Search Results (1,808)

Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide, with aberrant activation of the Wnt/β-catenin signaling pathway constituting a key driver of tumorigenesis. SALL2, a zinc finger transcription factor deregulated in various cancers, has been implicated in Wnt signaling regulation through its Xenopus ortholog; however, its role in human CRC remains unclear. In this study, we investigated the expression and function of SALL2 in CRC. Immunohistochemical analysis revealed that SALL2 is present in the epithelium and stroma of normal colon tissue but is significantly downregulated in adenomas, carcinomas, and CRC cell lines. Reduced SALL2 expression was associated with elevated levels of active β-catenin and poorer overall patient survival. Functional assays demonstrated that SALL2 transcriptionally activates AXIN2, a key negative regulator of the Wnt/β-catenin pathway. Chromatin immunoprecipitation and promoter-reporter assays confirmed SALL2 binding to the AXIN2 proximal promoter and enhanced promoter activity. Furthermore, SALL2 expression potentiated the pro-apoptotic effects of the Wnt pathway inhibitor XAV939 in CRC cells, suggesting a role in sensitizing cells to Wnt-targeted therapies. Collectively, these findings identify SALL2 as a negative regulator of Wnt/β-catenin signaling and support its potential as a prognostic biomarker and therapeutic target in colorectal cancer. Full article

Ferroptosis suppressor protein 1 (FSP1) has emerged as a critical regulator of ferroptosis, an iron-dependent form of programmed cell death with significant therapeutic potential in cancer treatment. Despite rapidly expanding research, current knowledge on FSP1 remains fragmented across various tumor types and experimental contexts. The aim of this review is to systematically integrate the latest evidence regarding the molecular structure, biological functions, and regulatory mechanisms controlling FSP1 expression, emphasizing its involvement in tumor progression and resistance to therapy. Readers can expect comprehensive coverage of FSP1’s structural characteristics, enzymatic roles, transcriptional and post-transcriptional regulation, and its pathological significance in hepatocellular carcinoma, colorectal cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, and leukemia. We further evaluate emerging therapeutic strategies targeting FSP1 aimed at overcoming resistance and improving clinical outcomes. Relevant studies were systematically identified by searching PubMed, Web of Science, and Embase databases, focusing particularly on the recent and impactful literature to guide future research directions. Full article

Ferroptosis is an iron-dependent form of regulated cell death marked by lipid peroxidation in polyunsaturated phospholipids. In head and neck cancer (HNC), where resistance to chemotherapy and immunotherapy is common, ferroptosis offers a mechanistically distinct strategy to overcome therapeutic failure. However, cancer cells often evade ferroptosis via activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant and iron-regulatory genes. HNC remains therapeutically challenging due to therapy resistance driven by redox adaptation. This review highlights the ferroptosis pathway—a form of regulated necrosis driven by iron and lipid peroxidation—and its regulation by Nrf2, a master antioxidant transcription factor. We detail how Nrf2 contributes to ferroptosis evasion in HNC and summarize emerging preclinical studies targeting this axis. The review aims to synthesize molecular insights and propose therapeutic perspectives for overcoming resistance in HNC by modulating Nrf2–ferroptosis signaling. We conducted a structured narrative review of the literature using PubMed databases. Relevant studies from 2015 to 2025 focusing on ferroptosis, Nrf2 signaling, and head and neck cancer were selected based on their experimental design, novelty, and relevance to clinical resistance mechanisms. In HNC, Nrf2 mediates resistance through transcriptional upregulation of GPX4 and SLC7A11, epigenetic stabilization by PRMT4 and ALKBH5, and activation by FGF5 and platelet-derived extracellular vesicles. Epstein–Barr virus (EBV) infection also enhances Nrf2 signaling in nasopharyngeal carcinoma. More recently, loss-of-function KEAP1 mutations have been linked to persistent Nrf2 activation and upregulation of NQO1, which confer resistance to both ferroptosis and immune checkpoint therapy. Targeting NQO1 in KEAP1-deficient models restores ferroptosis and reactivates antitumor immunity. Additionally, the natural alkaloid trigonelline has shown promise in reversing Nrf2-mediated ferroptosis resistance in cisplatin-refractory tumors. Pharmacologic agents such as auranofin, fucoxanthin, carnosic acid, and disulfiram/copper complexes have demonstrated efficacy in sensitizing HNC to ferroptosis by disrupting the Nrf2 axis. This review summarizes emerging mechanisms of ferroptosis evasion and highlights therapeutic strategies targeting the Nrf2–ferroptosis network. Integrating ferroptosis inducers with immune and chemotherapeutic approaches may provide new opportunities for overcoming resistance in head and neck malignancies. Full article

Disruption of the Hippo pathway leads to activation of the YAP/TAZ transcriptional program which promotes tumor initiation, progression and metastasis in diverse cancers. Aggressive triple-negative breast cancers (TNBC) lack an effective therapy; thus, inactivating YAP and TAZ has emerged as an attractive approach and a new treatment modality. Thus, we performed two complementary high-throughput RNAi-based kinome screens to uncover cancer-associated activators of YAP/TAZ in two TNBC cell lines, MDA-MB231 and MDA-MB468. Integrated analysis that combined a YAP/TAZ localization screen with a TEAD-luciferase reporter screen, identified novel regulators including BRSK1, STK32C and STK40. The AMPK family members NUAKs, MARKs and SIKs are known to inhibit the Hippo kinase cassette; here, we uncover BRSK1, another AMPK family member as a regulator of YAP/TAZ. We also reveal that two poorly studied kinases, STK32C, a member of the AGC family, and STK40, a pseudokinase, can also inhibit the activity of YAP/TAZ. Thus, our studies expand the repertoire of known AMPK family members and reveal two new kinases that modulate the Hippo pathway and may play a role in YAP/TAZ driven breast cancers. Further analysis of other screen hits may similarly uncover new regulators that could be targeted for therapeutic interventions. Full article

Respiratory syncytial virus (RSV) remains a leading cause of acute lower respiratory tract infections globally, particularly affecting infants, older adults, and immunocompromised individuals. While recent advances in prophylaxis, such as long-acting monoclonal antibodies and maternal immunization, offer promise for prevention, therapeutic options for active infection remain limited. Severe RSV disease is often driven not solely by viral replication but by dysregulated host immune responses, including excessive cytokine production, T helper type 2 (Th2) and T helper type 17 (Th17) cell polarization, and impaired interferon signaling. RSV has evolved sophisticated immune evasion strategies, such as inhibition of dendritic cell maturation, degradation of signal transducer and activator of transcription 2 (STAT2) via nonstructural proteins 1 and 2 (NS1/NS2), and interference with pattern recognition receptor signaling, particularly Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors. These mechanisms result in attenuated innate immune responses and defective adaptive immunity, contributing to viral persistence, immunopathology, and recurrent infections. Moreover, age-dependent vulnerabilities, such as immune immaturity in infants and immunosenescence in older adults, exacerbate disease severity. Excessive immune activation leads to bronchiolitis, airway remodeling, and long-term sequelae including wheezing and asthma. Emerging immunomodulatory therapies aim to restore immune balance, targeting cytokines (e.g., interleukin-6 [IL-6], interleukin-1 beta [IL-1β]), the Janus kinase–signal transducer and activator of the transcription (JAK-STAT) pathway, or inflammasome activity. Host-directed therapies and direct-acting antivirals are also under investigation. A better understanding of RSV–host immune interactions is critical for optimizing therapeutic strategies and designing effective vaccines. This review synthesizes current knowledge on RSV immunopathogenesis and highlights immunomodulation as a promising frontier for therapeutic intervention. Full article

High-risk neuroblastoma remains a major clinical challenge, with a five-year survival rate below 50% despite intensive multimodal therapies. MYCN amplification, a hallmark of high-risk disease, drives an aggressive transcriptional program that maintains undifferentiated and proliferative states in neuroblastoma cells. Given its central role in oncogenic transcription, MYCN represents an attractive therapeutic target; however, its undruggable nature has prompted efforts to identify upstream regulators or cofactors that sustain MYCN expression and oncogenic function. In this study, we investigate the role of the cohesin loading factor NIPBL in supporting the MYCN-driven transcriptional program. We demonstrate that elevated NIPBL expression is associated with undifferentiated, proliferative neuroblastoma cell states and poor clinical outcomes in neuroblastoma patients. Functionally, NIPBL depletion reduces MYCN mRNA and protein levels and induces widespread transcriptional reprogramming consistent with neuronal differentiation. These transcriptional changes are accompanied by decreased neuroblastoma cell proliferation and increased neuronal differentiation, reflecting impaired regulation of MYCN target genes upon NIPBL loss. Collectively, we have established a mechanistic link between NIPBL and the MYCN-driven transcriptome, highlighting NIPBL as a potential therapeutic vulnerability to promote differentiation in high-risk neuroblastoma. Full article

Cell-based therapies emerge as potential treatment options for various debilitating diseases. Preclinical research and clinical studies involving cells increased exponentially in the past decade. In addition to cell-based approaches, the use of extracellular vesicles (EVs), which are released by nearly all cell types, emerged as a promising cell-free alternative. Those approaches are also being explored in the field of ophthalmology. Several clinical trials involving EVs are underway to develop potential treatments for advanced ocular surface diseases, including corneal disorders, injuries, and dry eye disease. The cargo carried by EVs has been shown to include a diverse array of functional molecules such as transcription factors, cytokines, growth factors, mRNA, tRNA, rRNA, miRNA, and fragments of dsDNA. While the molecular composition of EVs is already well characterised, the specific activity of these molecules upon delivery to recipient cells remains poorly understood. In this review, we summarise recent studies investigating the bioactive molecules within EVs shown to influence or modulate cellular activity on the ocular surface. Among these, various miRNAs have most commonly been identified as therapeutic agents targeting distinct molecular pathways. The EVs studied were predominantly derived from various mesenchymal stem cells. Full article

Runt-related transcription factor-2 (RUNX2) is an integral player in osteogenesis and is highly expressed in osteosarcoma. Emerging evidence suggests that aberrant RUNX2 expression is a key factor in osteosarcoma oncogenesis. Patients with advanced stages of osteosarcoma overexpressing RUNX2 are more likely to have high tumour grades, metastasis, and lower overall or progression-free survival rates. Thus, RUNX2 is considered a potential candidate for targeted therapy of osteosarcoma. Hypoxia-inducible factor-1α (HIF-1α) is a key transcription factor involved in the regulation of cellular reprogramming in response to hypoxia. Overexpression of HIF-1α decreases overall survival, disease-free survival, and chemotherapy response and promotes tumour stage and metastasis. Hence, our review focused on highlighting the intricate network between RUNX2 and HIF-1α, which support each other or may work synergistically to develop resistance to therapy and osteosarcoma progression. An in-depth understanding of these two important tumour progression markers is required. Therefore, this review focuses on the role of RUNX2 and HIF-1α in the alteration of the tumour microenvironment, which further promotes angiogenesis, metastasis, and resistance to therapy in osteosarcoma. Full article

Epidermolysis Bullosa (EB) comprises a group of inherited blistering disorders caused by pathogenic variants in genes essential for skin and mucosal integrity. Nonsense mutations, which generate premature termination codons (PTCs), result in reduced or absent protein expression and contribute to severe disease phenotypes in EB. Readthrough therapies, which may continue translation past PTCs to restore full-length functional proteins, have emerged as promising approaches. This review summarizes findings from preclinical studies investigating readthrough therapies in EB models, clinical studies demonstrating efficacy in EB patients, and emerging readthrough agents with potential application to EB. Preclinical and clinical studies with gentamicin have demonstrated restored type VII collagen and laminin-332 expression, leading to measurable clinical improvements. Parallel development of novel compounds—including aminoglycoside analogs (e.g., ELX-02), translation termination factor degraders (e.g., CC-90009, SRI-41315, SJ6986), tRNA post-transcriptional inhibitors (e.g., 2,6-diaminopurine, NV848), and nucleoside analogs (e.g., clitocine)—has expanded the therapeutic pipeline. Although challenges remain regarding toxicity, codon specificity, and variable protein restoration thresholds, continued advances in molecular targeting and combination therapies offer the potential to establish readthrough therapies as localized or systemic treatments addressing both cutaneous and extracutaneous disease manifestations in EB. Full article

Background/Objectives: The breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene whose mutations are associated with increased susceptibility to develop breast or ovarian cancer. BRCA1 mainly exerts its protective effects through DNA double-strand break repair. Although not itself a transcriptional factor, BRCA1, through its multiple protein interaction domains, exerts transcriptional coregulation. In addition, BRCA1 expression alters cellular metabolism including inhibition of de novo fatty acid synthesis, changes in cellular bioenergetics, and activation of antioxidant defenses. Some of these actions may contribute to its global oncosuppressive effects. However, the breadth of metabolic pathways reprogrammed by BRCA1 is not fully elucidated. Methods: Breast cancer cells expressing BRCA1 were investigated by multiplatform metabolomics, metabolism-related transcriptomics, and joint metabolomics/transcriptomics data processing techniques, namely two-way orthogonal partial least squares and pathway analysis. Results: Joint analyses revealed the most important metabolites, genes, and pathways of metabolic reprogramming in BRCA1-expressing breast cancer cells. The breadth of metabolic reprogramming included fatty acid synthesis, bioenergetics, HIF-1 signaling pathway, antioxidation, nucleic acid synthesis, and other pathways. Among them, rewiring of glycerophospholipid (including phosphatidylcholine, -serine and -inositol) metabolism and increased arginine metabolism have not been reported yet. Conclusions: Rewired glycerophospholipid and arginine metabolism were identified as components of BRCA1-induced metabolic reprogramming in breast cancer cells. The study helps to identify metabolites that are candidate biomarkers of the BRCA1 genotype and metabolic pathways that can be exploited in targeted therapies. Full article

CD26 (dipeptidyl peptidase-4) is a marker of colorectal cancer stem cells with high metastatic potential and resistance to therapy. Although CD26 expression is known to be associated with tumor progression, its functional involvement in epithelial-mesenchymal transition (EMT) and metastasis remains to be fully elucidated. In this study, we aimed to investigate the effects of a monoclonal anti-CD26 antibody on EMT-related phenotypes and metastatic behavior in colorectal cancer cells. We evaluated changes in EMT markers by quantitative PCR and Western blotting, assessed cell motility and invasion using scratch wound-healing and Transwell assays, and examined metastatic potential in vivo using a splenic injection mouse model. Treatment with the anti-CD26 antibody significantly increased the expression of the epithelial marker E-cadherin and reduced levels of EMT-inducing transcription factors, including ZEB1, Twist1, and Snail1, at the mRNA and protein levels. Functional assays revealed that the antibody markedly inhibited cell migration and invasion in vitro without exerting cytotoxic effects. Furthermore, systemic administration of the anti-CD26 antibody significantly suppressed the formation of liver metastases in vivo. These findings suggest that CD26 may contribute to the regulation of EMT and metastatic behavior in colorectal cancer. Our data highlight the potential therapeutic utility of CD26-targeted antibody therapy for suppressing EMT-associated phenotypes and metastatic progression. Full article

Background: Immune checkpoint inhibitor therapy in patients with lung cancer and metastatic melanoma is associated with exacerbation of autoimmune-related diseases. The efficacy of treatment targeting the programmed cell death receptor-1 (PD-1) checkpoint relies upon a feedback loop between interferon gamma (IFN-γ) and the interleukin-12 isoform, IL-12p40. Paradoxically, both cytokines and the anti-PD-1 antibody worsen psoriasis. We previously reported an immunomodulating peptide, designated IK14004, that inhibits progression of Lewis lung cancer in mice yet uncouples IFN-γ from IL-12p40 production in human immune cells. Methods: Immune cells obtained from healthy donors were exposed to IK14004 in vitro to further characterise the signalling pathways affected by this peptide. Using C57BL/6 immunocompetent mice, the effect of IK14004 was tested in models of lung melanoma and psoriatic skin. Results: Differential effects of IK14004 on the expression of IFN-α/β, the interleukin-15 (IL-15) receptor and signal transducers and activators of transcription were consistent with immune responses relevant to both cancer surveillance and immune tolerance. Moreover, both melanoma and psoriasis were inhibited by the peptide. Conclusions: Taken together, these findings suggest mechanisms underlying immune homeostasis that could be exploited in the setting of cancer and autoimmune pathologies. Peptide administered together with checkpoint blockers in relevant models of autoimmunity and cancer may offer an opportunity to gain further insight into how immune tolerance can be retained in patients receiving cancer immunotherapy. Full article

Background: Accumulating evidence indicates that SARS-CoV-2 infection results in long-term multiorgan complications, with the kidney being a primary target. This study aimed to characterize the long-term transcriptomic changes in the kidney following coronavirus infection using a murine model of MHV-1-induced SARS-like illness and to evaluate the therapeutic efficacy of SPIKENET (SPK). Methods: A/J mice were infected with MHV-1. Renal tissues were collected and subjected to immunofluorescence analysis and Next Generation RNA Sequencing to identify differentially expressed genes associated with acute and chronic infection. Bioinformatic analyses, including PCA, volcano plots, and GO/KEGG pathway enrichment, were performed. A separate cohort received SPK treatment, and comparative transcriptomic profiling was conducted. Gene expression profile was further confirmed using real-time PCR. Results: Acute infection showed the upregulation of genes involved in inflammation and fibrosis. Long-term MHV-1 infection led to the sustained upregulation of genes involved in muscle regeneration, cytoskeletal remodeling, and fibrotic responses. Notably, both expression and variability of SLC22 and SLC22A8, key proximal tubule transporters, were reduced, suggesting a loss of segment-specific identity. Further, SLC12A1, a critical regulator of sodium reabsorption and blood pressure, was downregulated and is associated with the onset of polyuria and hydronephrosis. SLC transporters exhibited expression patterns consistent with tubular dysfunction and inflammation. These findings suggest aberrant activation of myogenic pathways and structural proteins in renal tissues, consistent with a pro-fibrotic phenotype. In contrast, SPK treatment reversed the expression of most genes, thereby restoring the gene profiles to those observed in control mice. Conclusions: MHV-1-induced long COVID is associated with persistent transcriptional reprogramming in the kidney, indicative of chronic inflammation, cytoskeletal dysregulation, and fibrogenesis. SPK demonstrates robust therapeutic potential by normalizing these molecular signatures and preventing long-term renal damage. These findings underscore the relevance of the MHV-1 model and support further investigation of SPK as a candidate therapy for COVID-19-associated renal sequelae. Full article

Melanoma is a highly aggressive skin cancer with limited therapeutic response. Targeting intracellular signaling pathways and promoting tumor cell differentiation are promising therapeutic strategies. Pentoxifylline (PTX) and norcantharidin (NCTD) have demonstrated antitumor properties, but their combined mechanisms of action in melanoma remain poorly understood. The effects of PTX (30 and 60 mg/kg) and NCTD (0.75 and 3 mg/kg), administered alone or in combination, in a DBA/2J murine B16-F1 melanoma model via intraperitoneal and intratumoral (IT) routes were evaluated. Tumor growth was monitored, and molecular analyses included RNA sequencing and immunofluorescence quantification of PI3K, AKT1, mTOR, ERBB2, BRAF, and MITF protein levels, and molecular docking simulations were performed. In the final stage of the experiment, combination therapy significantly reduced tumor volume compared to monotherapies, with the relative tumor volume decreasing from 18.1 ± 1.2 (SD) in the IT Control group to 0.6 ± 0.1 (SD) in the IT combination-treated group (n = 6 per group; p < 0.001). RNA-seq revealed over 3000 differentially expressed genes in intratumoral treatments, with enrichment in pathways related to oxidative stress, immune response, and translation regulation (KEGG and Reactome analyses). Minimal transcript-level changes were observed for BRAF and PI3K/AKT/mTOR genes; however, immunofluorescence showed reduced total and phosphorylated levels of PI3K, AKT1, mTOR, BRAF, and ERBB2. MITF protein levels and pigmentation increased, especially in PTX-treated groups, indicating enhanced melanocytic differentiation. Docking analyses predicted direct binding of both drugs to PI3K, AKT1, mTOR, and BRAF, with affinities ranging from −5.7 to −7.4 kcal/mol. The combination of PTX and NCTD suppresses melanoma progression through dual mechanisms: inhibition of PI3K/AKT/mTOR signaling and promotion of tumor cell differentiation. Full article

MicroRNA-211 (miR-211) is a versatile regulatory molecule that plays critical roles in cellular homeostasis and disease progression through the post-transcriptional regulation of gene expression. This review comprehensively examines miR-211’s multifaceted functions across various biological systems, highlighting its context-dependent activity as both a tumor suppressor and oncogene. In physiological contexts, miR-211 regulates cell cycle progression, metabolism, and differentiation through the modulation of key signaling pathways, including TGF-β/SMAD and PI3K/AKT. miR-211 participates in retinal development, bone physiology, and protection against renal ischemia–reperfusion injury. In pathological conditions, miR-211 expression is altered in various diseases, particularly cancer, where it may be a useful diagnostic and prognostic biomarker. Its stability in serum and differential expression in various cancer types make it a promising candidate for non-invasive diagnostics. The review also explores miR-211’s therapeutic potential, discussing both challenges and opportunities in developing miRNA-based treatments. Understanding miR-211’s complex regulatory interactions and context-dependent functions is crucial for advancing its clinical applications for diagnosis, prognosis, and targeted therapy in multiple diseases. Full article