Cancer, influenced by genetics and the environment, involves anoikis, a cell death mechanism upon extracellular matrix detachment crucial for metastasis. Understanding this relationship is key for therapy. We analyze cancer and anoikis trends using bibliometrics.

A search was conducted from Web of Science Core, PubMed, Scopus and non-English databases such as the CNKI (inception- 21 December 2024). Data analysis employed Microsoft Excel, VOSviewer, CiteSpace, R software, and the online platform (https://bibliometric.com/).

2510 publications were retrieved, with a significant increase in the last decade. China led, the University of Texas system was productive, and the Oncogene Journal was popular. Breast, and colorectal cancers were frequently studied. Among them, representative tumor-related mechanisms were identified, commonalities such as (EMT, ECM, autophagy) and respective specific mechanisms were summarized.

This bibliometric analysis highlights rapid advances in anoikis research in cancer, emphasizing EMT and FAK pathways' translational potential, guiding targeted therapies, and improving cancer treatment outcomes.

Urinary bladder cancer (UBC), the tenth most common cancer globally, is primarily categorized into non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) types. NMIBC has a low risk of metastasis but tends to recur frequently after transurethral resection, whereas MIBC is associated with a higher likelihood of metastasis and poorer prognosis. At diagnosis, roughly 75 % of UBC patients have NMIBC, while the remaining 25 % present with tumor invasion into the bladder's muscle layer. The molecular complexity of UBC has driven research toward identifying subtypes for more personalized treatment approaches. Glycogen synthase kinase-3β (GSK-3β) has emerged as a pivotal regulator in UBC through its dual roles across six key pathways: (1) Wnt/β-catenin regulation (tumor suppression vs oncogenic activation), (2) ER stress responses (apoptosis induction vs cytoprotection), (3) Akt/GSK-3β/β-catenin/c-Myc signaling, (4) PI3K/Akt/mTOR interactions, (5) NF-κB-mediated immune modulation, and (6) Snail1/β-catenin-driven epithelial mesenchymal transition (EMT). Our analysis reveals that GSK-3β's context-dependent functions create both therapeutic opportunities and challenges - while inhibition suppresses tumor growth via β-catenin degradation, it may simultaneously activate NF-κB-mediated oncogenic processes. These paradoxical effects are particularly evident in the tumor microenvironment, where GSK-3β modulation differentially regulates CD8+ T cell function and macrophage polarization. Understanding these complex pathway interactions is crucial for developing precision therapies that exploit GSK-3β's tumor-suppressive roles while mitigating its oncogenic potential.

Emerging evidence from recent studies demonstrates that the FGL1/LAG-3 interaction axis plays a crucial role in mediating tumor immune evasion mechanisms, particularly through the suppression of T lymphocyte effector functions. However, the role of FGL1 in prostate cancer (PCa) remains unclear. Data was downloaded from The Cancer Genome Atlas (TCGA) database, and subjected to differential expression analysis. Single gene differential analysis to determine the correlation between FGL1 and DNAJC12 expression levels in prostate cancer. The expression of FGL1 was silenced by siRNA in PC3 prostate cancer cells. Lentiviruses infected DU145 to overexpress FGL1. Cell proliferation, apoptosis and EMT-related markers were detected in vitro. Animal experiments further confirmed the effect of FGL1 on prostate cancer. Up-regulated gene FGL1 was identified as the selected gene in this study among 3011 Differentially expressed genes. FGL1 had the highest positive relation with DNAJC12. The OS of PCa patients with high expression of FGL1 was significantly shorter. After silencing FGL1, PC3 cell proliferation was inhibited by 0.58-fold, while apoptosis increased by 16%, and the expression of cleaved-caspase-3 increased, while the expression of DNAJC12 and BCL-2 decreased. After overexpression of FGL1, the number of DU145 cells increased by 2.05-fold, the expression of cleaved-caspase-3 was inhibited, E-cadherin expression decreased, while N-cadherin and Vimentin expression increased. Tumor growth was inhibited, and the expression of FN1, n-cadherin, Vimentin and β-catenin decreased, while the expression of E-cadherin increased after silencing FGL1. Silencing FGL1 promotes prostate cancer cell apoptosis and inhibits EMT progression. FGL1 may be an independent prognostic marker and therapeutic target in PCa.

The expression levels of DEAD-box 46 (DDX46) are elevated in several malignancies; however, the function of DDX46 in lung adenocarcinoma (LUAD), including its expression patterns and functional implications, has not been fully elucidated. The present study primarily explores the potential role and underlying mechanism of DDX46 in the malignant progression of LUAD. The present study analyzed both publicly available databases and clinical specimens to assess DDX46 expression in LUAD and explore its prognostic significance. The findings demonstrated that elevated DDX46 expression was associated with a worse prognosis in patients with LUAD in comparison with a low DDX46 expression. Functional assays, including Cell Counting Kit-8, colony formation, 5-ethynyl-2'-deoxyuridine incorporation, flow cytometry, wound healing and Transwell assays, indicated that silencing DDX46 suppressed cancer cell migration, enhanced apoptosis, and induced G0/G1 phase cell cycle arrest. Moreover, DDX46 expression was correlated with the infiltration of T cells, natural killer cells and monocytes, as well as with several immune checkpoints and chemokines. Additionally, the results identified a marked association between DDX46 and the Wnt signaling pathway in LUAD. Low DDX46 expression was also demonstrated to be associated with increased drug responsiveness in patients. In conclusion, DDX46 holds promise as a dual-purpose marker for the diagnosis and therapy of patients with LUAD.

Prostate cancer (PCa) is the second most commonly occurring cancer among men worldwide. Although the clinical management of PCa has significantly improved, a number of limitations have been identified in both early diagnosis and therapeutic treatment. Because multiple studies show that prostate-specific antigen (PSA) screening frequently results in overdiagnosis and overtreatment, the use of PSA alone as a diagnostic marker for PCa screening has been controversial. For individuals with locally advanced or metastatic PCa, androgen deprivation therapy (ADT) is the standard initially successful treatment; nonetheless, the majority of patients will eventually develop lethal metastatic castration-resistant prostate cancer (CRPC). Alternative treatment options, including chemo-, immuno-,or radio-therapy, can only prolong the survival of CRPC patients for several months with the most developing resistance. Considering this background, there is an urgent need to discuss about selective prostate-specific biomarkers that can predict clinically relevant PCa diagnosis and to develop biomarker-driven treatments to counteract CRPC. This review addresses several PCa-specific biomarkers that will assist physicians in determining which patients are at risk of having high-grade PCa, focusing on the clinical relevance of these biomarker-based tests among PCa patients. Secondly, this review highlights the effective use of these markers as drug targets to develop precision medicine or targeted therapies to counteract CRPC. Altogether, translating this biomarker-based research into the clinic will pave the way for the effective execution of personalized therapies for the benefit of healthcare providers, the biopharmaceutical industry, and patients.

Venenum Bufonis (VB), a traditional Chinese medicine (TCM), is renowned for its therapeutic detoxification, pain relief, and cognitive enhancement effects. VB has been classified as a toxic TCM in medical literature, and its clinical usage is currently subject to several limitations. However, the toxicological characteristics of VB and underlying mechanisms remain unclear.

We conducted a comprehensive assessment to confirm the target organs affected by VB using the zebrafish model. Subsequently, network pharmacology, transcriptomic and proteomic analyses were performed to explore the associated mechanisms, with the aim of providing a basis for its clinical application.

VB exhibited dose-dependent toxic effects on zebrafish, particularly causing gross morphological abnormalities in the liver along with aggravated hepatocyte apoptosis. Pericardial edema and an enlarged atrioventricular septum were also observed. The combined analyses revealed significant alterations induced by VB in gene expression enriched in multiple pathways and biological processes. Importantly, TLR4/RIPK2/NF-κB and Wnt signaling-mediated inflammation, fibrosis, and apoptosis were identified as the key functional signaling pathways underlying VB-mediated liver toxicity.

Our results present robust and direct evidence of the hepatotoxic effects induced by VB in zebrafish, while also providing novel insights into the molecular pathways involved. These results establish a solid theoretical foundation for the appropriate clinical application of VB.

Metastatic pancreatic ductal adenocarcinoma (PDAC) is highly lethal. Promoter hypermethylation of SFRP1 (phSFRP1) in cell-free DNA is an established prognostic biomarker in PDAC. We used digital droplet PCR (ddPCR) to examine whether the prognostic impact of phSFRP1 was allele fraction (AF) dependent.

Prospectively collected plasma samples were analyzed blinded. Dual-strand methylation ddPCR assays were designed for SFRP1, with single-strand assay for the reference gene EPHA3. Patients were stratified into unmethylated SFRP1 (umSFRP1), low phSFRP1 AF (phSFRP1low), and high phSFRP1 AF (phSFRP1high). Survival was assessed with Kaplan-Meier curves. The 3-, 6-, and 12-month absolute risk difference (ARD) was calculated, and performance assessed with ROC analyses.

Overall, 354 patients were included. Patients with umSFRP1 (n=137) had a mOS of 9.1 months compared to 7.2 months in phSFRP1low (n=78) and 3.4 months in phSFRP1high (n=143, P<0.01). phSFRP1high was associated with increased mortality at 3 (ARD 26%, 95%CI: 15, 37), 6 (ARD 37%, 95%CI: 26, 48), and 12 months (ARD 23%, 95%CI: 14, 33). phSFRP1low was associated with increased mortality at 12 months (ARD 13%, 95%CI: 2, 25) but not at 3 (ARD -3%, 95%CI: -13, 8) or 6 months (ARD 3%, 95%CI: -10, 17). phSFRP1 significantly improved performance in predicting mortality compared to only clinical variables (AUC: 0.70-0.71 vs. 0.54-0.57).

Patients with phSFRP1high had significantly shorter survival than phSFRP1low or umSFRP1, indicating AF-dependent prognostic effects. phSFRP1low had a worse prognosis than umSFRP1 at only 12 months, indicating dynamic changes. This could help personalize the treatment of PDAC.

Ion channels are emerging as regulators of intracellular signalling pathway, yet the molecular mechanisms underlying this role remain poorly understood. KCNQ1, a potassium channel with tumour suppressor functions, restricts Wnt/β-catenin signalling, a pathway whose dysregulation, often driven by protein-altering mutations, is a hallmark of several epithelial cancers. Here, we identify loss-of-function (LOF) mutations in KCNQ1 across multiple epithelial cancers and elucidate their impact on Wnt/β-catenin signalling. Our findings reveal that cancer-associated KCNQ1-LOF mutations regulate the β-catenin pathway through a dual mechanism. First, they drive β-catenin transcriptional activity through triggering MET receptor, bypassing Frizzled/LRP6 receptor complex activation. Second, these mutations suppress the expression of key negative regulators of Wnt signalling, such as DKK-1, Wif-1 and NKD-1, leading to amplified pathway activation in response to Wnt ligand stimulation. This dysregulation disrupts epithelial homeostasis, as demonstrated by impaired crypt organization and increased proliferation in mouse colon-derived organoids. Together, these findings uncover an original mechanism linking KCNQ1 dysfunction to aberrant Wnt/β-catenin signalling, highlighting the role of ion channels in regulating epithelial signalling networks and tissue homeostasis.

Lithium (Li+) is a first-line therapy for millions of people with bipolar disorder. However, the molecular mechanism underlying Li+'s action remains unclear. Here we resolve a key issue concerning its bioactive form that is central to all hypotheses proposed to explain its therapeutic action─under cellular conditions, it is unclear as to what fraction of Li+ is free vs bound to ATP. We address this using molecular dynamics (MD) simulations and kinetic modeling. The polarizable force field (AMOEBA-HFC) employed in MD is benchmarked against quantum mechanical and experimental data, including local ion-ligand interactions, aqueous phase ion properties, and ion-ATP binding free energies. The kinetic model is built using observations from MD and parametrized using MD and experimental data. We discover that Mg2+-bound ATP (ATP·Mg) has two binding sites for monovalent cations, and both sites can be loaded simultaneously. In Li+'s absence, ATP·Mg predominantly exists as a ternary or quaternary complex with Na+ and/or K+ ions. Li+ also competes for these two sites. Although its standard affinity is stronger than Na+ and K+, its loading its limited by its low therapeutic concentration. Nevertheless, the extent of Li+ loading increases with ATP levels, and 50% of Li+ can be sequestered by ATP·Mg at physiological extremes. This means that both Li+ forms can be present in high fractions, providing a basis to investigate molecular modes of Li+ action. Overall, our work provides new structural, thermodynamic, and kinetic insights into how ATP binds ions in cellular solutions, also revealing Li's bioactive form.

Wnt signaling is important in embryonic development and tumorigenesis. These biological effects can be exerted by the activation of the β-catenin-dependent canonical pathway or the β-catenin-independent non-canonical pathway. DKK1 is a potent inhibitor of Wnt signaling by competing with Wnt binding to LRP5/6 co-receptors. DKK1 is tumorigenic in multiple cancer types and immunosuppressive in NK cells. Emerging evidence indicates that DKK1 is involved in T cell differentiation and induces cancer evasion of immune surveillance by accumulating MDSCs. Consequently, DKK1 has become a promising target for cancer immunotherapy, and the mechanisms by which DKK1 affects cancer and immune cells have received considerable attention. Using Twist's precision DNA writing technologies, we created phage display libraries with a diversity greater than 1 × 1010 individual members, and machine learning models were utilized for optimal discovery. We found that anti-DKK1 antibodies blocked the binding of DKK1 to LRP co-receptors. Binding of antibodies to different cysteine-rich domains (CRDs) of hDKK1 leads to different activation effects. In vitro functional assays showed that the interaction of Wnt with LRP5/6 co-receptors was restored in the presence of anti-DKK1 antibodies binding to DKK1 C-terminal CRD2, resulting in the upregulation of Wnt canonical TCF/LEF signaling and reactivation of osteoblast differentiation. Moreover, anti-DKK1 antibodies binding to DKK1 N-terminal CRD1 induced Wnt non-canonical JNK phosphorylation, immune cell activation, and tumor cell cytotoxicity. In vivo studies indicated that these anti-DKK1 antibody leads targeting DKK1 CDR1 are potent in inhibition of tumor growth and may have promising efficacy as cancer immunotherapy due to activation of the Wnt non-canonical pathway.

Frizzled class receptor 2 (FZD2), is a critical protein in the Wnt signaling pathway, which plays significant roles in various cancers. However, its role in cancer progression, prognosis, and diagnosis remains largely unexplored. This study investigates the correlation between FZD2 expression and clinical outcomes, as well as its underlying molecular mechanisms in pan-cancer.

A comprehensive bioinformatic analysis was performed using pan-cancer data from The Cancer Genome Atlas (TCGA), which included 33 cancer types. Gene set enrichment analysis (GSEA) was conducted to explore functional pathways, while a protein-protein interaction (PPI) network was constructed to further elucidate the role of FZD2 in tumor biology. The relationship between FZD2 expression and immune cell infiltration across 22 categories was assessed using CIBERSORT. Additionally, single-cell analysis was employed to examine FZD2 expression levels across different cell types. To investigate the functional impact of FZD2, loss-of-function experiments were carried out in gastric cancer cell lines using siRNA-mediated knockdown. Subsequent assays, including Polymerase Chain Reaction (PCR), Western blotting (WB), Cell Counting Kit-8 (CCK8), Flow Cytometry, wound healing, and transwell migration and invasion assays, were performed to assess cellular responses. A subcutaneous gastric cancer xenograft model was established in nude mice to investigate the effect of FZD2 knockdown on tumor growth in vivo.

Our analysis revealed significant upregulation of FZD2 in multiple malignancies, including stomach adenocarcinoma (STAD), bladder cancer (BLCA), and cholangiocarcinoma (CHOL). FZD2 expression was correlated with various cancer characteristics, including stemness score, matrix score, immune score, tumor mutational burden (TMB), microsatellite instability (MSI), RNA modification genes, and drug sensitivity. Notably, FZD2 was associated with altered sensitivity to several anticancer agents, suggesting its role in modulating treatment responses. FZD2 knockdown was demonstrated by both in vitro and in vivo experiments to suppress tumor cell proliferation, migration, and invasion in gastric cancer cell lines, indicating its critical role in tumor progression. Furthermore, FZD2 exhibited significant correlations with other Wnt pathway genes (e.g., Wnt2, Wnt4, Wnt5B), indicating a complex interaction network contributing to tumorigenesis.

FZD2 is widely upregulated in various tumor types, with its expression closely associated with key clinical outcomes, including overall survival, disease-specific survival, disease-free interval, as well as tumor mutations, drug sensitivity, immune cell infiltration, and immunotherapy-related biomarkers such as TMB and MSI. These findings highlight the pivotal role of FZD2 in cancer prognosis and treatment, offering potential for novel therapeutic approaches and the development of personalized medicine strategies in oncology.

Oral Squamous Cell Carcinoma (OSCC), the main form of oral cancer, is a major health problem globally that affects 400,000 people every year. It has been postulated that periodontitis, a chronic inflammatory disease characterized by alveolar bone resorption, is an independent risk factor for OSCC. However, the mechanisms underlying this link are not fully elucidated. It has been demonstrated that the Wnt/β-catenin pathway is key to the transformation of oral potentially malignant disorders (OPMD) towards OSCC (i.e., leukoplakia), particularly in OPMD histologically diagnosed as oral dysplasia. Using a GEO database of oral carcinogenesis (GSE85195), the transcriptional modification of 19 Wnt ligands and 4 key regulatory proteins of β-catenin, including E-cadherin, APC, AXIN and GSK3B, during leukoplakia, and early and late stages OSCC, was determined. The transcriptional expression of these targets was also assessed in periodontitis (GEO database GSE223924). Together, it was found that Wnt ligands Wnt3, Wnt3a, Wnt5b and Wnt7b are concomitantly upregulated in periodontitis and oral carcinogenesis. With these results, and the information retrieved from the literature, this review discusses the potential role of the Wnt/β-catenin pathway as a molecular mechanism that could interlink periodontitis and OSCC.

Breast cancer is the most commonly diagnosed cancer in women. The Wnt pathway is involved in the regulation of cell proliferation, differentiation, survival, and migration. Its disruption may promote the induction of breast cancer and its further development. The aim of the study was to identify micro RNA (miRNAs) that could potentially influence the activity of Wnt-related genes in five types of breast cancer in Polish women. Study included patients with five breast cancer subtypes: 130 luminal A, 96 HER2-positive luminal B, 100 HER2-negative luminal B, 36 non-luminal HER2-positive, 43 triple negative breast cancer (TNBC). Tumor tissue was removed during surgery along with a margin of healthy tissue (control group). Expression profile of Wnt-related genes was assessed with mRNA microarrays and reverse transcription quantitative polymerase chain reaction (RT-qPCR). Protein expression was conducted with enzyme-linked immunosorbent assay (ELISA). miRNA profiling was carried out with miRNAs microarrays and the miRDB database. Reduced activity of miR-130a could be related to overexpression of CCND1 and GSK3B. Similarly for miR-199a and GSK3B. High activity of miR-2115 could be associated with downregulation of TCF7L2. WNT5 A overexpression may be linked to low levels of miR-497. In addition, study revealed increased levels of APC, DVL3, LEF1 with reduced activity of FZD4 and TCF7L1 in all five subtypes of breast cancer.

Mutations to wingless integration site (WNT) ligands in cancer are poorly understood. WNT ligands are a family of secreted proteins that trigger the activation of the WNT pathway, with essential roles in cell development and carcinogenesis, particularly in the colorectal tract. While the structure of WNT ligands has been elucidated, little is known about how mutations in these proteins affect colorectal cancer. Here, we show that mutations in WNT ligands found in colorectal cancer show regional specificity and selectivity for particular conserved sequences. We further show that mutations in colorectal cancer are not selecting for changes in the binding affinity of the ligands to their receptor. We use clinical data to identify mutations to WNT5A as under selection and correlating with patient outcomes in colorectal cancer, and by combining mutational data and folding energy calculations, elastic network modeling, and molecular dynamics simulations, we show that these mutations alter its structural dynamics and flexibility. Thus, we predict a novel structure-function relationship for mutations in WNT ligands in human cancers.

Endocytosis is essential for cancer cell motility, which is predominantly mediated by the sorting nexin (SNX) family. Previous studies have demonstrated that SNX5 is elevated in several tumors, while its clinical significance and underlying mechanism in gastric cancer (GC) remain uninvestigated. In this study, we reported that SNX5 is highly expressed in GC and promotes the malignant biological behavior of GC cells. Its upregulation is closely related to poor prognosis in GC patients. Mechanistically, we observed an interaction between SNX5 and low-density lipoprotein receptor-related protein5 (LRP5) in GC cells. SNX5 inhibits LRP5 internalization and promotes its recycling to the cell membrane, which prevents LRP5 from being degraded in the lysosome. The increased membrane localization of LRP5 facilitates β-catenin stabilization, thus activating the Wnt signaling pathway, leading to tumorigenesis and progression.

The ubiquitin (Ub) system, a ubiquitous presence across eukaryotes, plays a crucial role in the precise orchestration of diverse cellular protein processes. From steering cellular signaling pathways and orchestrating cell cycle progression to guiding receptor trafficking and modulating immune responses, this process plays a crucial role in regulating various biological functions. The dysregulation of Ub-mediated signaling pathways in prevalent cancers ushers in a spectrum of clinical outcomes ranging from tumorigenesis and metastasis to recurrence and drug resistance. Ubiquitination, a linchpin process mediated by Ub, assumes a central mantle in molding cellular signaling dynamics. It navigates transitions in biological cues and ultimately shapes the destiny of proteins. Recent years have witnessed an upsurge in the momentum surrounding the development of protein-based therapeutics aimed at targeting the Ub system under the sway of cancer stem cells. The article provides a comprehensive overview of the ongoing in-depth discussions regarding the regulation of the Ub system and its impact on the development of cancer stem cells. Amidst the tapestry of insights, the article delves into the expansive roles of E3 Ub ligases, deubiquitinases, and transcription factors entwined with cancer stem cells. Furthermore, the spotlight turns to the interplay with pivotal signaling pathways the Notch, Hedgehog, Wnt/β-catenin, and Hippo-YAP signaling pathways all play crucial roles in the regulation of cancer stem cells followed by the specific modulation of Ub-proteasome.

RSPO2 (R-spondin 2) is a key regulator of the Wnt/β-catenin signaling pathway, involved in embryogenesis, tissue homeostasis, and cancer progression. Despite its therapeutic potential, effective agents targeting RSPO2 remain elusive. To address the unmet need for RSPO2-targeted therapies, we aimed to develop high-affinity nanobodies via phage display and prokaryotic expression, characterizing their binding specificity and functional blockade of RSPO2-LGR4 interactions. This study provides foundational insights into nanobody-mediated inhibition of Wnt signaling, supporting future therapeutic strategies against RSPO2-driven pathologies.

Recombinant RSPO2 proteins were constructed and purified using PCR-based recombination. Camels (Camelus bactrianus) were immunized with RSPO2, and phage display was employed to screen nanobody libraries. High-affinity nanobodies were cloned, expressed, purified, and assessed for specificity and binding affinity using biolayer interferometry and protein blotting. Functional validation was performed using TOPFLASH assays to evaluate their impact on Wnt/β-catenin signaling.

Nanobodies with high specificity and nanomolar-range affinity constants (KDs) for RSPO2 were identified. The nanobody effectively inhibited RSPO2-induced Wnt/β-catenin signaling in human renal epithelial cells.

The development of RSPO2-targeting nanobodies offers new prospects for treating RSPO2-related diseases. The nanobody serve as valuable tools for functional research and hold potential as diagnostic and therapeutic agents for RSPO2-driven conditions.

This review explores the current understanding and recent advancements in neuroblastoma, one of the most common extracranial solid pediatric cancers, accounting for ~ 15% of childhood cancer-related mortality. The hallmarks of NBL, including angiogenesis, metastasis, apoptosis resistance, cell cycle dysregulation, drug resistance, and responses to hypoxia and ROS, underscore its complex biology. The tumor microenvironment's significance in disease progression is acknowledged in this study, along with the pivotal role of cancer stem cells in sustaining tumor growth and heterogeneity. A number of molecular signatures are being studied in order to better understand the disease, with many of them serving as targets for the development of new therapeutics. This includes inhibitor therapies for NBL patients, which notably concentrate on ALK signaling, MDM2, PI3K/Akt/mTOR, Wnt, and RAS-MAPK pathways, along with regulators of epigenetic mechanisms. Additionally, this study offers an extensive understanding of the molecular therapies used, such as monoclonal antibodies and CAR-T therapy, focused on both preclinical and clinical studies. Radiation therapy's evolving role and the promise of stem cell transplantation-mediated interventions underscore the dynamic landscape of NBL treatment. This study has also emphasized the recent progress in the field of diagnosis, encompassing the adoption of artificial intelligence and liquid biopsy as a non-intrusive approach for early detection and ongoing monitoring of NBL. Furthermore, the integration of innovative treatment approaches such as CRISPR-Cas9, and cancer stem cell therapy has also been emphasized in this review.

Frizzled (FZD) receptors are a subset of G-protein-coupled receptors (GPCRs), the largest class of human cell surface receptors and a major target of FDA-approved drugs. Activated by Wnt ligands, FZDs regulate key cellular processes such as proliferation, differentiation, and polarity, positioning them at the intersection of developmental biology and disease, including cancer. Despite their significance, FZD signaling remains incompletely understood, particularly in distinguishing receptor-specific roles across canonical and non-canonical Wnt pathways. Challenges include defining ligand-receptor specificity, elucidating signal transduction mechanisms, and understanding the influence of post translational modifications and the cellular context. Structural dynamics, receptor trafficking, and non-canonical signaling contributions also remain areas of active investigation. Recent advances in structural biology, transcriptomics, and functional genomics are beginning to address these gaps, while emerging therapeutic approaches-such as small-molecule modulators and antibodies-highlight the potential of FZDs as drug targets. This review synthesizes current insights into FZD receptor biology, examines ongoing controversies, and outlines promising directions for future research and therapeutic development.

Stem cells, both normal somatic (SSC) and cancer stem cells (CSC) exist in minimally two states, i.e., quiescent and activated. Regulation of these two states, including their reliance on different metabolic processes, i.e., FAO and glycolysis in quiescent versus activated stem cells respectively, involves the analysis of a complex array of factors (nutrient and oxygen levels, adhesion molecules, cytokines, etc.) to initiate the epigenetic changes to either depart or enter quiescence. Quiescence is a critical feature of SSC that is required to maintain the genomic integrity of the stem cell pool, particularly in long lived complex organisms. Quiescence in CSC, whether they are derived from mutations arising in SSC, aberrant microenvironmental regulation, or via dedifferentiation of more committed progenitors, is a critical component of therapy resistance and disease latency and relapse. At the beginning of vertebrate evolution, approximately 450 million years ago, a gene duplication generated the two members of the Kat3 family, CREBBP (CBP) and EP300 (p300). Despite their very high degree of homology, these two Kat3 coactivators play critical and non-redundant roles at enhancers and super-enhancers via acetylation of H3K27, thereby controlling stem cell quiescence versus activation and the cells metabolic requirements. In this review/perspective, we discuss the unique regulatory roles of CBP and p300 and how specifically targeting the CBP/β-catenin interaction utilizing small molecule antagonists, can correct lineage infidelity and safely eliminate quiescent CSC.

Hepatocellular carcinoma (HCC) is one of the deadliest malignant tumors in the world, and its incidence and mortality have increased year by year. HCC research has increasingly focused on understanding its pathogenesis and developing treatments.The Wnt signaling pathway, a complex and evolutionarily conserved signal transduction system, has been extensively studied in the genesis and treatment of several malignant tumors. Recent investigations suggest that the pathogenesis of HCC may be significantly influenced by dysregulated Wnt/β-catenin signaling. This article aimed to examine the pathway that controls Wnt signaling in HCC and its mechanisms. In addition, we highlighted the role of this pathway in HCC etiology and targeted treatment.

Glioblastoma (GBM) is the most invasive and lethal brain tumor, with limited therapeutic options due to its highly infiltrative nature, resistance to conventional therapies, and blood-brain barriers. Recent advancements in near-infrared II (NIR-II) fluorescence imaging have facilitated greater tissue penetration, improved resolution, and real-time visualization of GBM, providing a promising approach for precise diagnosis and treatment. The inorganic and hybrid NIR-II fluorescent materials have developed rapidly for NIR-II fluorescence imaging-guided diagnosis and therapy of many diseases, including GBM. Herein, we offer a timely update to explore the contribution of inorganic/hybrid NIR-II fluorescent nanomaterials, such as quantum dots, rare-earth-doped nanoparticles, carbon-based nanomaterials, and metal nanoclusters in imaging-guided treatment for GBM. These nanomaterials provide high photostability, strong fluorescence intensity, and tunable optical properties, allowing for multimodal imaging and enhanced therapeutic efficacy. Additionally, their integration with modern therapeutic strategies, such as photothermal therapy, chemodynamic therapy, photodynamic therapy, sonodynamic therapy, and immunotherapy, has shown significant potential in overcoming the limitations of traditional treatments. Looking forward, future advancements including safe body clearance, long-term biocompatibility, efficient BBB penetration, and extended emission wavelengths beyond 1500 nm could enhance the theranostic outcomes. The integration of dual imaging with immunotherapy and AI-driven strategies will further enhance precision and accelerate the clinical translation of smart theranostic platforms for GBM treatment.

Impaired differentiation is a hallmark of myeloid malignancies1,2. Therapies that enable cells to circumvent the differentiation block, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), are by and large curative in acute promyelocytic leukaemia3, but whether 'differentiation therapy' is a generalizable therapeutic approach for acute myeloid leukaemia (AML) and beyond remains incompletely understood. Here we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the WNT pathway antagonist GSK3 kinase4 (GSK3i) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumour burden and significantly extending survival in a patient-derived xenograft mouse model. Mechanistically, this combination promotes differentiation by activating genes in the type I interferon pathway via inducing expression of transcription factors such as IRF7 (LSD1i) and the co-activator β-catenin (GSK3i), and their selective co-occupancy at targets such as STAT1, which is necessary for combination-induced differentiation. Combination treatment also suppresses the canonical, pro-oncogenic WNT pathway and cell cycle genes. Analysis of datasets from patients with AML suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, this combination strategy rewires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and WNT-driven cancers beyond AML.

Human diphtheria toxin-like ADP-ribosyltransferases, PARPs and tankyrases, transfer ADP-ribosyl groups to other macromolecules, thereby controlling various signaling events in cells. They are considered promising drug targets, especially in oncology, and a vast number of inhibitors have already been successfully developed. These inhibitors typically occupy the nicotinamide binding site and extend along the NAD+ binding groove of the catalytic domain. Quinazolin-4-ones have been explored as compelling scaffolds for such inhibitors and we have identified a new position within the catalytic domain that has not been extensively studied yet. In this study, we investigate larger substituents at the C-8 position and, using X-ray crystallography, we demonstrate that nitro- and diol-substituents engage in new interactions with TNKS2, improving both affinity and selectivity. Both diol- and nitro-substituents exhibit intriguing inhibition of TNKS2, with the diol-based compound EXQ-1e displaying a pIC50 of 7.19, while the nitro-based compound EXQ-2d's pIC50 value is 7.86. Both analogues impact and attenuate the tankyrase-controlled WNT/β-catenin signaling with sub-micromolar IC50. When tested against a wider panel of enzymes, the nitro-based compound EXQ-2d displayed high selectivity towards tankyrases, whereas the diol-based compound EXQ-1e also inhibited other PARPs. Compound EXQ-2d displays in vitro cell growth inhibition of the colon cancer cell line COLO 320DM, while compound EXQ-1e displays nonspecific cell toxicity. Collectively, the results offer new insights for inhibitor development targeting tankyrases and PARPs by focusing on the subsite between a mobile active site loop and the canonical nicotinamide binding site.

Ovarian cancer (OC) is a significant threat to the health of women. Biglycan (BGN) plays a crucial role in the oncogenesis and progression of various human cancers. The aim of this study was to clarify the role of BGN in OC.

Immunohistochemical analysis was performed to detect BGN levels in the OC tissues of 68 patients who underwent cytoreductive surgery. Normal ovarian tissues were collected from 21 patients with benign gynecological tumors who underwent oophorectomy. Western blot analysis was conducted to detect BGN levels in human OC and normal ovarian cells. The functions of BGN in OC cells were assessed with the Cell Counting Kit-8, wound healing, and transwell migration assays following upregulation or downregulation of BGN in vitro.

BGN expression was elevated in OC tissues as compared to normal tissues. The basal level of BGN was also higher in OC cells than in normal cells. Knockdown of BGN reduced the proportion of surviving OC cells, increased wound healing, and decreased cell migration, while overexpression produced the opposite effects.

These findings suggest that high BGN expression enhances proliferation and migration of OC cells, indicating that BGN is a potential target for treatment of OC.

Rheumatoid arthritis (RA) is the most common chronic autoimmune arthropathy. If the disease is aggressive or left untreated, it becomes debilitating, affects a patient's functionality, and reduces the quality of life. Disease-modifying anti-rheumatic drugs (DMARDs), both conventional, targeted, and biological, decrease the disease progression and are key components of effective treatment. Recently, there has been a continuous debate about the possible carcinogenicity of various DMARDs. Lung cancer is a leading cause of cancer death worldwide. The available data show an increased risk of lung cancer in RA patients, but the link between RA and cancer is poorly understood. Carcinogenesis in RA seems to be related to chronic inflammation, familial predisposition, risky behaviors (e.g., smoking), and iatrogenic complications. The main mechanisms of carcinogenic processes in patients with RA are the up-regulation of interleukin-6 (IL-6) cytokine production and wingless/integrated WNT signaling. Up-regulation of WNT5A is an important mechanism that links chronic inflammatory pathways to carcinogenesis observed in RA patients. Concomitant up-regulation of transcription factor STAT3 promotes cell proliferation and inhibits apoptosis. Conversely, suppressed inflammatory processes by DMARDs may decrease the risk of lung cancer. In this article, we discuss the molecular mechanisms of lung cancer in RA and the role of DMARDs in this process. Furthermore, we analyze the molecular effect of drug-induced cancer, which affects transcription factors and thus modulates carcinogenic processes. Finally, we describe risk factors and present preventive and therapeutic approaches.

Despite significant advances in the treatment of lung cancer (LC), there are no reliable biomarkers to effectively predict therapy response and overall survival (O/S) in non-small cell lung cancer (NSCLC) subtypes. While targeted therapies have improved survival rates in lung adenocarcinoma (LUAD), effective treatment options for lung squamous cell carcinoma (LUSC) are still limited. Recent evidence indicates that exosome-bound WNT5A may significantly contribute to disease progression. Our study assessed the WNT5A protein as a potential biomarker for diagnosing patients and predicting prognosis to assist in therapy selection.

Primary tumor tissue and serum samples were collected from a cohort of 60 patients with histologically confirmed NSCLC before therapy. Healthy serum donors served as controls. Exosomes were isolated, then exosome number and size were measured, and WNT5A protein levels were identified in tissue and in vesicle-free, vesicle-bound fractions of the serum by ELISA.

Extensive statistical analysis (ROC, AUC, Cox, etc.) revealed that elevated WNT5A levels on the serum-exosome surface correlated with distant metastasis, advanced disease stage, and lymph node involvement in LUSC but not in LUAD patients. Moreover, a high WNT5A exosome surface expression was associated with a poor response to therapy and shorter O/S in LUSC patients. Additionally, serum-exosome surface + cargo WNT5A content distinguished LUAD and LUSC subtypes.

WNT5A, particularly its serum exosome-bound form, may serve as a valuable biomarker after further validation for differentiating NSCLC subtypes and predicting disease progression. Importantly, the information can become available from a simple serum sample at the time of diagnosis.

The canonical Wnt signaling pathway controls the continuous renewal of the intestinal epithelium and the specification of epithelial cell lineages. Tcf4, a nuclear mediator of Wnt signaling, is essential for the differentiation and maintenance of Paneth cells in the small intestine. Its deficiency is associated with reduced expression of key α-defensins, highlighting its role in host-microbe interactions. However, the exact function of Tcf4 in specifying the secretory lineage and its contribution to antimicrobial peptide production remain incompletely understood. Remarkably, α-defensin expression has also been detected in human colon adenomas, where aberrant Wnt signaling is a hallmark. This raises important questions: What is the role of these Paneth-like cells in tumor biology, and how does Tcf4 influence their identity and function?

We investigated cell specification in small intestinal crypts and colon tumors using conditional Tcf7l2 deletion, cell type-specific Cre recombinases, and reporter alleles in mice. Transcriptomic (single-cell and bulk RNA sequencing) and histological analyses were performed and complemented by microbiome profiling, antibiotic treatment, and intestinal organoids to functionally validate the main findings.

The inactivation of Tcf4 depletes Paneth cells and antimicrobial peptides, disrupting the gut microbiota balance. In secretory progenitors, loss of Tcf4 shifts differentiation toward goblet cells. In the small intestine, alternative secretory progenitors produce Wnt ligands to support stem cells and epithelial renewal in the absence of Paneth cells. In colon tumors, Paneth-like cells form a tumor cell population, express Wnt ligands, and require Tcf4 for their identity. Loss of Tcf4 redirects their differentiation toward goblet cells.

Tcf4 controls the balance between Paneth and goblet cells and is essential for antimicrobial peptide production in the small intestine. In colon adenomas, Paneth-like tumor cells drive antimicrobial gene expression and provide Wnt3 ligands, which may have implications for cancer therapy.

Plant extracts contain many small molecules that are less investigated. The present paper aims to study in silico physical-chemical, pharmacokinetic, medicinal chemistry and lead/drug-likeness properties and the ability to interfere with the activity of P-glycoprotein (P-gp) transporter and cytochrome P450 (CYP) oxidase system in humans of phloridzin, phloretin, 4-methylchalcone metabolic series alongside the top three compounds found in the ethanolic extract from strawberries (S), namely 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one, 2-pyrrolidinone 5-(cyclohexylmethyl) and hexadecanoic acid. The phloridzin derivatives also were studied for their inhibitory potential upon Bcl-2, TNKS1 and COX-2 molecular targets. In vitro, Caco-2 studies analyzed the cytoprotective and anti-proliferative activity of S and the three phloridzin derivatives (pure compounds) in comparison with their combination 1:1 (GAE/pure compound, w/w), in the range 1 to 50 µg active compounds per test sample. Altogether, it was concluded that phloretin (Phl) can be used alone or in combination with S to support intestinal cell health in humans. Phloridzin (Phd) and phloridzin combined with S were proven ineffective. 4-methylchalcone (4-MeCh) combined with S indicated no advantages, while the pure compound exhibited augmented inhibitory effects, becoming a candidate for combinations with anticancer drugs. Overall, in silico studies revealed possible limitations in the practical use of phloridzin derivatives due to their potential to interfere with the activity of several major CYP enzymes.

The Wnt signaling pathway is critically involved in orchestrating cellular functions such as proliferation, migration, survival, and cell fate determination during development. Given its pivotal role in cellular communication, aberrant Wnt signaling has been extensively linked to the pathogenesis of various diseases. This review offers an in-depth analysis of the Wnt pathway, detailing its signal transduction mechanisms and principal components. Furthermore, the complex network of interactions between Wnt cascades and other key signaling pathways, such as Notch, Hedgehog, TGF-β, FGF, and NF-κB, is explored. Genetic mutations affecting the Wnt pathway play a pivotal role in disease progression, with particular emphasis on Wnt signaling's involvement in cancer stem cell biology and the tumor microenvironment. Additionally, this review underscores the diverse mechanisms through which Wnt signaling contributes to diseases such as cardiovascular conditions, neurodegenerative disorders, metabolic syndromes, autoimmune diseases, and cancer. Finally, a comprehensive overview of the therapeutic progress targeting Wnt signaling was given, and the latest progress in disease treatment targeting key components of the Wnt signaling pathway was summarized in detail, including Wnt ligands/receptors, β-catenin destruction complexes, and β-catenin/TCF transcription complexes. The development of small molecule inhibitors, monoclonal antibodies, and combination therapy strategies was emphasized, while the current potential therapeutic challenges were summarized. This aims to enhance the current understanding of this key pathway.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumors in the digestive tract, characterized by a high recurrence rate and inadequate immunotherapy options. We analyzed mutation data of ESCC from public databases and employed 10 machine learning algorithms to generate 101 algorithm combinations. Based on the optimal range determined by the concordance index, we randomly selected one combination from the best-performing algorithms to construct a prognostic model consisting of five genes (DLX5, MAGEA4, PMEPA1, RCN1, and TIMP1). By validating the correlation between the prognostic model and antigen-presenting cells (APCs), we revealed the antigen-presentation efficacy of the model. Through the analysis of immune infiltration in ESCC, we uncovered the mechanisms of immune evasion associated with the disease. In addition, we examined the potential impact of the five prognostic genes on ESCC progression. Based on these insights, we identified anti-tumor small-molecule compounds targeting these prognostic genes. This study primarily simulates the tumor microenvironment (TME) and antigen presentation processes in ESCC patients, predicting the role of the neoantigen-based prognostic model in ESCC patients and their potential responses to immunotherapy. These results suggest a potential approach for identifying therapeutic targets in ESCC, which may contribute to the development of more effective treatment strategies.

The Wnt signaling pathway plays a crucial role in development and tissue homeostasis, regulating key cellular processes such as proliferation, differentiation, and apoptosis. However, its abnormal activation is strongly associated with tumorigenesis, metastasis, and resistance to therapy, making it a vital target for cancer treatment. This review provides a comprehensive insight into the role of Wnt signaling in cancer, examining its normal physiological functions, dysregulation in malignancies, and therapeutic potential. We emphasize the importance of predicting Wnt signaling sensitivity and identify key biomarkers across various cancer types. Additionally, we address the challenges and future prospects of Wnt-targeted therapies, including biomarker discovery, advancements in emerging technologies, and their application in clinical practice.

The Wnt/β-catenin signalling pathway normally maintains cellular and tissue homeostasis by regulating cellular differentiation and survival in a controlled manner. An aberrantly regulated Wnt/β-catenin signalling pathway can transform into an oncogenic pathway, which is associated with Colorectal cancer (CRC) as well as other cancers. CRC is one of the most frequently occurring gastrointestinal cancers worldwide. In CRC tissues, deregulation of Wnt/β-catenin pathway is observed, which indicates that this oncogenic pathway directly promotes CRC malignancy, cell migration, angiogenesis, chemoresistance, as well as shorter lifespan of a patient. Growing evidence suggests that human commensal microbes have a strong association with carcinogenesis, particularly the prevalence and high enrichment of Fusobacterium nucleatum in CRC progression. The Wnt/β-catenin pathway is one of the targeted pathways by F. nucleatum in CRC, where Fusobacterium adhesin attaches to E-cadherin to initiate infection. Also, Wnt/β-catenin pathway can be a potential target for the treatment of both CRC and F. nucleatum-positive CRC. Here, we discuss the underlying mechanisms of F. nucleatum-positive CRC development through modulation of Wnt/β-catenin signalling and its possibility for the application in targeted therapy of F. nucleatum-positive CRC.

This study defines biochemical mechanisms that contribute to novel neural-regenerative activities we recently demonstrated for thiol-modified ManNAc analogs in human neural stem cells (hNSCs) by comparing our lead drug candidate for brain repair, "TProp," to a "size-matched" N-alkyl control analog, "But." These analogs biosynthetically install non-natural sialic acids into cell surface glycans, altering cell surface receptor activity and adhesive properties of cells. In this study, TProp modulated sialic acid-related biology in hNSCs to promote neuronal differentiation through modulation of cell adhesion molecules (integrins α6, β1, E-cadherin, and PSGL-1) and stem cell markers. By comparison, But elicited minimal change to these endpoints, indicating dependence on the chemical properties of the thiol group of non-natural sialic acids and not the size of this sugar's N-acyl group. Conversely, But elicited distinct intracellular responses including increased nestin expression (~6-fold) and the modulation of several metabolites identified through cell-wide screening. Metabolites up-regulated by But included dopamine and norfenenfrine, suggesting that this analog may be a drug candidate for treating neural damage associated with conditions such as Parkinson's disease. The metabolomics data also provided new insights into the neuroprotective effects of TProp when used to treat brain injury by upregulation of anti-inflammatory metabolites (e.g., α- & γ-linolenic acids) valuable for dampening injury- and treatment-related inflammation. Finally, these analogs modulate compounds that control proline (e.g., 1-pyrroline-2-carboxylate), a master regulator of many cellular activities. Overall, this study presents new mechanisms and pathways to exploit metabolic glycoengineering for neural repair and treatment of neurodegenerative diseases.

Malignant melanoma (MM) is a highly aggressive subtype of skin cancer characterized by a poor prognosis, particularly in the advanced stages. Despite advancements in targeted therapy and immunotherapy, the survival rates for MM remain low, underscoring the need for new therapeutic targets. Pleckstrin homology domain‑containing family A member 4 (PLEKHA4), which has regulatory functions in pivotal cellular processes, has emerged as a potential target in melanoma. The present study aimed to investigate the role of PLEKHA4 in melanoma progression, focusing on its influence on the MAPK and Wnt/β‑catenin signaling pathways. Bioinformatics analysis revealed that PLEKHA4 was upregulated in melanoma tissues, whereas PLEKHA4 knockdown in melanoma cell lines (A375 and A2058) significantly inhibited cell proliferation and migration, enhanced apoptosis and inhibited tumor growth in vivo. Mechanistic studies demonstrated that PLEKHA4 may exert its effects by modulating the MAPK signaling pathway through interactions with key proteins, including ERK, JNK and MEK. Additionally, PLEKHA4 was shown to impact apoptosis by regulating caspase‑3, COX2 and p65. Additionally, β‑catenin nuclear translocation was affected via the Wnt pathway. Moreover, PLEKHA4 knockdown reduced cMyc ubiquitination, consequently promoting its degradation. The present findings suggested that PLEKHA4 could promote melanoma cell proliferation by regulating both the MAPK and Wnt/β‑catenin pathways, thereby proposing PLEKHA4 as a promising therapeutic target for MM. Further studies are warranted to elucidate the mechanisms underlying PLEKHA4‑mediated modulation of cMyc ubiquitination.

Glypicans (GPCs) are a family of cell surface proteoglycans involved in multiple signaling pathways that regulate cell fate and proliferation. They share a characteristic structure composed of a core protein with two or more heparan sulfate chains and a glycosyl-phosphatidylinositol anchor that attaches them to the cell membrane. Aberrant expression of certain glypicans such as GPC1, GPC2, and GPC3 has been found in multiple types of cancer and causes the dysregulation of Wnt, hedgehog, and other signaling pathways, making them emerging targets for cancer immunotherapy. The molecular mechanism by which glypicans interact with signaling factors will provide insights for the development of cancer therapeutics. However, the structural complexes of human glypicans with Wnt and other key signaling factors remain unsolved. In this brief review, we analyze the current protein structural evidence for glypicans, with an emphasis on their interaction with Wnt, in an effort to provide insights to understand the molecular mechanisms by which glypicans play positive or negative roles in Wnt signaling in cancer and to discuss their translational potentials.

Mounting research indicates that circRNAs are pivotal elements in tumorigenesis and progression. Understanding the mechanisms by which circRNAs function in tumors is crucial for identifying undiscovered diagnostic and treatment targets. This research centers on unraveling the mechanisms by which the novel circRNA, circFADS1, influences hepatocellular carcinoma (HCC) progression. CircFADS1 shows elevated expression in HCC and is linked to unfavorable prognosis. Functionally, circFADS1 overexpression accelerates HCC progression through inducing HCC proliferation and inhibited apoptosis. Mechanistically, RNA-seq analysis demonstrates its connection to the Wnt/β-catenin pathway. Moreover, circFADS1 interacts with GSK3β and promotes its ubiquitination and degradation by recruiting the ubiquitin ligase RNF114 while EIF4A3 facilitates the biogenesis of circFADS1. Additionally, circFADS1 is closely linked to lenvatinib resistance. Overall, this study reveals that circFADS1 regulates GSK3β function, influencing the progression of hepatocellular carcinoma. The EIF4A3/circFADS1/GSK3β/β-catenin axis is discovered to hold promise as a novel therapeutic target for hepatocellular carcinoma, while circFADS1 is also a significant factor in lenvatinib resistance.