Search Results (122)

Annexin A6 (AnxA6) is a predominantly intracellular calcium-dependent membrane-binding multifunctional protein that is also detected extracellularly and in small extracellular vesicles (exosomes). We previously demonstrated that lapatinib resistance in triple-negative breast cancer (TNBC) cells is associated with AnxA6 upregulation and accumulation of cholesterol in late endosomes. Here, we investigated the fate of AnxA6 and cholesterol in lapatinib-resistant (LAP-R) cells and whether extracellular AnxA6 influences TNBC cell survival. We demonstrate that reduced expression of AnxA6 in LAP-R cells decreased the secretion of MCP-1/CCL2, CCL8/IL-8, DKK1, TSP-1, and OPN by antibody arrays. The secretion of exosomes was also markedly reduced in AnxA6-depleted LAP-R cells, while AnxA6 upregulation stimulated the release of MCP-1 and exosomes. Compared to the respective controls, exosome-associated AnxA6, Rab7, and cholesterol levels were increased in exosomes isolated from AnxA6-expressing LAP-R cells. Mechanistically, we demonstrated by co-immunoprecipitation, GST pulldown, and proximity ligation assays that AnxA6 interacts with SNAP23, a component of the membrane fusion machinery. Finally, blocking extracellular AnxA6 with neutralizing antibodies reduced the viability of AnxA6-low TNBC cells but had little effect on AnxA6-high cells. These findings suggest that extracellular AnxA6 is critical for the survival of highly proliferative AnxA6-low basal-like breast cancer cells and that AnxA6 influences TNBC progression by facilitating the secretion of pro-inflammatory cytokines and cholesterol-enriched exosomes. Full article

Background: The early detection of prostate and testicular tumors remains challenging as standard diagnostic tools often lack sensitivity and produce ambiguous results. Seminal fluid is a biologically rich medium that closely reflects the state of male reproductive tissues and has therefore emerged as a promising source of non-invasive molecular biomarkers. Objective: This study aimed to critically evaluate the evidence regarding cell-free DNA, RNA, proteins and metabolites in seminal fluid, and to assess their potential for improving the early detection of male reproductive cancers. Methods: A systematic review was performed according to PRISMA guidelines. Comprehensive searches of the PubMed and Scopus databases were conducted to identify original clinical studies analyzing molecular biomarkers in seminal fluid from patients with prostate or testicular tumors. For each study, data were extracted on biomarker types, cohort characteristics, analytical methods and diagnostic performance. Results: Forty-two eligible studies were included, covering multiple biomarker classes. Most were observational, single-center investigations classified as level 3b evidence. Across the different types of biomarkers, seminal fluid was associated with tumor-associated molecular changes. Alterations in the concentration, fragmentation and methylation patterns of cell-free DNA (e.g., GSTP1, RARβ2, LGALS3 and OCT3/4) distinguished malignant from benign conditions with sensitivities of up to 80–100%. RNA-based markers, including microRNAs, small non-coding RNAs, and tRNA fragments, showed improved performance in several studies, with multimarker models achieving areas under the curve (AUCs) of 0.85–0.93. Proteomic analyses identified high-specificity candidates such as TGM4, AMACR, PROS1 and DKK3. Metabolomic profiling further strengthened the diagnostic potential; reduced seminal citrate outperformed prostate-specific antigen (AUC 0.748 vs. 0.548), and reproducible shifts in amino acid and lipid profiles were observed in testicular tumors. However, substantial heterogeneity in study design, patient selection, and analytical platforms was observed. Risk of bias varied, and large prospective validation cohorts were lacking. Conclusions: Current evidence suggests that seminal fluid contains molecular signals associated with tumors that could be used for diagnosis. However, the available data are predominantly exploratory and methodologically heterogeneous. Before seminal fluid-based biomarkers can be considered for routine clinical implementation, robust prospective studies with standardized protocols are required. Full article

Background and Objectives: Sclerostin or dickkopf-1 (DKK1) inhibits the canonical Wnt/β-catenin signaling pathway, which regulates vascular calcification and may contribute to the development of arterial stiffness. The brachial–ankle pulse wave velocity (baPWV) measures peripheral arterial stiffness (PAS). This study aimed to investigate the correlation between sclerostin and DKK1 levels and PAS in patients with type 2 diabetes mellitus (T2DM). Materials and Methods: Biochemical data and sclerostin and DKK1 levels were analyzed in the fasting blood samples of 125 patients with T2DM. baPWV measurements using the VaSera VS-1000 automatic pulse wave analyzer classified patients with values > 18.0 m/s on either side into the PAS group. Results: Among patients with T2DM, 47 (37.6%) were classified as having PAS. These patients exhibited higher hypertension prevalence (p = 0.002); greater age (p < 0.001); elevated systolic (p < 0.001) and diastolic blood (p = 0.012) pressures; and increased fasting glucose (p = 0.001), glycated hemoglobin (p = 0.008), triglyceride (p = 0.001), blood urea nitrogen (p < 0.001), and creatinine (p = 0.001) levels, urine albumin-to-creatinine ratio (p = 0.039), and C-reactive protein (p = 0.024) and serum sclerostin (p < 0.001) levels, but decreased estimated glomerular filtration rate (p < 0.001). Multivariate logistic regression analysis identified serum sclerostin level (odds ratio, 1.127; 95% confidence interval, 1.058–1.200; p < 0.001) as an independent PAS predictor in patients with T2DM. Serum log-transformed sclerostin levels were positively correlated with left (p = 0.005) and right (p = 0.001) baPWV via Spearman’s rank-order correlation coefficient analysis. Conclusions: Serum sclerostin levels, but not DKK1 levels, are positively correlated with PAS in patients with T2DM. Full article

Background: Gastric cancer (GC) remains a global health challenge, with high mortality rates often linked to late-stage diagnosis. Novel, non-invasive biomarkers are urgently needed to improve the detection and prognosis of this malignant pathology. This study aimed to evaluate the diagnostic and prognostic utility of serum Cluster of Differentiation 276 (CD276) and Dickkopf Related Protein 3 (DKK3) in patients with GC. Methods: In this case–control study, serum levels of CD276 and DKK3 were quantified in 40 GC patients and 40 age-matched healthy controls. The diagnostic performance of each marker and their combination was assessed using Receiver Operating Characteristic (ROC) curve analysis. Correlations between biomarker levels and clinicopathological features were evaluated using Spearman’s correlation. The Kaplan–Meier method and the Cox Proportional Hazards Regression Model were used to assess survival. Results: Serum CD276 levels were found to be significantly elevated in GC patients compared to healthy controls (median 60.06 vs. 18.71 units, p < 0.001). Conversely, serum DKK3 levels were significantly suppressed in the GC group (median 92.47 vs. 121.02 units, p < 0.001). In ROC analysis, CD276 demonstrated excellent diagnostic accuracy as a standalone biomarker (AUC: 0.836). DKK3 showed independent diagnostic value (AUC: 0.792), but adding DKK3 to CD276 did not provide statistically significant incremental benefit (DeLong’s p = 0.443). Survival analysis was underpowered due to limited events and short follow-up duration. Conclusions: In patients with predominantly locally advanced gastric cancer, CD276 can be a primary diagnostic marker, and the addition of DKK3 does not demonstrate a statistically significant improvement but may provide complementary information. Performance in early-stage disease requires validation in future studies. The opposing dysregulation of these markers, reflecting immune checkpoint activation (CD276) and tumor suppressor loss (DKK3), provides a robust and synergistic noninvasive signature. To assess the prognostic value of these two markers, studies involving a larger number of patients and a longer follow-up period are needed. Full article

Following the establishment of the four molecular subtypes of breast cancer, additional biomarkers are required to further refine prognostication and patient stratification. Krüppel-like factors (KLFs), components of Wnt signaling, estrogen receptor beta (ERβ) isoforms, cyclin D1, and E-cadherin have been implicated in epithelial–mesenchymal transition, tumor proliferation, and disease progression. In this monocentric retrospective cohort study, tissue microarrays from 153 patients with histologically confirmed breast cancer were analyzed by immunohistochemistry to assess the expression of cytoplasmic Dkk1, β-catenin, and E-cadherin, as well as nuclear cyclin D1, KLF-4, KLF-5, and ERβ isoforms, using the Remmele and Stegner immunoreactive score. Associations between protein expression patterns with clinicopathological characteristics and survival outcomes using univariable and multivariable Cox regression analyses were examined. High cytoplasmic E-cadherin expression was associated with improved overall survival [hazard ratio (HR) 0.37, 95% confidence interval (95% CI) 0.18–0.77, p = 0.008], whereas high nuclear expression of KLF-4 (HR 2.63, 95% CI 1.32–5.22, p = 0.006) and KLF-5 (HR 2.16, 95% CI 1.01–4.65, p = 0.048) was associated with reduced overall survival. High ERβ1 expression showed a marginally protective association with the development of metastases (log-rank test p = 0.045). Importantly, nuclear KLF-4 expression remained independently associated with adverse overall survival after adjustment for tumor stage, lymph node status, molecular subtype, and other molecular markers (adjusted HR 4.09, 95% CI 1.93–8.67, p < 0.001). These findings identify nuclear KLF-4 as an adverse prognostic marker in breast cancer and support its potential relevance for molecular patient stratification. Full article

Background: Danhong injection (DHI), a standardized traditional Chinese medicine formulation, has shown clinical benefits in treating cerebrovascular diseases. Blood–brain barrier (BBB) disruption is a key pathological feature of ischemic stroke, but its modulation by DHI under hyperlipidemic conditions remains unclear. This study aimed to investigate the protective effects and mechanisms of DHI in cerebral ischemia/reperfusion injury (CI/RI) under hyperlipidemia, focusing on BBB integrity and the Wnt/β-catenin signaling pathway. Methods: Rats were divided into control, ischemic, hyperlipidemic, and treatment subgroups to evaluate DHI’s dose-dependent effects and pathway specificity using DKK1 inhibition. Assessments included neurological scores, TTC and Nissl staining, TEM, and molecular analyses (qRT-PCR/Western blot/immunofluorescence/immunohistochemistry). Results: DHI significantly improved neurological function, reduced cerebral infarct size, and alleviated cortical damage. DHI treatment upregulated the expression of tight junction proteins (Claudin-5, Occludin, ZO-1) and downregulated MMP-9 expression. Mechanistically, DHI promoted the nuclear translocation of β-catenin and increased the expression of Wnt3α, p-GSK-3β, and Cyclin D1, thereby activating the Wnt/β-catenin pathway. Additionally, DHI treatment increased the count of NeuN-positive neurons, suppressed astrocyte activation, and markedly reduced IgG infiltration in the ischemic cerebral cortex. These effects were reversed by DKK1. Conclusions: The results indicate that DHI protects BBB integrity and alleviates CI/RI in hyperlipidemic rats independently of direct lipid-lowering activity. Specifically, DHI activates the Wnt/β-catenin pathway by enhancing β-catenin nuclear translocation, which in turn mediates the upregulation of tight junction proteins and suppression of MMP-9, ultimately preserving BBB integrity. These findings support its therapeutic potential in ischemic stroke with comorbid hyperlipidemia. Full article

Objective: This study investigated the anti-prostate cancer mechanism of dictamnine (DIC), focusing on its potential to reverse EMT via DKK1-mediated Wnt/β-catenin inhibition and modulate the tumor microenvironment. Methods: Cell viability, proliferation, migration, and invasion were assessed using CCK-8, colony formation, EdU, wound healing, and Transwell assays. Key targets were identified via transcriptomics and bioinformatics, and validated through molecular docking, co-immunoprecipitation, and cellular thermal shift assay. Protein expression was analyzed by Western blot. Gain/loss-of-function and rescue experiments confirmed target roles. A subcutaneous xenograft model and immunohistochemistry were used for in vivo validation. Results: DIC suppresses prostate cancer malignancy in a concentration-dependent manner. The primary mechanism involves its direct binding to and stabilization of DKK1, which enhances DKK1’s interaction with LRP6. This upregulation of DKK1 inhibits the Wnt/β-catenin signaling pathway, downregulating downstream targets β-catenin/c-Myc/Cyclin D1, and reverses epithelial–mesenchymal transition (EMT) markers. Additionally, DIC modulates key tumor microenvironment factors, including VEGF-A, MMP-9, IL-11, and CXCL-12. Overexpression of DKK1 mimics the antitumor effects of DIC, while knockdown of DKK1 attenuates them. In vivo, DIC inhibits tumor growth, an effect partly mediated through the DKK1/β-catenin axis. Furthermore, DIC potently suppresses angiogenesis (reduced CD31+ staining) independently of DKK1. It also increases tumor-associated macrophage infiltration (elevated F4/80+ cells) in a DKK1-independent manner. Conclusions: DIC exerts its core antitumor effects by targeting DKK1 to inhibit Wnt/β-catenin signaling and EMT. Additionally, it independently suppresses angiogenesis and remodels the immune tumor microenvironment. This multi-level mechanism positions DIC as a promising lead compound for prostate cancer therapy. Full article

Background: Lactate accumulation is increasingly recognized as a feature of tumor metabolic reprogramming that can coincide with immune dysregulation and aggressive phenotypes. The prognostic and immunologic relevance of lactate-associated heterogeneity in lung cancer remains to be clarified. Methods: We curated lactate-related genes and identified prognostic candidates in lung cancer cohorts. Consensus clustering was applied to define lactate-associated molecular subtypes, followed by characterization of survival and tumor microenvironment features. A LASSO-based gene signature was developed to generate an individual-level risk score and an integrated nomogram. Multi-omics analyses were used to evaluate concordance between transcriptomic and proteomic alterations. Single-cell transcriptomic data were analyzed to explore cellular heterogeneity in lactate-related programs. In vitro assays evaluated the response of candidate genes to lactate exposure and assessed cell migration and invasion under proliferation-inhibited conditions after genetic perturbation. Results: Two lactate-associated molecular subtypes were identified with distinct overall survival and divergent immune microenvironment features. Subtype 1 was associated with better outcomes and a more immune-inflamed profile, whereas Subtype 2 was associated with poorer outcomes and a myeloid-enriched, immunosuppressive contexture. Pathway analyses indicated subtype-associated differences in extracellular matrix-related processes and apoptosis-associated signaling. We developed an 11-gene prognostic signature and nomogram that stratified patients by risk across TCGA and GEO cohorts. Multi-omics integration highlighted ANLN, FGA, and DKK1 as consistently dysregulated at both transcript and protein levels. Among these candidates, DKK1 showed lactate-responsive induction in vitro. DKK1 perturbation altered lactate-enhanced migratory and invasive phenotypes and was accompanied by changes in intracellular lactate levels and global protein lactylation, supporting a potential feedforward relationship between lactate exposure, DKK1 expression, and lactylation. Conclusions: This study characterizes lactate-associated molecular heterogeneity in lung cancer and provides a lactate-related subtype framework and prognostic risk model for patient stratification. The findings nominate DKK1 as a lactate-responsive candidate linked to migration/invasion phenotypes and lactate/lactylation changes in vitro. Full article

Androgen receptor (AR) signaling plays a key role in male pattern baldness. We investigated whether targeting Dickkopf 1 (DKK1) and Secreted frizzled-related protein 1 (SFRP1), two AR-regulated genes, offers a novel therapeutic strategy for hair loss. AR expression was validated in freshly frozen human scalp hair follicles (HFs). AR knockdown was induced in human HFs using AR spherical nucleic acid (SNA). DKK1 and SFRP1 siRNA treatment were performed in HEK293 cells, human dermal papilla cells (hDPC), and human HFs ex vivo. Functional effects of single and combined DKK1 and SFRP1 knockdown were analyzed in human HFs ex vivo by quantitative (immuno)histomorphology. AR knockdown decreased SFRP1 and DKK1 expression. We found reciprocal mRNA upregulation between DKK1 and SFRP1 following their siRNA knockdown in HEK293 and hDPC. We therefore applied a single and combined treatment of DKK1 and SFRP1 siRNA in HFs ex vivo. SFRP1 knockdown prolonged anagen, increased hair matrix keratinocyte proliferation, reduced apoptosis, and increased DKK1 levels in HFs ex vivo, whereas DKK1 knockdown had no effect, and combined knockdown did not enhance SFRP1’s benefits. The culture-dependent compensatory regulation of SFRP1 and DKK1 underscores Wnt-signaling complexity in hair growth and strengthens the rationale for SFRP1 based therapies in anagen maintenance and hair loss. Full article

Previous studies have shown that miR-5110 regulates pigmentation by cotargeting melanophilin (MLPH) and WNT family member 1 (WNT1). In order to find the possible molecular mechanism for pigmentation, we examined the mRNA expression profiles in melanocytes of alpaca transfected with miR-5110, inhibitor or negative control (NC) plasmids using high-throughput RNA sequencing. The results showed that a total of 91,976 unigenes were assembled from the reads, among which 13,262 had sequence sizes greater than 2000 nucleotides. According to the KEGG pathway analysis, four pathways related to melanogenesis, the MAPK signaling pathway, Wnt signaling pathway, and cAMP signaling pathway were identified. Compared to the NC, 162 gene were upregulated and 41 genes were downregulated in melanocytes over expressed by miR-5110. The differential expressions of mRNAs Dickkopf 3 (DKK3), premelanosome protein (Pmel), insulin-like growth factor 1 receptor (IGF1R), cyclin-dependent kinase 5 (CDK5), endothelin receptor type B (Ednrb), kit ligand (Kitl), Myc, and S100 were verified using qRT-PCR, which agreed with the results of RNA sequencing. We also verified the differential expressions of mRNAs of some genes in the MAPK signaling pathway using qRT-PCR, which agreed with the results of RNA sequencing. Interestingly, several genes were screened as candidates for the melanogenesis regulated by miR-5110, including Kitl and MAPK-activated protein kinase 3 (MAPKAPK3). These findings provide new insights for further molecular studies on the effects of miR-5110 on the melanogenesis and pigmentation. Full article

Mesenchymal stromal cells (MSCs) are promising therapeutic agents, largely due to their capacity for self-renewal, differentiation, and immunomodulation. Importantly, these beneficial effects are frequently mediated by the MSC secretome, which contains factors with anti-inflammatory, anti-apoptotic, and pro-regenerative properties. However, cellular senescence can impair these critical functions. To identify senescence-associated changes in the MSC secretome that may regulate aging and intercellular communication, we performed a mass spectrometry-based proteomic analysis of the conditioned medium from MSCs undergoing stress-induced senescence. Our analysis confirmed the upregulation of established aging markers, such as IL-6, PAI-1, and IGFBP7. Furthermore, we identified a significant increase in lesser-known senescence-associated secretory phenotype (SASP) components, including INHBA—a known inhibitor of proliferation—and DKK3, which blocks stromal cell pluripotency. Pathway analysis revealed that stress-induced senescence broadly affected proteins involved in glycolysis, immune response, hemostasis, and the regulation of cell death and the cell cycle. These alterations are likely to negatively impact the MSC microenvironment. Interestingly, the cellular response to senescence was dualistic. Alongside detrimental SASP factors, we observed an increase in protective proteins such as annexins (ANXA1, ANXA2), antioxidants (TXN, PRDX1, PRDX6), and the heat shock protein HSPB1, which collectively defend neighboring cells from inflammation and oxidative stress. These findings underscore the complex etiology of cellular senescence and the paradoxical nature of the SASP. The obtained data also emphasize the necessity of comprehensive proteomic profiling of the MSC secretome across different aging models to harness the full therapeutic potential of MSCs and their secretomes for regenerative medicine. Full article

Type 2 diabetes (T2D) is associated with normal or higher bone mineral density (BMD), but there is a higher fracture rate. Hypoglycaemia does not affect BMD but may cause fractures directly through falls and may affect bone cellular metabolism. We examined circulating bone marker proteins (BMPs) in response to induced hypoglycaemia in T2D versus controls. A prospective exploratory parallel study design was conducted in T2D patients (n = 23) and healthy controls (n = 23) who underwent blood SOMAscan proteomic analysis of bone biomarkers at baseline, hypoglycaemia, and post-hypoglycaemia time points. Unadjusted repeated measures linear mixed modeling was used for analysis. Linear mixed modeling of the proteins showed that the way most BMPs changed over time did not differ between groups. At baseline, Dickkopf-related protein 1 (DKK1), cathepsin A, cathepsin S, and cathepsin Z were increased in T2D versus controls (p < 0.05), whilst fibroblast growth factor 23 (FGF23) was lower in T2D versus controls (p ≤ 0.05). Following hypoglycemia, transient changes from baseline occurred in DKK1, cathepsin A, cathepsin G, cathepsin H, cathepsin S, cathepsin Z, parathyroid hormone (PTH), Sphingosine kinase 1 and 2 (SPK1/2), and interleukin-1 beta (IL1 beta) over the post-hypoglycaemia time course. There was decreased cathepsin S in T2D from baseline to 24 h compared to the control group, and increased cathepsin Z at 24 h for both groups overall compared to baseline (p < 0.05). Baseline-raised cathepsins (A, S, Z) in T2D may enhance osteoclastic resorption, whilst raised DKK1 could inhibit osteoblast differentiation and suppress bone formation. Hypothetically, this may lead to a decline in bone quality through a resorption-enhanced, low bone formation imbalance. The effects of hypoglycaemia on bone physiology appear to extend significantly beyond the initial insult, as seen for cathepsin S and Z, which differed at 24 h compared to baseline. Full article

Background: Periostin can be considered a stimulator of Wnt. Elucidating the relationship between Wnt10a and Periostin in dental pulp stem cells is considered necessary for a deeper understanding of the mechanisms of dental pulp regeneration. Methods: Regenerated dental pulp from ectopic root grafts was double-stained with BrdU and Wnt10a, and the positivity rates were analyzed. Furthermore, the expression levels of Wnt10a, LRP5/6, DKK1, and Periostin within the regenerated tissue were analyzed by PCR. The expression levels of Wnt10a, LRP5/6, DKK1, and Periostin in cells stimulated with Periostin were analyzed by PCR. Wnt10a protein expression was analyzed by Western blotting and ELISA. Similar evaluations were performed with co-stimulation by Periostin and DKK1(Sample size:4). In each experiment, cells not stimulated with periostin served as the control group. Statistical analysis involved confirming the normal distribution of data using QQ plots, followed by one-way analysis of variance and post hoc Turkey’s test. Results: Migrating dental pulp stem cells expressed Wnt10a, and migration was additionally inhibited by its antagonist DKK1. Furthermore, Periostin stimulation increased Wnt10a secretion and suppressed DKK1. Conclusions: Periostin significantly increased Wnt10a expression and DPSC migration, while DKK1 inhibited these effects. Full article

Background and Clinical Significance: In gastric cancer, splenic metastases are found in less than 7% of cases and are usually associated with other systemic secondary determinations; much more rarely, they represent the sole secondary determination of the malignant disease. Case presentation: In this paper, we present the case of a 64-year-old patient who underwent curative surgery for gastric adenocarcinoma 10 months ago and, during oncological monitoring, was diagnosed with a splenic tumor formation with intense metabolic activity on PET-CT examination, raising suspicion of splenic metastases. The medical team observed an increase in carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, and Cluster of Differentiation (CD) 276 values, along with a slight decrease in Dickkopf Related Protein 3 (DKK 3). Considering that the spleen was the only site of secondary localization of the malignant disease, the patient underwent laparoscopic splenectomy with histopathological confirmation of the presence of gastric adenocarcinoma. There are no signs of loco-regional or distant recurrence 15 months postoperatively. In patients with radical excision of gastric cancer who present only with splenic metastases, splenectomy is indicated and is associated with good disease-free survival. If other secondary manifestations of malignant gastric disease are identified or suspected, chemotherapy treatment and the wait-and-see approach are recommended, as the patient does not have a real benefit from splenectomy. Until now, there is no standard protocol for the diagnostic and therapeutic management of patients with gastric cancer and metachronous splenic metastases; thus, the development of a decision-making scheme for these situations is necessary. Conclusions: The multidisciplinary approach, including the tumor board and an infectious disease specialist, are important steps in the effective management of these cases. The role of new biological markers such as CD 276 and DKK 3 for assessing the progression of malignant disease could constitute a new direction for research. Full article

Cytoskeleton-associated protein 4 (CKAP4) has emerged as a critical player in gastrointestinal (GI) cancer progression, diagnosis, and therapy. This comprehensive review synthesizes current knowledge on CKAP4′s multifaceted roles across GI malignancies, providing novel insights into its mechanisms of action and clinical potential. Its interaction with DKK1 and subsequent activation of the PI3K/AKT pathway underscores its role in promoting tumor growth. This review also highlights novel insights into CKAP4′s mechanisms of action beyond the well-established DKK1-CKAP4 axis, including its interaction with integrin β1 and involvement in angiogenesis through the FMNL2/EGFL6/CKAP4/ERK pathway. CKAP4′s impact on tumor microenvironment and immune evasion is elucidated, offering a new perspective on its contribution to cancer progression. In addition, CKAP4 arises as a promising serum biomarker for early detection and prognosis across multiple GI cancers, emphasizing its potential superiority over traditional markers. The therapeutic potential of targeting CKAP4 is extensively explored, including novel approaches like anti-CKAP4 antibodies and aptamers, and their synergistic effects with existing treatments. By integrating findings from esophageal, gastric, pancreatic, and colorectal cancers, this review provides a unique, comprehensive overview of CKAP4 in GI oncology, underscoring CKAP4′s potential to revolutionize GI cancer diagnosis and treatment and paving the way for future translational research. Full article