis drives GBM growth. In conclusion, SIX5 functions as a critical oncogenic driver in GBM, regulated by KDM5C and promoting tumor progression through UBE2C-mediated activation of AKT/mTOR signaling and glycolytic reprogramming. The KDM5C-SIX5-UBE2C regulatory axis represents a potential prognostic biomarker and therapeutic target in glioblastoma.

Endotoxin tolerance (ET) is an immunological state in which repeated exposure to endotoxins such as lipopolysaccharide (LPS) leads to reprogramming of the immune system and a diminished inflammatory response. In this study, we used a murine model to explore the role of ET in breast cancer progression, hypothesizing that ET may foster a tumor-permissive immune environment. We compared endotoxin tolerant breast cancer-bearing mice (ETBC group) with non-endotoxin tolerant breast cancer-bearing controls (BC group). ETBC mice exhibit significantly faster tumor progression and earlier disease onset. Hematological analysis revealed reduced leukocyte counts in the ETBC group, indicating compromised immune cell recruitment. Additionally, ETBC mice showed decreased spleen weight relative to that in the BC group, further supporting systemic immune suppression. Gene expression profiling in both spleen and tumor tissues revealed marked immunological alterations in ETBC mice. In the spleen, there was notable downregulation of key pro-inflammatory cytokines, including interleukin (IL) 6 and interferon (IFN) γ. Conversely, genes associated with immune modulation and tumor progression such as IL-1β, inducible nitric oxide synthase (NOS2), cyclooxygenase (COX) 2, vascular endothelial growth factor (VEGF), and colony stimulating factor 1 (CSF-1) were upregulated. Notably, IL-1β, NOS2, COX-2, IL-10, and VEGF were consistently upregulated in tumor tissues of ETBC mice. We conclude that ET not only impairs immune surveillance but also reshapes the tumor microenvironment in favor of cancer growth. This highlights the potential role of ET in oncology and suggests that its modulation could represent a novel avenue for therapeutic intervention.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, with its pathogenesis primarily linked to activating mutations in the KIT or platelet derived growth factor receptor alpha (PDGFRA) genes. Surgical resection remains the standard curative treatment for localized GIST; however, ~50% of patients eventually develop recurrence or metastasis. Since the introduction of imatinib in the early 21st century, the management of metastatic GIST has shifted from solely surgical intervention to a systemic, chronic disease management model centered on tyrosine kinase inhibitors (TKIs). However, during the course of treatment, most patients develop drug resistance. Despite the transformative impact of TKIs, some critical clinical challenges remain unresolved. Intratumoral heterogeneity, in particular, poses a significant obstacle, as tumors often comprise diverse populations of cells with varying genetic and molecular profiles. This diversity means that while some subclones may initially respond well to TKI therapy, others harboring inherent or acquired resistance mutations can continue to proliferate, ultimately leading to treatment failure. Additionally, the limited durability of TKIs responses, even in tumors initially sensitive to treatment, remains a pressing concern. Moreover, the lack of curative systemic options for advanced GIST, along with adverse drug reactions, underscores the unmet needs within this patient population. These challenges underscore the necessity of this review, which discusses current standard drug treatment strategies for advanced GIST, including sequential TKIs therapy and investigations into mechanisms of drug resistance. Finally, the review explores precise and actionable future directions for GIST drug development and clinical management, including mutation-stratified therapeutic sequencing, rational TKI-based combination regimens, and circulating tumor DNA (ctDNA)-guided real-time treatment monitoring and resistance surveillance.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide. Although the transcription-export (TREX) complex plays a central role in RNA maturation and nuclear export, the clinical and biological relevance of individual THO Complex Subunit (including THOC1, THOC2, THOC3, THOC5, THOC6, and THOC7) in LUAD is not well defined. We performed integrative analyses combining bulk transcriptomics from TCGA/GTEx and independent GEO cohorts, survival modeling, DNA methylation profiling, protein-level annotation from public resources, protein-protein interaction network analysis, immune infiltration estimation (TIMER), and single-cell RNA sequencing (scRNA-seq) to evaluate the relevance of THOC3 and THOC7 in LUAD. Across TCGA and external GEO validation datasets, THOC3 and THOC7 were consistently upregulated in LUAD and associated with poorer overall and disease-free survival, whereas other THO complex members showed weaker or inconsistent associations. Given these comparatively consistent and reproducible signals, we therefore prioritized THOC3 and THOC7 for downstream multi-layer analyses. Epigenetic profiling and interaction network analyses placed both genes within conserved RNA processing and export programs linked to genome maintenance pathways. Single-cell transcriptomic analysis provided additional resolution, demonstrating predominant enrichment of THOC3 and THOC7 in malignant epithelial clusters, with THOC3 aligning with transcriptional programs associated with DNA replication and repair, and THOC7 with proliferative and checkpoint-related states. Notably, expression of both genes was also detectable in myeloid and neutrophil subsets, and THOC7 expression remained elevated in recurrent LUAD samples, indicating association with aggressive and treatment-resistant disease states. Collectively, by integrating bulk, single-cell, epigenetic, and immune profiling across multiple independent cohorts, this study identifies THOC3 and THOC7 as reproducible molecular correlates of aggressive LUAD phenotypes. These highlight dysregulated RNA export programs as potential biomarkers of poor prognosis and motivate future functional studies to assess RNA export dependencies in LUAD.