Search Results (1,857)

The mesenchymal–epithelial transition (MET) receptor is a tyrosine kinase activated by its sole known ligand, hepatocyte growth factor (HGF). MET signaling regulates key cellular processes, including proliferation, survival, migration, motility, and angiogenesis. Dysregulation and hyperactivation of this pathway are implicated in multiple malignancies, including lung, breast, colorectal, and gastrointestinal cancers. In non–small cell lung cancer (NSCLC), aberrant activation of the MET proto-oncogene contributes to 1% of known oncogenic drivers and is associated with poor clinical outcomes. Several mechanisms can induce MET hyperactivation, including MET gene amplification, transcriptional upregulation of MET or HGF, MET fusion genes, and MET exon 14 skipping mutations. Furthermore, MET pathway activation represents a frequent mechanism of acquired resistance to EGFR- and ALK-targeted tyrosine kinase inhibitors (TKIs) in EGFR- and ALK-driven NSCLCs. Although MET has long been recognized as a promising therapeutic target in NSCLC, the clinical efficacy of MET-targeted therapies has historically lagged behind that of EGFR and ALK inhibitors. Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment of MET exon 14 skipping mutations. They have also demonstrated potential in overcoming MET-driven resistance to EGFR TKIs or ALK TKIs. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC. Full article

Background/Objectives: Cigarette smoke (CS) drives pathogenesis across the spectrum of chronic respiratory disorders, exerting its detrimental effects primarily through oxidative stress and programmed cell death. Scutellarein (Scu), a botanical-origin flavonoid enriched in respiratory therapeutics-oriented Chinese medicinal herbs, demonstrates established anti-inflammatory applications. This study systematically evaluated the protective roles of Scu against CS-induced lung injury and explored the underlying mechanisms. Methods: Subacute CS-exposed mice were used to evaluate the therapeutic effects of Scu on lung injury. Immunofluorescence and quantitative PCR were used to examine the expression levels of junctional proteins and proinflammatory mediators. Apoptotic cell death was quantified using Annexin V-FITC/7-AAD staining. Transepithelial electrical resistance and dextran permeability assay were used to access the barrier integrity in alveolar epithelial MLE-12 cells. Western blotting was used to detect the changes in the signal pathway. Results: In CS-exposed mice, Scu administration dose-dependently reduced histopathological scores, pulmonary edema, changes in the alveolar structure, and inflammatory cell infiltration. In MLE-12 cells, Scu significantly suppressed cigarette smoke condensate (CSC)-induced inflammatory mediators, oxidative stress, caspase-3 activation, and apoptosis and preserved CSC-suppressed tight junction protein expression and barrier disruption. Scu also rescued CSC-altered expression levels of Hrk, Ecscr, and Myo5b and mitigated the CSC-suppressed PI3K/AKT/mTOR pathway. Conclusions: Scu alleviates CS-induced subacute lung injury through its antioxidant, anti-apoptotic effects to maintain epithelial barrier integrity likely via the mitigation of the CSC-suppressed PI3K/AKT/mTOR pathway. Full article

Pulmonary involvement in cystic fibrosis (CF) is characterised by respiratory infections caused by bacteria, viruses, and fungi, as well as by dysregulated inflammatory and immune responses. Although essential for the host’s initial defence against these microorganisms, the innate immune response is altered in its main cellular (airway epithelial cells (AECs), monocytes, macrophages, and neutrophils) and molecular (cytokines, chemokines, signal transduction pathways, and transcription factors) components. MicroRNAs (miRNAs) form a regulatory network at the level of inflammatory and immune responses, and their dysregulation has been observed in immortalised and primary CF AECs as well as in monocytes, macrophages, and neutrophils from CF patients. Although the study of individual miRNAs is helping to dissect the specific altered events in CF lung disease (CFLD), large-scale genomic and transcriptomic studies are more likely to capture its full complexity. The studies we identified suggest that miRNAs are involved in various processes related to CFLD, including impaired pathogen response, compensation for hyperinflammation, altered antigen presentation, and wound healing in AECs and macrophages. However, clinical studies involving large cohorts of patients are needed to obtain meaningful results and identify new therapeutic targets. Equally important will be the study of the miRNome as circulating biomarkers for the purposes of diagnostic and prognostic precision medicine. Full article

Background: Lung adenocarcinoma (LUAD) exhibits pronounced cellular and molecular heterogeneity that shapes tumor progression and therapeutic response. Although nucleotide metabolism is essential for sustaining tumor proliferation and coordinating immune interactions, its single-cell heterogeneity and clinical implications remain incompletely defined. Methods: We integrated a publicly available scRNA-seq dataset derived from independent LUAD patients to construct a comprehensive LUAD cellular atlas, identified malignant epithelial cells using inferCNV, and reconstructed differentiation trajectories via Monocle2. Cell–cell communication patterns under distinct nucleotide metabolic states were assessed using CellChat. A nucleotide metabolism-related signature (NMRS) was subsequently developed across TCGA-LUAD and multiple GEO cohorts using 101 combinations of machine learning algorithms. Its prognostic and immunological predictive value was systematically evaluated. The functional relevance of the key gene ENO1 was further verified through pan-cancer analyses and in vitro experiments. Results: We identified substantial nucleotide metabolic heterogeneity within malignant epithelial cells, closely linked to elevated proliferative activity, glycolytic activation, and increased CNV burden. Pseudotime analysis showed that epithelial cells gradually acquire enhanced immune-modulatory and complement-related functions along their differentiation continuum. High-metabolism epithelial cells exhibited stronger outgoing communication—particularly via MIF, CDH5, and MHC-II pathways—highlighting their potential role in shaping an immunosuppressive microenvironment. The NMRS built from metabolism-related genes provided robust prognostic stratification across multiple cohorts and surpassed conventional clinical parameters. Immune profiling revealed that high-NMRS tumors displayed increased T-cell dysfunction, stronger exclusion, higher TIDE scores, and lower IPS, suggesting poorer responses to immune checkpoint blockade. ENO1, markedly upregulated in high-NMRS tumors and functioning as a risk factor in several cancer types, was experimentally shown to promote invasion in LUAD cell lines. Conclusions: This study delineates the profound impact of nucleotide metabolic reprogramming on epithelial cell states, immune ecology, and malignant evolution in LUAD. The NMRS provides a robust predictor of prognosis and immunotherapy response across cohorts, while ENO1 emerges as a pivotal metabolic–immune mediator and promising therapeutic target. Full article

Brake wear particles (BWPs) represent a major source of non-exhaust particulate matter from road traffic, contributing substantially to human exposure, particularly in urban environments. While traditionally associated with coarse and fine fractions, mounting evidence shows that brake systems emit large quantities of ultrafine particles (UFPs; <100 nm), which dominate number concentrations despite contributing little to mass. This paper synthesizes current knowledge on BWP formation mechanisms, physicochemical characteristics, environmental behavior, and toxicological effects, with a specific emphasis on UFPs. Mechanical friction and high-temperature degradation of pad and disc materials generate nanoscale primary particles that rapidly agglomerate yet retain ultrafine structural features. Reported real-world and laboratory number concentrations commonly range from 10³ to over 10⁶ particles/cm³, with diameters between 10 and 100 nm, rising sharply during intensive braking. Toxicological studies consistently demonstrate that UFP-rich and metal-laden BWPs, particularly those containing Fe, Cu, Mn, Cd, and Sb compounds, induce oxidative stress, inflammation, mitochondrial dysfunction, genotoxicity, and epithelial barrier disruption in human lung and immune cells. Ecotoxicological studies further reveal adverse impacts across aquatic organisms, plants, soil invertebrates, and mammals, with evidence of environmental persistence and food-chain transfer. Despite these findings, current regulatory frameworks address only the mass of particulate matter from brakes and omit UFP number-based limits, leaving a major gap in emission control. Full article

Lineage plasticity, the ability of cancer cells to alter their differentiated state through transcriptional and epigenetic reprogramming, has emerged as a key mechanism of therapeutic resistance across cancers. This adaptive process can manifest in multiple ways, including epithelial–mesenchymal transition, acquisition of stem-like features, and histological transformation, the most striking and clinically apparent example. In EGFR-mutant lung adenocarcinoma (LUAD), lineage plasticity is increasingly recognized as a prevalent mechanism of acquired resistance to tyrosine kinase inhibitors (TKIs). Among its visible manifestations, histologic transformation into small-cell lung cancer (SCLC) is the most frequent, while squamous transformation and other phenotypic shifts also occur. Transformed tumors typically retain the initiating EGFR mutation but lose EGFR dependence, acquire neuroendocrine features, and display aggressive clinical behavior with poor clinical outcomes compared with both de novo SCLC and non-transformed LUAD. Recent studies show that plasticity arises through combined genomic, transcriptomic, and epigenetic reprogramming, often foreshadowed by molecular alterations before overt histological change. Spatial and single-cell profiling reveal heterogeneous trajectories and intermediate states, while functional models and multi-omics approaches have begun to identify therapeutic vulnerabilities distinct from both de novo EGFR-mutated SCLC and classical EGFR-mutated LUAD. Thus, lineage plasticity, whether manifested as histologic transformation or through more subtle epigenetic reprogramming, represents a formidable resistance mechanism in NSCLC. Defining its molecular basis and temporal dynamics will be essential for early detection, prognostication, and the development of tailored therapies. Full article

Lung cancer, as one of the most prevalent and lethal malignancies, requires immediate and effective therapeutic solutions. Therefore, additional innovative methods are continually sought to achieve optimal treatment outcomes. Various markers are used to select the most effective therapies, assess clinical responses, and facilitate follow-up care for the patients. Circulating tumor cells (CTCs) remain a valuable biomarker in clinical management of cancer patients due to the range of information they provide and their high prognostic and predictive potential in monitoring anticancer therapy. CTCs constitute a heterogeneous population of cancer cells that undergo an epithelial-to-mesenchymal transition (EMT), are shed from the tumor mass, and migrate through the peripheral blood, ultimately causing metastases. In this literature review, we focus on the biological, biochemical, and biophysical properties of CTCs, specifically from the perspective of the design of CTC enumeration technologies. Furthermore, we combine the available data on the application of CTC count in monitoring various treatment modalities in lung cancer, including radiotherapy, chemotherapy, tyrosine kinase inhibitors, and immunotherapy. Although many published reports indicate that an increased number of CTCs in blood samples of lung cancer patients correlates with worse treatment outcomes, several limitations hinder the widespread usage of CTCs in the clinical setting. Full article

The reactivation of Wnt signaling pathways plays an important role in driving myofibroblast differentiation in fibrotic diseases; however, the mechanism is not clearly understood. In this study, we investigate the role of non-canonical Wnt11 signaling in human lung fibroblasts and its contributions to myofibroblast differentiation. Our results show that components of the non-canonical Wnt pathway are upregulated in bleomycin-induced pulmonary fibrosis and that in vivo depletion of Wnt11 in mouse lung fibroblasts significantly reduces lung fibrosis. Furthermore, co-culture studies using fibroblasts and alveolar type II epithelial cells (AECII) revealed a Wnt11-mediated mechanism that promotes myofibroblast differentiation. Finally, we demonstrate that in human lung fibroblasts, TGFβ can increases Wnt11 transcription by regulating Smad3 binding to the Wnt11 promoter and by modulating Wnt11 promoter activity. Together, these findings identify non-canonical Wnt11 as a regulator of myofibroblast differentiation and lung fibrosis. Full article

The gut microbiome has emerged as a key regulator of human health, influencing not only metabolism and immunity but also the development and treatment of cancer. Mounting evidence suggests that microbial dysbiosis contributes to oncogenesis by driving chronic inflammation, producing genotoxic metabolites, altering bile acid metabolism, and disrupting epithelial barrier integrity. At the same time, the gut microbiome significantly modulates the host response to oncotherapies including chemotherapy, radiotherapy, and especially immunotherapy, where microbial diversity and specific taxa determine treatment efficacy and toxicity. This review synthesizes current evidence on the role of the gut microbiome in both oncogenesis and oncotherapies, focusing on thirteen cancers with the strongest and most clinically relevant microbiome associations, colorectal cancer, gastric cancer, hepatocellular carcinoma, gallbladder cancer, esophageal cancer, pancreatic cancer, oral squamous cell carcinoma, cervical cancer, prostate cancer, breast cancer, lung cancer, brain cancer, and melanoma. These cancers were selected based on robust mechanistic data linking microbial alterations to tumor initiation, progression, and therapy modulation, as well as their global health burden and translational potential. In addition, we have provided mechanistic insights or clinical correlations between the microbiome and cancer outcomes. Across cancers, common microbial mechanisms included pro-inflammatory signaling (e.g., NF-κB and STAT3 pathways), DNA damage from bacterial toxins (e.g., colibactin, nitrosating species), and metabolite-driven tumor promotion (e.g., secondary bile acids, trimethylamine N-oxide). Conversely, beneficial commensals such as Faecalibacterium prausnitzii and Akkermansia muciniphila supported antitumor immunity and improved responses to immune checkpoint inhibitors. In conclusion, the gut microbiome functions as both a driver of malignancy and a modifiable determinant of therapeutic success. Integrating microbiome profiling and modulation strategies such as dietary interventions, probiotics, and fecal microbiota transplantation into oncology practice may pave the way for personalized and more effective cancer care. Full article

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible interstitial lung disease characterized by progressive scarring of the lungs. The available therapeutic strategies are limited and primarily focus on slowing disease progression rather than achieving fibrosis reversal. Cardamonin (CDN), a food-derived natural chalcone, has exhibited anti-fibrotic activity in liver and kidney fibrosis models; however, its role and underlying mechanism in IPF remain unelucidated. Herein, we integrated network pharmacology, machine learning, molecular simulations, and in vitro experiments. Network pharmacology identified 135 overlapping targets between CDN and IPF, which demonstrated a significant enrichment in the Phosphatidylinositol 3-Kinase/Protein Kinase B signaling pathway (PI3K/AKT). Machine learning further prioritized 6 core targets, with IGF1 emerging as a key candidate. Molecular docking revealed a favorable binding energy of −7.9 kcal/mol for the CDN-IGF1 complex. Subsequent 100 ns molecular dynamics simulations further confirmed its robust binding stability, yielding a mean binding free energy of −150.978 kcal/mol. In vitro, CDN significantly mitigated fibrosis in bleomycin (BLM)-challenged A549 cells, downregulating the expression of α-smooth muscle actin (α-SMA) and fibronectin. This effect was accompanied by a beneficial reversal of epithelial–mesenchymal transition (EMT), as indicated by increased E-cadherin levels and decreased vimentin expression. Mechanistically, CDN significantly suppressed the IGF1/PI3K/AKT axis; this inhibitory effect was partially reversed by exogenous IGF1 supplementation and further enhanced by the PI3K-specific inhibitor LY294002. This work provides the evidence that CDN alleviates BLM-induced pulmonary fibrosis by targeting the IGF1/PI3K/AKT-EMT axis. These findings lend support to a robust mechanistic basis for developing CDN as a potential therapeutic candidate for IPF. It should be noted that these conclusions are drawn from in vitro experiments using A549 cells, and further validation in primary alveolar epithelial cells and animal models is warranted to confirm their physiological relevance. Full article

Antibiotic-resistant infections remain a major challenge in cystic fibrosis (CF), where chronic Pseudomonas aeruginosa colonization drives lung infection. The overexpression of adhesion-related proteins and extracellular matrix components, including fibronectin (Fn), facilitates bacterial colonization. Recent evidence identifies the RNA-binding protein Human Antigen R (HuR) as a key regulator of this process, as it stabilizes Vav3 mRNA, promoting Fn deposition and the formation of bacterial docking platforms. Here, we report the synthesis, optimization, and functional evaluation of the HuR-targeted small-molecule (2S,3S)-BOPC1. Functional assays in CF human airway epithelial cells demonstrated that (2S,3S)-BOPC1 significantly reduced P. aeruginosa adhesion in a dose-dependent manner without detectable cytotoxic effects. These findings provide the first evidence that targeting HuR can disrupt the HuR–Vav3–Fn axis, reducing bacterial attachment. This host-directed approach represents a promising strategy to prevent chronic infections in CF without promoting antibiotic resistance. Full article

Potassium (K⁺) channel blockers are promising anticancer agents but suffer from off-target toxicities. We designed cross-linked poly-2-Hydroxyethyl methacrylate (HEMA)–pectin nanogels (HPN) to deliver two model blockers—dofetilide (Dof) and azimilide (Azi)—and evaluated their physicochemical properties, release behavior, and in vitro anticancer activity. HPN was synthesized by surfactant-assisted aqueous nanogel polymerization and comprehensively characterized (FTIR, DLS, TEM/SEM, XRD, BET). The particles were monodispersed with a mean diameter ~230 nm, compatible with tumor accumulation via the Enhanced Permeability and Retention (EPR) effect, and exhibited a microporous matrix suitable for controlled release. Drug loading was higher for Dof than for Azi, with DL% values of 82.30 ± 3.1% and 17.84 ± 2.9%, respectively. Release kinetics diverged: Azi-HPN followed primarily first-order diffusion with a rapid burst, whereas Dof-HPN showed mixed zero/first-order behavior. Cytotoxicity was assessed in A549 lung cancer and BEAS-2B bronchial epithelial cells. Both free and nano-formulated blockers were selectively toxic to A549 with minimal effects on BEAS-2B. Notably, a hormesis-like pattern (low-dose stimulation/high-dose inhibition in MTT) was evident for free Dof and Azi; encapsulation attenuated this effect for Dof but not for Azi. Co-administration with paclitaxel (Ptx) potentiated Dof-HPN cytotoxicity in A549 but did not enhance Azi-HPN, suggesting mechanism-dependent drug-drug interactions. Overall, HPN provides a biocompatible platform that improves K⁺ blocker delivery. Full article

Background: Breast cancer is the most prevalent cancer in women, and metastatic breast cancer remains a major cause of cancer-related deaths. Resveratrol (RSV) is a natural compound found in various plants and is known to exhibit various anti-cancer effects. The present study aims to investigate the therapeutic effects and mechanisms of RSV in inhibiting breast cancer metastasis in a murine model of 4T1 breast tumor that shares close molecular features with human triple negative breast cancer. Methods: Murine breast cancer 4T1 cells were used to examine the effects of RSV on breast cancer metastasis and epithelial–mesenchymal transition (EMT). In vitro cell proliferation and Transwell migration assays and in vivo 4T1 tumor transplantation models were established in female Balb/c mice to determine the anti-metastatic effects of RSV and its mechanism of action. Results: RSV significantly inhibited 4T1 tumor cell migration and significantly decreased expression levels of EMT markers Snail and Vimentin, as well as the nuclear translocation of β-catenin both in vitro and in vivo. Knockdown of β-catenin similarly reduced the expression levels of EMT markers. RSV significantly decreased the number of lung metastases in 4T1-implanted mice by inhibiting Wnt/β-catenin signaling pathway activation. RSV (150 mg/kg/day) reduced the number of visible tumor metastatic nodules and the histological count of metastatic lung carcinomas by 51.82% and 62.58%, respectively, compared to vehicle administration. Conclusions: Our study provides important new mechanistic insight into the strong anti-cancer effects of RSV in inhibiting 4T1 breast cancer metastasis by preventing Wnt/β-catenin signaling pathway-mediated epithelial–mesenchymal transition. These findings suggest the therapeutic potential of RSV as a promising drug in the treatment of metastatic breast cancer. Full article

Lung cancer (LC) remains the leading cause of cancer-related death in the United States despite advances in therapy. Growth hormone (GH) action has been implicated in tumor progression and therapy resistance across multiple cancers, but its role in LC, particularly non-small cell lung cancer (NSCLC), remains poorly defined. In cancer cells, GH promotes chemoresistance through upregulation of drug-efflux pumps, induction of epithelial-to-mesenchymal transition (EMT), and inhibition of apoptosis. Notably, GH receptor (GHR) expression is significantly elevated in NSCLC compared to normal lung tissue, suggesting a potential therapeutic opportunity. In this study, we investigated the impact of GH action on therapy resistance and tumor progression using integrated transcriptomic analyses and in vitro experiments. Analyses of transcriptomic data from NSCLC patients revealed that high tumoral GHR expression correlates with reduced overall survival, and with upregulation of genes involved in distinct therapy refractory pathways. Our in vitro studies demonstrated that GH promotes chemoresistance in NSCLC cell lines through activation of ABC transporters and EMT pathways, whereas GHR antagonism with the GH receptor antagonist, pegvisomant, effectively counteracts these effects and improves chemotherapy efficacy significantly. Together, our findings identify GHR signaling as a contributor to aggressive and therapy-resistant phenotypes in NSCLC in vitro and suggest that GHR antagonism may enhance chemotherapy sensitivity. These results provide a rationale for further in vivo and mechanistic studies to evaluate the therapeutic potential of targeting GHR in NSCLC. Full article

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with progressive evolution and high mortality. Magnesium, copper and zinc are essential biometals involved in numerous biological processes in all organs of the human body. A lower level of zinc and magnesium and a higher cooper/zinc ratio are frequently encountered in patients with idiopathic pulmonary fibrosis but also in other forms of pulmonary fibrosis. These imbalances are involved in the main pathogenic mechanisms of idiopathic pulmonary fibrosis: alveolar epithelial cell lesions, oxidative stress, inflammation, fibroblast and myofibroblast proliferation, mitochondrial activity, excessive extracellular matrix accumulation, high collagen production, alveolar macrophage dysfunctions, and apoptosis. A multitude of experimental and clinical studies have shown the importance of these bivalent cations for the synthesis or activity of some important endogenous active substances (fatty acids, eicosanoids, sirtuin1, p53 protein, interleukins, growth factors, some enzymes, and others) involved in one form or another in the pathogenesis of IPF. There are no randomized clinical trials yet, but some clinical and experimental results suggest that the association of zinc and magnesium with pirfenidone and nintedanib could be beneficial and should be assessed as soon as possible after the onset of this disease. The correction of hypomagnesemia and hypozincemia, whenever they exist, must be performed as soon as possible after the diagnosis of fibrosis. Full article