Search Results (3,811)

Cardio-renal metabolic (CRM) syndrome, characterized by insulin resistance and dyslipidemia, disrupts renal insulin signaling, enhances oxidative stress, and activates inflammasome pathways, ultimately promoting renal fibrosis and kidney dysfunction. Aberrant renal gluconeogenesis has emerged as a critical contributor to tubular injury under cardiometabolic stress; however, its mechanistic linkage to inflammatory and fibrotic remodeling remains incompletely defined. In this study, ApoE^−/− mice subjected to streptozotocin administration and a high-fat diet developed pronounced cardiometabolic dysfunction, accompanied by elevated blood urea nitrogen, creatinine, uric acid, and glycated hemoglobin levels, as well as severe renal histopathological alterations. N-Acetylcysteine (NAC) supplementation significantly improved metabolic abnormalities and attenuated tubular dilation, glomerular hypertrophy, and mesangial expansion. Mechanistically, NAC suppressed renal gluconeogenesis by downregulating glucose-6-phosphatase and phosphoenolpyruvate carboxykinase expression and mitigated epithelial–mesenchymal transition by restoring E-cadherin and reducing vimentin expression, thereby limiting fibrotic remodeling. Consistent with in vivo findings, NAC reduced reactive oxygen species production, restored PI3K/Akt-dependent insulin signaling, and inhibited inflammasome activation in NRK-52E renal tubular cells exposed to high glucose and oleic acid, resulting in attenuation of inflammatory signaling and gluconeogenic activity. Collectively, these results demonstrate that NAC mitigates cardiometabolic stress-induced renal injury by modulating inflammasome activation and gluconeogenic reprogramming, highlighting its potential as a mechanistic modulator of renal fibrosis under CRM conditions. Full article

Background/objective: Approximately 90% of breast cancer-related deaths result from recurrence and metastasis. Emerging evidence indicates that tumor recurrence, invasion, and metastatic spread are strongly influenced by both the tumor microenvironment (TME) and the metastatic niche. M2 macrophages promote immune suppression, inhibit inflammation, and facilitate epithelial-to-mesenchymal transition, invasion, neovascularization, and tumor progression. These phenomena are particularly pronounced in triple-negative breast cancer (TNBC). The objectives of this study were to develop engineered exosomes to selectively deplete CD206+ M2 macrophages from the TME to delay the growth of primary tumors and distal metastasis and enhance overall survival. Methods: Engineered exosomes were developed using our invented platform to selectively target and deplete alternatively activated CD206+ M2 macrophages in primary and metastatic TMEs via antibody-dependent cell-mediated cytotoxicity (ADCC). The engineered exosomes were characterized for size, zeta potential, and successful incorporation of targeting peptides and proteins. Whole-body and tumor-specific biodistribution were assessed. In vitro and in vivo experiments were conducted to evaluate targeting specificity. Toxicity and immunogenicity were examined in immunocompetent animal models. Two treatment paradigms were employed. Results: Engineered exosomes containing M2 macrophage-targeting peptides and Fc-mIgG2b were successfully made, and no significant size difference was observed between the engineered and control exosomes. Both in vitro and in vivo studies confirmed the specificity of the engineered exosomes. Biodistribution studies showed no significant uptake or retention by the resident macrophages in the lung and liver. No significant immune activation, based on cytokine profiling, or organ-specific toxicity was observed in immunocompetent models. Flow cytometry studies using splenocytes showed significant depletion of M2 macrophages following treatments with engineered exosomes; however, no effect on the distribution of T cells was observed. M2-targeting engineered exosomes significantly delayed the post-resection recurrence and metastasis of tumors, and improved animal survival. Conclusions: These findings support the potential of precision exosome-based strategies for enhancing therapeutic outcomes in breast cancer. Full article

Hypoxia is a hallmark feature of solid tumors and is increasingly recognized as an important factor in tumor progression, aggressiveness, and therapeutic resistance. In the tumor microenvironment, hypoxia is associated with genetic instability, abnormal angiogenesis, metabolic reprogramming, and crosstalk with oncogenic signaling pathways, thereby potentially enhancing tumor invasiveness and metastatic potential. Furthermore, hypoxia may impair the sensitivity of tumor cells to conventional therapies and contribute to treatment resistance. This article reviews current evidence on the role of hypoxia in thyroid cancer, focusing on its biological effects, clinical implications, and therapeutic relevance. Available studies suggest that hypoxia may affect thyroid cancer progression and treatment tolerance by modulating hypoxia-inducible factor (HIF) signaling, epithelial–mesenchymal transition (EMT), angiogenesis, metabolic adaptation, cancer stem-like properties, extracellular matrix remodeling, and stress-adaptive responses. However, the strength of evidence varies across these pathways, and many hypoxia-targeted strategies remain under preclinical investigation. Approaches such as HIF inhibition, redifferentiation therapy, and vascular modulation may offer potential therapeutic directions for advanced and refractory thyroid cancer. Given the marked heterogeneity of thyroid cancer, further thyroid cancer-specific studies are needed to clarify the prognostic and therapeutic significance of hypoxia. Full article

Esophageal squamous cell carcinoma (ESCC) progression involves dynamic cellular state transitions and tumor microenvironment remodeling, accompanied by extensive transcriptional regulation reprogramming. Here, we systematically mapped the TF-mediated regulatory landscape underlying ESCC progression at single-cell resolution by integrating stage-specific ESCC single-cell transcriptomic datasets comprising over 200,000 cells with TF–target interaction networks. Using a random walk algorithm combined with hypergeometric testing, we identified malignant progression-associated TFs (mpTFs) across multiple cell types and disease stages. Our analysis revealed extensive stage-dependent regulatory remodeling during ESCC progression. TCF4 was identified as an early-stage regulator associated with epithelial–mesenchymal transition activation and malignant invasive phenotypes. In immune lineages, BATF and IRF4 exhibited trajectory-associated activation during CD4⁺ T-cell differentiation and CD8⁺ T-cell exhaustion, suggesting critical roles in immunosuppressive T-cell state transitions. Additionally, mpTF-mediated remodeling of M2 macrophage subpopulations contributed to immunosuppressive tumor microenvironment formation during advanced ESCC progression. We further identified prognosis-associated cell-type-specific and shared mpTFs, including TFAP2C, which was associated with stabilized fibroblast and monocyte functional states and a less aggressive tumor microenvironment phenotype. Collectively, this study provides a comprehensive single-cell atlas of TF-mediated regulatory programs during ESCC progression and offers potential therapeutic targets for precision oncology. Full article

Background/Objectives: Over the past two decades, non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, reshaping the classical view of the genome as predominantly protein-coding. Among them, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play central roles in controlling gene expression at multiple levels. Rather than acting independently, these molecules form complex and interconnected regulatory networks, and their interplay appears particularly relevant in cancer. This review aims to examine the mechanisms underlying miRNA-lncRNA cross-regulation and to explore their functional and clinical implications in tumor biology. Methods: We performed a comprehensive analysis of the current literature focusing on studies investigating miRNA-lncRNA interactions in cancer. Particular attention was given to mechanistic insights, including the competing endogenous RNA (ceRNA) hypothesis, as well as alternative regulatory models involving direct RNA interactions and chromatin-associated processes. Results: miRNA-lncRNA interactions have been associated with cancer progression and therapeutic response across different tumor types, although their mechanisms are highly context-dependent. While the ceRNA hypothesis, based on competition for shared microRNA response elements (MREs), provides a useful framework, it does not fully explain all observed phenomena. Evidence shows that miRNAs can directly regulate lncRNA stability, whereas lncRNAs can influence miRNA biogenesis. Additionally, chromatin-related mechanisms suggest that these interactions extend beyond post-transcriptional regulation. These RNA networks intersect with major oncogenic pathways, including PI3K/AKT/mTOR signaling, hypoxia responses, and epigenetic regulators such as EZH2, thereby affecting key cancer processes such as proliferation, epithelial–mesenchymal transition (EMT), and metabolic reprogramming. From a clinical perspective, the stability of ncRNAs in biological fluids highlights their potential as biomarkers. Combined miRNA-lncRNA signatures may improve diagnostic and prognostic accuracy compared to single markers, although further validation is required. Therapeutic strategies targeting ncRNA networks, such as miRNA mimics, antagomiRs, and lncRNA-directed approaches, are under investigation; however, challenges related to delivery, specificity, and toxicity remain. Conclusions: miRNA-lncRNA cross-regulation represents a complex and multifaceted layer of gene regulation in cancer. A deeper understanding of these interactions could support the development of more accurate diagnostic tools and more effective RNA-based therapeutic strategies, although significant technical and biological challenges still need to be addressed. Full article

The phenotypic plasticity of epithelial cells along the epithelial–mesenchymal (E-M) axis, or epithelial–mesenchymal transition (EMT), is a critical aspect of tumour progression and therapeutic resistance. During EMT, epithelial cells gradually acquire mesenchymal traits, facilitating vital functions in embryogenesis, wound healing, fibrosis, and tumour metastasis. This review article investigates the potential interplay between hyperglycaemia-induced metabolic stress and EMT in the context of therapeutic resistance. The study examines a complex, multifaceted network of molecular mechanisms regulating EMT, including specialised transcription factors and signalling pathways as well as growth factors, integrins, and matrix metalloproteinases in various epithelial carcinomas. Emerging findings have demonstrated the existence of EMT hybrid states along the continuum, possessing heightened metastatic potential and distinctive metabolic signatures that play critical roles in the development of therapeutic resistance in cancer cells. Hyperglycaemia has been particularly highlighted for its potential to promote EMT-driven therapeutic resistance through various interconnected mechanisms. Elevated glucose levels induce the increased production of reactive oxygen species (ROS), activation of EMT-promoting transcription factors, and a metabolic shift towards glycolysis. This hyperglycaemic stress involves upregulation of glucose transporters and glycolytic enzymes, creating feed-forward loops that support drug efflux mechanisms and help maintain the mesenchymal phenotype. Clinical data also indicate that hyperglycaemia in OSCC patients is associated with more advanced tumour stages, more extended hospital stays, less effective treatments, and higher rates of local recurrence and distant metastasis. Overall, these insights reveal a deleterious feed-forward loop in which hyperglycaemia promotes EMT-driven therapeutic resistance, with the strongest clinical evidence in oral squamous cell carcinoma (OSCC) and supportive data from pancreatic and breast cancers. Although glycaemic control represents a promising low-risk adjunctive approach, its clinical benefit remains to be validated in prospective interventional studies. Full article

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive malignancy, characterized by rapid progression, early metastasis, and resistance to conventional therapies. Increasing evidence indicates that the behavior of residual tumor cells is strongly influenced by physicochemical properties of their microenvironment. Surface engineering strategies using nanostructured materials may therefore represent a complementary approach to modulating cancer cell activity. In this study, we investigated whether a graphene oxide (GO) aerosol nanofilm modifies the biological behavior of PDAC cells in vitro. The GO aerosol (4.5 g/L) was characterized using STEM, DLS, zeta potential measurements, LIBS, EDX, and FTIR spectroscopy. Ultrastructural analysis revealed thin, wrinkled GO sheets forming partially overlapping lamellar structures, while physicochemical characterization confirmed a highly oxidized stable nanomaterial. Human PDAC cell lines (BxPC-3 and AsPC-1) were cultured on GO-modified substrates to assess morphology (SEM), metabolic activity (XTT assay), migratory capacity (wound healing assay over 72 h), and expression of genes related to proliferation and epithelial–mesenchymal transition (EMT) by RT-qPCR. GO nanofilm significantly reduced cell viability and inhibited migration in both cell lines. SEM analysis demonstrated shortened cytoplasmic projections and altered membrane integrity. Gene expression profiling revealed cell line-dependent transcriptional responses, including modulation of components of the PI3K/AKT/mTOR pathway and EMT-associated markers. Collectively, our findings demonstrate that GO aerosol nanofilm alters PDAC cell morphology, viability, and migratory behavior in vitro. Surface-mediated modulation of tumor cell activity may represent a promising adjunct strategy for limiting residual cancer cell survival and metastatic potential. Full article

Colorectal cancer (CRC) progression is driven by dysregulated signaling networks that promote proliferation and metastasis. While SLC25A5 is a well-characterized mitochondrial ADP/ATP transporter, its potential non-canonical roles in cancer remain unclear. This study investigated whether SLC25A5 exerts tumor-suppressive functions in CRC. Using transcriptomic datasets and clinical cohorts, we found that SLC25A5 is significantly downregulated in CRC tissues, and low expression is associated with poor patient survival. Restoration of SLC25A5 suppressed CRC cell proliferation, epithelial–mesenchymal transition (EMT), and metastasis in vitro and in vivo. Mechanistically, co-immunoprecipitation and protein stability assays suggested an association between SLC25A5 and EIF3A and indicated that SLC25A5 may promote EIF3A destabilization through the ubiquitin–proteasome pathway without altering its mRNA levels. Subcellular fractionation further suggested the presence of a cytoplasmic pool of SLC25A5, providing a potential basis for this interaction. Rescue experiments showed that EIF3A overexpression partially reversed the tumor-suppressive effects of SLC25A5. In addition, SLC25A5 expression was associated with reduced PI3K/AKT signaling activity, and pharmacological activation of AKT partially restored invasive phenotypes. Collectively, these findings suggest an SLC25A5–EIF3A–PI3K/AKT regulatory axis and reveal a potential non-canonical role for this mitochondrial carrier in tumor progression. This study provides insight into how mitochondrial proteins may influence cytoplasmic signaling pathways in cancer. Full article

Background/Objectives: Breast cancer remains a leading cause of cancer-related mortality worldwide, primarily due to the systemic toxicity and drug resistance associated with conventional doxorubicin (DOX) therapy. To overcome these limitations, we developed and optimized a novel cationic-ionizable lipid nanoparticle platform, QTPlus, for the co-delivery of DOX and siRNA targeting fibroblast growth factor 2 (siFGF2). Methods: The study evaluated the physicochemical properties, cellular uptake, gene regulation, apoptosis induction, and in vivo antitumor efficacy and safety of QTPlus-DOX-siFGF2 in breast cancer models. Results: QTPlus nanoparticles based on the A-066 formulation achieved uniform particle size (~218 nm), low polydispersity (PDI 0.164–0.214), and high encapsulation efficiencies (DOX: 49.56 ± 0.15%; siFGF2: 77.66 ± 1.30%). In vitro release studies revealed a robust pH-responsive profile, characterized by sustained stability at physiological pH (7.4) and rapid burst release at acidic endosomal pH (5.5). In MCF-7 and MDA-MB-231 cells, QTPlus-DOX-siFGF2 significantly enhanced cellular uptake, downregulated FGF2 (0.639-fold) and VIM (0.373-fold), and upregulated CASP3 (3.364-fold in siFGF2 group) and BRCA1 (4.041-fold). Flow cytometry showed markedly increased apoptosis (78.5% vs. 42.65% for QTPlus-DOX alone). In the MDA-MB-231 xenograft model, QTPlus-DOX-siFGF2 achieved 65.87% tumor growth inhibition with stable body weights and favorable trends in cardiotoxic biomarkers. Conclusions: These results demonstrate that QTPlus enables effective co-delivery of DOX and siFGF2, producing synergistic antitumor effects through apoptosis induction and suppression of epithelial–mesenchymal transition while improving the safety profile. QTPlus-DOX-siFGF2 represents a promising nanotherapeutic strategy for breast cancer warranting further clinical development. Full article

Metastasis is a primary driver of poor outcomes in clear cell renal cell carcinoma (ccRCC), yet the role of Aquaporin-9 (AQP9) in this process remains unclear. This study aimed to investigate the function, clinical significance, and therapeutic potential of AQP9 in ccRCC. AQP9 expression was analyzed using TCGA data and validated in human tissues and cell lines via Western blot. Functional assays assessed malignant behaviors, while bioinformatics and rescue experiments explored the involvement of the JAK/STAT pathway and epithelial–mesenchymal transition (EMT). Virtual screening, molecular docking, and cellular thermal shift assays (CETSAs) were employed to identify Tedizolid as a potential AQP9 inhibitor, followed by functional validation in vitro and in a xenograft model. AQP9 was significantly upregulated in ccRCC and associated with poor prognosis. The knockdown of AQP9 suppressed proliferation, migration, invasion, and EMT, whereas its overexpression promoted these effects by activating the JAK/STAT pathway. Tedizolid bound directly to AQP9, inhibited cell viability, reversed AQP9-induced malignant phenotypes, and suppressed JAK/STAT signaling both in vitro and in vivo. In conclusion, AQP9 promotes ccRCC metastasis through the JAK/STAT-EMT axis and represents a potential prognostic biomarker and therapeutic target. Tedizolid, identified as a novel AQP9 inhibitor, offers a promising repurposed strategy for ccRCC treatment. Full article

Prostate cancer (PCa) management has evolved with biomarker-driven strategies, yet biological heterogeneity, adaptive resistance, and an immunosuppressive microenvironment limit their efficacy. Galectin-3 (Gal-3) has emerged as a central node in PCa pathobiology, influencing tumor survival, metastasis, and immune escape. This review comprehensively reviews Gal-3’s dual role as a biomarker and a therapeutic target. We first delineate the limitations of the current diagnostic, prognostic, and predictive biomarkers in PCa, establishing the unmet need. We then elucidate the multifunctional biology of Gal-3, detailing its compartment-specific roles in anti-apoptosis, angiogenesis, epithelial-to-mesenchymal transition, and, notably, its function as a master regulator of immunosuppression. The interaction between Gal-3 and prostate-specific antigen (PSA) is explored as a key regulatory interface. Furthermore, we catalog and analyze emerging Gal-3-targeted therapies, emphasizing their rationale for combination with immune checkpoint blockade to reverse therapeutic resistance. Finally, we outline a translational roadmap, advocating for standardized Gal-3 biomarker assays and biomarker-enriched clinical trials. Integrating Gal-3 into the PCa precision medicine toolkit offers a novel strategy to address heterogeneity and improve therapeutic durability. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with limited effective therapies. Dihydroartemisinin (DHA), a derivative of artemisinin, exhibits potent antitumor activity, but its molecular mechanisms in HCC are unclear. Here, we identified kinesin family member 11 (KIF11) as a critical effector of DHA. Methods: Bioinformatic analyses revealed that KIF11 is significantly upregulated in HCC and associated with poor prognosis, and gene expression profiling suggested its oncogenic role via the PI3K/Akt pathway. Functional studies demonstrated that DHA inhibits HCC cell proliferation, migration, invasion, and colony formation, while inducing apoptosis. Xenograft models of nude mice were established for validation. Results: DHA downregulated KIF11 and epithelial–mesenchymal transition markers, whereas KIF11 overexpression attenuated DHA’s inhibitory effects; the inhibition of PI3K restored DHA sensitivity in KIF11-overexpressing cells. In vivo, DHA markedly suppressed tumor growth and malignancy in xenograft models, consistent with modulation of KIF11 and EMT-related proteins. Conclusions: DHA exerts antitumor effects in HCC by acting via KIF11 and PI3K/Akt modulation, providing a potential therapeutic strategy. Full article

Bladder cancer remains a major clinical challenge because of its high recurrence rate, marked molecular heterogeneity, frequent progression, and limited durability of current therapeutic strategies. Increasing evidence indicates that acetylation, as a reversible and druggable epigenetic modification, plays a central role in bladder cancer biology by linking chromatin remodeling to transcriptional regulation, DNA damage repair, metabolic adaptation, and immune modulation. Both histone and non-histone acetylation are frequently dysregulated in bladder cancer, and these alterations contribute to multiple malignant phenotypes, including sustained proliferation, defective cell-cycle control, apoptosis evasion, epithelial–mesenchymal transition, metastatic progression, and therapeutic resistance. In this review, we summarize the mechanistic basis of acetylation imbalance in bladder cancer, with particular emphasis on the roles of histone acetyltransferases, histone deacetylases, sirtuins, and acetylation-associated metabolic regulators. We further discuss the emerging evidence that natural products can modulate acetylation-related pathways in bladder cancer, mainly through targeting HDAC-dependent histone deacetylation and SIRT1-associated non-histone deacetylation. Representative compounds, including sulforaphane, erucin, puerarin, capsaicin, curcumin, trichostatin A, trichostatin C, and pinocembrin, highlight the potential of natural products to suppress tumor growth, promote apoptosis, impair migration, and enhance antitumor immunity through acetylation-related mechanisms. Beyond summarizing individual agents, the evidence was evaluated based on the integration of acetylation-related target engagement, acetylation remodeling, and bladder cancer-relevant phenotypic outcomes. The current evidence is heterogeneous. SFN/ECN, capsaicin, and pinocembrin offer the most convincing bladder cancer-specific support, whereas several other compounds remain limited by context-dependent effects, indirect pathway inference, or incomplete validation of the proposed acetylation mechanisms. These findings support an evidence-oriented translational framework that prioritizes natural products according to mechanistic robustness, bladder cancer specificity, and combination potential. Overall, acetylation-targeting natural products represent a promising but still evolving therapeutic strategy for bladder cancer, warranting further subtype-specific, mechanistically rigorous, and translationally oriented investigation. Full article

CXCL14 is a highly conserved chemokine with potential roles in tumor progression and immune modulation. This study investigates the functional impact of CXCL14 on colon cancer by exploring its effects on tumor cell behavior and the immune microenvironment. We generated stable cell lines overexpressing CXCL14 in mouse MC38 and CT26 cells and human HCT15 colon cancer cells, and used these models to assess tumor growth, invasion, and immune cell infiltration. Our results demonstrate that CXCL14 suppresses colon cancer cell proliferation, migration, and metastasis. In vitro, CXCL14 inhibited the expression of matrix metalloproteinases (MMPs), key regulators of epithelial–mesenchymal transition (EMT), suggesting a role in promoting mesenchymal–epithelial transition (MET). Additionally, in vivo studies using a subcutaneous tumor model showed that CXCL14 not only suppressed tumor growth but also enhanced the infiltration of immune cells, including NK cells, dendritic cells (DCs), and T cells, converting the tumor microenvironment from a “cold” to a “hot” phenotype. RNA sequencing and pathway analyses revealed that CXCL14 regulates the expression of genes associated with angiogenesis, immune response, and cell signaling, particularly through the MAPK pathway. Furthermore, CXCL14’s influence on tumor progression was confirmed in a spleen-to-liver metastasis model, where its overexpression reduced metastatic spread. In conclusion, CXCL14 inhibits colon cancer progression by modulating both tumor cell behavior and the immune landscape, making it a promising candidate for targeted immunotherapy. Our findings highlight CXCL14’s potential to enhance anti-tumor immunity and provide new insights into its therapeutic applications in colon cancer. Full article

Glypican-1 (GPC1) has emerged as a critical mediator of malignant tumor progression. GPC1 plays essential roles in regulating various signaling pathways involved in tumor cell proliferation, invasiveness, and tumorigenesis. Overexpression of GPC1 in tumors mediates oncogenic transformation, epithelial-to-mesenchymal transition, metastatic dissemination, and therapeutic resistance. Accordingly, GPC1-targeted therapeutic strategies have been investigated in clinical and preclinical studies. However, clinical efficacy has been limited. We previously developed an anti-GPC1 monoclonal antibody (mAb), G₁Mab-28 (mouse IgG₁, κ), which exhibits high affinity and specificity for GPC1. In the present study, we generated recombinant isotype-converted G₁Mab-28, including G₁Mab-28-mG_2a (mouse IgG_2a) and G₁Mab-28-hG₁ (human IgG₁). Both mAbs recognized GPC1-expressing human tumor cell lines, including lung squamous cell carcinoma PC-10 and pancreatic ductal adenocarcinoma PK-45H, by flow cytometry. Moreover, both mAbs exerted antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against those cell lines. In mouse xenograft models, treatment with the mAbs resulted in potent antitumor efficacy against PC-10 and PK-45H tumors. Collectively, these findings support the therapeutic potential of G₁Mab-28 for the treatment of GPC1-positive tumors. Full article