Yi Liu

Eosinophils are key immunopathological cells in respiratory diseases and contribute to airway inflammation, tissue remodeling, and disease heterogeneity. Although eosinophils have traditionally been regarded as biomarkers of type 2 inflammation, increasing evidence indicates that they also function as active mediators of lung function impairment in selected respiratory diseases, including chronic obstructive pulmonary disease, asthma, and eosinophilic pneumonia. These disorders were selected because they represent distinct yet complementary models of eosinophil-associated airway and parenchymal injury, allowing comparison of shared and disease-specific mechanisms. Mechanistically, eosinophils impair lung function through the coordinated release of cytotoxic granule proteins, reactive oxygen species, lipid mediators, and cytokines, while interacting with epithelial, immune, and structural cells to amplify inflammation, airway remodeling, and tissue injury. These advances have improved understanding of eosinophil biology and facilitated the development of clinically relevant biomarkers and targeted therapies. Blood and sputum eosinophil counts remain the most widely used biomarkers, whereas emerging biomarkers, including eosinophil-derived neurotoxin, may further improve disease stratification and treatment monitoring. Biologics targeting interleukin-5 and its receptor have demonstrated therapeutic benefit in selected eosinophilic respiratory diseases, although treatment responses differ among disease phenotypes. This review summarizes current evidence regarding the molecular mechanisms linking eosinophils to lung function impairment, discusses the evolving role of eosinophils as both biomarkers and pathogenic drivers, and highlights the biomarker and therapeutic implications for precision management of respiratory diseases.

Background Lung adenocarcinoma (LUAD) and chronic airway obstruction frequently coexist and are associated with poorer clinical outcomes. Although airway obstruction is recognized as a risk factor for adverse prognosis in LUAD, the molecular alterations associated with airway obstruction in LUAD remain incompletely understood. Most previous studies have been confounded by smoking-related molecular changes. Objective To identify proteins associated with airway obstruction status in non-smoking patients with LUAD using a proteomics-based approach. Methods Proteomic analysis was performed on paired tumor and adjacent normal tissues obtained from 12 non-smoking LUAD patients, including 6 patients with airway obstruction and 6 without airway obstruction. A four-group design combined with a three-step intersection strategy was used to identify candidate proteins associated with both airway obstruction status and tumor-related alterations. Functional enrichment, protein–protein interaction (PPI) network analysis, Western blot validation, correlation with pulmonary function, and transcriptomic validation using The Cancer Genome Atlas (TCGA) database were subsequently performed. Results A total of 2036 differentially expressed proteins were identified in tumor tissues between airway obstruction and non-obstruction groups. The three-step intersection strategy identified 15 candidate proteins. PPI network analysis and expression-direction consistency screening further identified four core proteins: Cystatin B (CSTB), Bone Morphogenetic Protein Receptor Type 1A (BMPR1A), Complement C4B (C4B), and Potassium Channel Tetramerization Domain Containing 10 (KCTD10). Western blot validation supported the differential expression patterns of these four core proteins in tumor tissues. Functional enrichment analysis indicated involvement in DNA damage repair, immune regulation, and cellular proliferation pathways. CSTB expression was positively correlated with FEV1%, whereas BMPR1A expression showed a negative correlation. TCGA analyses demonstrated that expression of these proteins' corresponding genes was associated with LUAD prognosis, and C4B expression was significantly associated with tumor stage. Conclusions This study identified CSTB, BMPR1A, C4B, and KCTD10 as proteins associated with airway obstruction status in non-smoking LUAD patients. These findings provide preliminary insights into molecular differences related to airway obstruction in LUAD and generate candidate biomarkers for future validation studies. Western blot validation provided additional experimental support for the proteomic findings. Larger multicenter cohorts and functional experiments are required to clarify the biological and clinical significance of these proteins.

Background The extracellular matrix (ECM) plays a pivotal role in lung adenocarcinoma (LUAD) progression and chemoresistance, yet its regulatory mechanisms remain incompletely understood. Here, we identify ZNF514 as a novel tumour suppressor that critically governs ECM remodelling. Methods To elucidate the role of ZNF514 in LUAD, we employed a multi-platform approach integrating LUAD organoids, tumour specimens, xenograft mouse models, and cancer cell lines. Transcriptomic profiling was performed to assess ZNF514 expression and its clinical prognostic relevance. Mechanistically, chromatin immunoprecipitation (ChIP) assay, dual-luciferase reporter assay and pathway enrichment analyses identified ZNF514 as a transcriptional repressor of collagen-encoding genes. Results Analyses of LUAD clinical tissues, patient-derived organoids, and The Cancer Genome Atlas (TCGA) datasets revealed a significant downregulation of ZNF514, which correlated with poor prognosis. Functionally, ZNF514 overexpression suppressed organoid formation, subcutaneous tumour growth, and cellular migration and invasion, while enhancing cisplatin (DDP) sensitivity. Mechanistically, RNA sequencing, ChIP assay and dual-luciferase reporter assays identified COL1A1 as a direct transcriptional target of ZNF514. ZNF514 directly binds to the COL1A1 promoter and represses its transcription, thereby contributing, at least in part, to altered extracellular matrix (ECM) remodelling and attenuation of COL1A1-associated epithelial–mesenchymal transition (EMT) in LUAD models. Conclusions Together, these findings identify ZNF514 as a tumour-suppressive transcription factor that inhibits LUAD proliferation, invasion, and migration and enhances cisplatin sensitivity, at least in part, through transcriptional repression of COL1A1 and modulation of ECM remodelling.

The online version contains supplementary material available at 10.1186/s12935-026-04288-1.

Background: Molecular testing has become an essential part of managing non-small cell lung cancer (NSCLC). The detection of EGFR, BRAF, and MNNG HOS transforming gene (MET) mutations, and the analysis of anaplastic lymphoma kinase (ALK), ROS1, RET, and NTRK rearrangements have been incorporated into NSCLC diagnostic standards, and inhibitors of these kinases are used routinely in clinical practice. Although targeted therapies, represented by ALK-tyrosine kinase inhibitor (ALK-TKI), have significantly improved the prognosis of ALK-positive NSCLC patients, acquired resistance (such as MET amplification) remains a core challenge faced by clinicians. Currently, there is no standardized treatment regimen established in Chinese and international clinical guidelines for patients with ALK-TKI resistance caused by MET amplification. Although clinical practice has attempted to combine targeted drugs for MET amplification, such as crizotinib, with first and second-generation ALK-TKIs and observed preliminary efficacy, there is no published research on the combination of third-generation ALK-TKI lorlatinib with new MET inhibitors such as vebreltinib. Case Description: This report describes a patient with advanced NSCLC with multiple systemic metastases and ALK gene fusion, in whom MET amplification emerged as a resistance mechanism following disease progression on targeted therapy. The first-line treatment was lorlatinib, a third-generation ALK inhibitor, but the disease progressed rapidly. The second biopsy showed that MET amplification is the main mechanism of resistance to ALK-targeted therapy in the patient. Specifically, MET amplification was not present at baseline but appeared after lorlatinib treatment, confirming it as an acquired rather than intrinsic resistance mechanism. Due to complications, such as elevated transaminase (an indication of hepatotoxicity), hyperlipidemia, and depression, that occurred during the patient’s first-line treatment, combined ALK- and MET-TKI targeted therapy was not administered. Subsequent second-line treatment with single-agent vebreltinib failed to halt disease progression. After thorough systemic evaluation, a combination regimen of lorlatinib and vebreltinib was initiated, resulting in sustained partial remission (PR), excellent treatment tolerance, and notable improvement in quality of life. Conclusions: Our case report first successfully documented the use of third-generation ALK inhibitor (lorlatinib) in combination with novel MET inhibitor (vebreltinib) for the treatment of advanced NSCLC patients with ALK-TKI resistance due to MET amplification, enabling sustained clinical remission. This case highlights the importance of repeat biopsy to identify acquired resistance mechanisms arising from intratumoral heterogeneity in response to targeted therapy, which is critical for making clinical decisions and adjusting treatment plans for patients with NSCLC.

Mitochondrial dysfunction is a hallmark of diabetic kidney disease (DKD), yet its regulatory mechanisms remain poorly defined. Mitochondrial transcription

Eosinophilic asthma, affecting more than 50% of adult asthma patients, demonstrates airway inflammation severity directly correlated with eosinophil infilt

Clear cell renal cell carcinoma (ccRCC) is characterized by mitochondrial dysfunction and the Warburg effect, which refers to enhanced aerobic glycolysis. Mitochondrial ribosomal protein 12 (MRPL12) plays a pivotal role in mitochondrial biogenesis by promoting mitochondrial transcription through its interaction with POLRMT. Our previous studies have demonstrated that MRPL12 is involved in the progression of diabetic kidney disease (DKD) and acute kidney injury (AKI). However, its specific role in ccRCC remains unclear. Therefore, this study aims to elucidate the function of MRPL12 in the metabolic reprogramming of ccRCC. Online databases and tissue microarray analysis were utilized to explore the role of MRPL12 in ccRCC. Quantitative real-time PCR (qRT-PCR) was performed to quantify mRNA expression levels, while Western blotting, immunofluorescence (IF), and immunohistochemistry (IHC) were employed to evaluate protein expression of the relevant genes. In vitro functional assays were conducted to determine the biological effects of MRPL12, and aerobic glycolysis was assessed using Seahorse XF Analyzers to measure cellular metabolic activity. Mass spectrometry analysis, combined with Gene Ontology (GO) analysis and integrated with Ingenuity Pathway Analysis (IPA), was carried out to identify potential pathway interconnections. To investigate the regulatory mechanism, chromatin immunoprecipitation (ChIP) assays were performed to examine the binding interaction between HIF-1α and the MRPL12 promoter. Finally, an in vivo mouse model was established to further elucidate the functional role of MRPL12 in ccRCC progression. MRPL12 is significantly downregulated in ccRCC tissues, and its reduced expression is associated with poor prognosis. MRPL12 inhibits ccRCC cell proliferation, migration, and invasion by modulating mitochondrial metabolism. Overexpression of MRPL12 enhances oxidative phosphorylation (OXPHOS) and suppresses aerobic glycolysis, while MRPL12 knockdown produces the opposite effects. Potential interconnections between the MRPL12, ILK, ISGylation, and SUMO pathways have been identified. Additionally, HIF-1α was found to act as a transcriptional repressor of MRPL12. Our study reveals that MRPL12 regulates mitochondrial metabolism to inhibit ccRCC cell proliferation, migration, and invasion, suggesting that targeting MRPL12 may represent a promising therapeutic strategy for ccRCC.

Metastasis remains the leading cause of cancer‐related mortality, yet effective interventions against KRAS ^G12C/D driven lung adenocarcinoma metastasis ared limited. In this study, using KRAS ^G12D/– ; TP53 ^–/– ; COA4 ^–/– transgenic mice, clinical specimens, organoid models, RNA sequencing, xenograft assays, and Seahorse metabolic profiling are employed to identify COA4 as an evolutionarily conserved regulator of cytochrome c oxidase (COX) and activator of CDC42. COA4 is found to be highly overexpressed in KRAS mutant tumors, correlating with increased metastatic burden and poor prognosis. Notably, COA4 deficiency markedly reduces lymph node metastasis. Mechanistically, KRAS ^G12C/D upregulates COA4 via PI3K signaling and E2F1‐mediated transcriptional activation. Functionally, COA4 overexpression enhances transendothelial migration, extravasation, metastatic colonization, and organoid formation in vitro and in vivo, while its knockdown reverses KRAS ‐driven metastasis without affecting proliferation. Subcellular fractionation reveals that mitochondrial COA4 augments COX activity to drive oxidative phosphorylation, while cytosolic COA4 binds and activates CDC42 to regulate pseudopodia formation. Pharmacological blockade of COX, oxidative phosphorylation, or CDC42 effectively suppressed COA4‐driven metastasis, with combination treatments yielding synergistic inhibition. Remarkably, the Saccharomyces cerevisiae COA4 ortholog recapitulates these dual functions, underscoring their evolutionary conservation. These findings establish COA4 as a critical KRAS ^G12C/D effector governing metastasis through dual COX‐CDC42 modulation, highlighting its therapeutic potential for KRAS ^G12C/D ‐driven malignancies.