OBJECTIVES: To investigate the effect of curcumin on lipid metabolism in non-small cell lung cancer (NSCLC) and its molecular mechanism. METHODS: The inhibitory effect of curcumin (0-70 μmol/L) on proliferation of A549 and H1299 cells was assessed using MTT assay, and 20 and 40 μmol/L curcumin was used in the subsequent experiments. The effect of curcumin on lipid metabolism was evaluated using cellular uptake assay, wound healing assay, triglyceride (TG)/free fatty acid (NEFA) measurements, and Oil Red O staining. Western blotting was performed to detect the expressions of PGC-1α, PPAR-α, and HIF-1α in curcumin-treated cells. Network pharmacology was used to predict the metabolic pathways, and the results were validated by Western blotting. In a nude mouse model bearing A549 cell xenograft, the effects of curcumin (20 mg/kg) on tumor growth and lipid metabolism were assessed by measuring tumor weight and observing the changes in intracellular lipid droplets. RESULTS: Curcumin concentration-dependently inhibited the proliferation of A549 and H1299 cells and significantly reduced TG and NEFA levels and intracellular lipid droplets. Western blotting revealed that curcumin significantly upregulated PGC-1α and PPAR‑α expressions in the cells. KEGG pathway enrichment analysis predicted significant involvement of the HIF-1 signaling pathway in curcumin-treated NSCLC, suggesting a potential interaction between HIF-1α and PPAR‑α. Western blotting confirmed that curcumin downregulated the expression of HIF-1α. In the tumor-bearing mice, curcumin treatment caused significant reduction of the tumor weight and the number of lipid droplets in the tumor cells. CONCLUSIONS Curcumin inhibits NSCLC cell proliferation and lipid metabolism by downregulating the HIF-1α pathway.
Curcumin/pharmacology* ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Animals ; Lipid Metabolism/drug effects* ; Carcinoma, Non-Small-Cell Lung/pathology* ; Lung Neoplasms/pathology* ; Mice, Nude ; Down-Regulation ; Mice ; Cell Proliferation/drug effects* ; Cell Line, Tumor ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; PPAR alpha/metabolism* ; Signal Transduction/drug effects* ; A549 Cells

OBJECTIVES: To investigate the inhibitory effect of Fuzheng Huaji Decoction against non-small cell lung cancer (NSCLC) cells in vitro and explore the underlying mechanism. METHODS: The active ingredients and targets of Fuzheng Huaji Decoction were identified using TCMSP and SwissTargetPrediction databases. NSCLC-related targets from GeneCards and PharmGKB were intersected with the targets of the Decoction, and a protein-protein interaction (PPI) network was constructed to identify the core targets, which were analyzed with GO and KEGG pathway enrichment analysis. Cultured A549 cells were treated with different concentrations of Fuzheng Huaji Decoction-medicated serum, and the changes in cell proliferation, apoptosis, and protein expressions were examined using CCK-8 assay, annexin V-FITC/PI staining and Western blotting. RESULTS: Fuzheng Huaji Decoction contained 140 active ingredients, and 707 drug-disease intersecting targets were identified. Among these targets, TP53, AKT1, HIF1A, GAPDH, ALB, EGFR, CTNNB1, and TNF were identified as the core targets which were involved in the biological processes related to kinases and receptors and the PI3K-AKT, Ras, calcium, and MAPK pathways. Molecular docking studies indicated strong binding affinity of the active ingredients with TP53, AKT1, and HIF1A. In cultured A549 cells, treatment with 2.5%, 5%, and 10% Fuzheng Huaji Decoction-medicated serum significantly inhibited cell proliferation, promoted cell apoptosis, and downregulated the expression levels of HIF1A, p-AKT (Thr308), and TP53 proteins. CONCLUSIONS Fuzheng Huaji Decoction inhibits proliferation of NSCLC cells possibly by downregulating the expressions of HIF1A, p-AKT (Thr308), and TP53.
Humans ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Drugs, Chinese Herbal/pharmacology* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Lung Neoplasms/metabolism* ; A549 Cells ; Proto-Oncogene Proteins c-akt/metabolism* ; Protein Interaction Maps ; Signal Transduction/drug effects* ; Cell Line, Tumor

Mitochondria are the convergence point of multiple pathways that trigger programmed cell death (PCD). Mitochondrial-associated PCD (mtPCD) is involved in the pathogenesis of several diseases. However, the role of mtPCD in the prognostic prediction of cancers including non-small-cell lung cancer (NSCLC) remains to be investigated. Here, 12 mtPCD patterns were analyzed in transcriptomics, genomics, and clinical data collected from 4 datasets containing 977 patients. A risk-score assessment system containing 18 genes was established. We found that NSCLC patients with a high-risk score had a poorer prognosis. A nomogram was constructed by incorporating the risk score with clinical features. The risk score was further associated with clinicopathological information, tumor-mutation frequency, and immunotherapy responses. NSCLC patients with a high risk score had more Treg cells infiltration. However, these patients had higher tumor-mutation burden scores and may be more sensitive to immunotherapy. Moreover, receptor-interacting serine/threonine protein kinase 2 (RIPK2) was selected from mtPCD gene model for validation. We found that RIPK2 exhibited oncogenic function, and its expression level was inversely associated with the overall survival of NSCLC. Taken together, our results indicated the accuracy and practicability of the mtPCD gene model and RIPK2 in predicting the prognosis of NSCLC.
Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Lung Neoplasms/pathology* ; Prognosis ; Male ; Female ; Nomograms ; Middle Aged ; Mitochondria/metabolism* ; Apoptosis/genetics* ; Mutation ; Biomarkers, Tumor/genetics* ; Aged

Our previous research demonstrated that the Wenxia Changfu Formula (WCF), as a neoadjuvant therapy, inhibits M2 macrophage infiltration in the tumor microenvironment and prevents lung cancer metastasis. Given tumor-associated macrophages (TAMs) in epithelial-mesenchymal transition (EMT), this study investigated whether WCF impedes lung cancer metastasis by attenuating TAM-induced EMT in non-small cell lung cancer (NSCLC) cells. Utilizing a co-culture model treated with or without WCF, we observed that WCF downregulated cluster of differentiation 163 (CD163) expression in macrophages, reduced CCL18 levels in the conditioned medium, and inhibited the growth, invasion, and EMT of NSCLC cells induced by macrophage co-culture. Manipulation of CCL18 levels and Src overexpression in NSCLC cells revealed that WCF's effects are mediated through CCL18 and Src signaling. In vivo, WCF inhibited recombinant CCL18 (rCCL18)-induced tumor metastasis in nude mice by blocking Src signaling. These findings indicate that WCF inhibits NSCLC metastasis by impeding TAM-induced EMT via antagonistic modulation of CCL18, providing evidence for its potential development and clinical application in NSCLC patients.
Epithelial-Mesenchymal Transition/drug effects* ; Carcinoma, Non-Small-Cell Lung/metabolism* ; Humans ; Animals ; Lung Neoplasms/metabolism* ; Chemokines, CC/antagonists & inhibitors* ; Mice ; Mice, Nude ; Drugs, Chinese Herbal/administration & dosage* ; Cell Line, Tumor ; Neoplasm Metastasis ; Tumor-Associated Macrophages/drug effects* ; Mice, Inbred BALB C ; Signal Transduction/drug effects*

For patients with advanced non-small cell lung cancer (NSCLC) harboring sensitive epidermal growth factor receptor (EGFR) mutations, guidelines prioritize the use of third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), which offer higher objective response rate (ORR), longer progression-free survival (PFS), and better quality of life. However, due to the low proportion of elderly patients enrolled in clinical trials, the existing evidence is insufficient to fully guide clinical practice. This review examines the efficacy and safety differences of third-generation EGFR-TKIs as monotherapy or in combination in the elderly NSCLC by integrating subgroup analyses or pre-specified research objectives from prospective and retrospective studies. The results show that third-generation EGFR-TKIs have comparable efficacy in elderly patients to younger populations and are well-tolerated. Although combination therapies may extend survival time, the associated increased toxicity necessitates careful risk-benefit assessment.
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Humans ; Carcinoma, Non-Small-Cell Lung/enzymology* ; Lung Neoplasms/enzymology* ; ErbB Receptors/metabolism* ; Protein Kinase Inhibitors/adverse effects* ; Aged ; Antineoplastic Agents/adverse effects*

Non-small cell lung cancer (NSCLC) ranks among the most lethal malignancies worldwide. The clinical application of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have successfully revolutionized the treatment paradigm for EGFR-mutant NSCLC, significantly prolonging progression-free survival and establishing EGFR-TKIs as the standard first-line therapy for advanced lung adenocarcinoma. However, acquired resistance remains a major obstacle to sustained clinical benefit, with mechanisms that are highly heterogeneous. A phenomenon of "oxidative stress compensation" is commonly observed in EGFR-TKIs-resistant cells, where in redox homeostasis, through the precise regulation of reactive oxygen species (ROS) generation and elimination, plays a pivotal role in maintaining the balance between tumor cell proliferation and apoptosis. This review aims to innovatively construct a theoretical framework describing how dynamic redox regulation influences resistance to third-generation EGFR-TKIs. It focuses on the multifaceted roles of ROS in both EGFR-dependent and EGFR-independent resistance mechanisms, and further explores therapeutic strategies that target ROS kinetic thresholds and antioxidant systems. These insights not only propose an innovative "metabolic checkpoint" regulatory pathway to overcome acquired resistance to third-generation EGFR-TKIs, but also lay a molecular foundation for developing the redox biomarker-based dynamic therapeutic decision-making systems, thereby facilitating a shift in NSCLC therapy from single-target inhibition toward multi-dimensional metabolic remodeling in the context of precision medicine.
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Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; ErbB Receptors/genetics* ; Drug Resistance, Neoplasm/drug effects* ; Lung Neoplasms/genetics* ; Oxidation-Reduction/drug effects* ; Homeostasis/drug effects* ; Protein Kinase Inhibitors/therapeutic use* ; Reactive Oxygen Species/metabolism* ; Animals

Human epidermal growth factor receptor 2 (HER2) mutations play a role as a driver gene in non-small cell lung cancer (NSCLC). Patients with advanced NSCLC harboring HER2 mutations exhibit poor responses to conventional chemotherapy and immunotherapy, hence targeted therapies against HER2 are under extensive investigation. This review analyzes the biological characteristics of HER2, an overview of clinical trials for targeted therapy drugs, including monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and antibody-drug conjugate, and research directions for drug resistance in NSCLC. Currently, Pyrotinib and Trastuzumab deruxtecan have been approved for the treatment of advanced NSCLC with HER2 mutations, suitable for patients who have failed standard therapy, which is far from meeting the clinical demands. Novel selective HER2 TKIs are gradually emerging. Future exploration trends are gradually shifting from single drugs to combination strategies, and are exploring more precise selection strategies as well as research on resistance mechanisms. These studies will provide a theoretical basis for clinical treatment strategies for advanced NSCLC with HER2 mutations, promoting the development of personalized therapy.
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Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Lung Neoplasms/pathology* ; Receptor, ErbB-2/metabolism* ; Mutation ; Molecular Targeted Therapy ; Protein Kinase Inhibitors/therapeutic use* ; Antineoplastic Agents/therapeutic use*

BACKGROUND: In the real world, the plasma drug concentration range of Icotinib treated with epidermal growth factor receptor (EGFR) gene mutant non-small cell lung cancer (NSCLC) is not yet clear, and there may be a correlation between drug concentration and its efficacy, as well as adverse reactions. This study conducted therapeutic drug monitoring (TDM) of Icotinib. The aim of this study was to analyze the drug exposure of Icotinib in targeted therapy for NSCLC, and to investigate the relationship between Icotinib drug concentration and its efficacy and safety. METHODS: Prospective blood samples were collected from NSCLC patients with EGFR-sensitive mutations who received treatment with Icotinib in Peking University Cancer Hospital from April 2022 to July 2024. The drug trough concentration of Icotinib in plasma was detected, and the correlation between drug concentration and efficacy, as well as the toxic side effects, were further analyzed based on the patient's clinical medical records. RESULTS: 22 patients who were treated with Icotinib underwent TDM, but one of them did not acquire the data due to prolonged discontinuation. The remaining 21 patients, each with 1-7 blood draws, obtained a total of 32 plasma drug concentration data. The drug concentration of icotinib is a range of 126.9-2317.1 ng/mL. Among the 21 patients, 18 cases were female (85.7%), and 3 cases were male (14.3%), with an age range of 44-85 years old. The pathological types are all lung adenocarcinoma. Except for 5 patients receiving postoperative adjuvant therapy, 16 patients had assessable tumors. The objective response rate was 43.8% (7/16), and the disease control rate reached 100.0% (16/16). The median value of drug concentration is 805.5 ng/mL among those 21 patients. Compared with the patients who achieved stable disease, the median value of drug concentrations of Icotinib in patients who achieved partial response were 497.2 and 1195.5 ng/mL, respectively (P=0.017). The median value of drug concentrations for patients who did not experience adverse reactions during treatment and those who experienced adverse reactions were 997.0 and 828.6 ng/mL, respectively (P=0.538). CONCLUSIONS Icotinib demonstrates good therapeutic effect and tolerable toxicity on the EGFR gene mutant NSCLC. There is a certain negative correlation between the plasma drug concentration of Icotinib and its efficacy, while there seems no significant correlation with safety.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; ErbB Receptors/metabolism* ; Lung Neoplasms/genetics* ; Male ; Female ; Crown Ethers/blood* ; Middle Aged ; Drug Monitoring ; Aged ; Quinazolines/blood* ; Mutation ; Adult ; Aged, 80 and over ; Antineoplastic Agents/blood* ; Prospective Studies

The mesenchymal-epithelial transition factor (MET) gene, located on human chromosome 7, plays a crucial role in the regulation of physiological processes such as cell proliferation, migration, invasion, and angiogenesis. The MET gene is one of the key drivers in non-small cell lung cancer (NSCLC), with various forms of abnormalities including MET exon 14 (METex14) skipping mutations, MET gene amplification, MET fusions, MET protein overexpression, MET activating mutations and etc. With an increasing understanding of the mechanisms underlying MET abnormalities, therapeutic strategies targeting these abnormalities have gained significant attention, and numerous studies have confirmed that NSCLC patients with MET abnormalities can derive substantial benefits from such treatments. Lung Cancer Specialty Committee of Chinese Elderly Health Care Association organized a panel of experts to provide professional recommendations on current clinical issues in the diagnosis and treatment of MET-aberrant NSCLC, combining clinical practice experiences and evidence-based medical evidences. The "Expert Consensus on Diagnosis and Treatment of NSCLC with MET Abnormalities (2025 Version)" has been formulated to provide standardized guidances for clinical practice in China, with the aim of optimizing the treatment outcomes.
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Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy* ; Lung Neoplasms/drug therapy* ; Proto-Oncogene Proteins c-met/metabolism* ; Consensus ; Mutation

BACKGROUND: Abnormalities of the switch/sucrose nonfermentable (SWI/SNF) chromatin-remodeling complex are closely related to various cancers, and ARID1B (AT-rich interaction domain 1B) is one of the core subunits of the SWI/SNF complex. Mutations or copy number deletions of the ARID1B gene are associated with impaired DNA damage response and altered chromatin accessibility. However, whether ARID1B deficiency affects the proliferation, migration and invasion abilities of non-small cell lung cancer (NSCLC) cells and its molecular mechanisms remain poorly understood. This study aims to reveal the regulatory role of ARID1B gene deletion on the malignant phenotype of NSCLC cells and its molecular mechanism. METHODS: Online databases were used to analyze the relationship between ARID1B and the prognosis of patients with lung cancer, and the expression levels of ARID1B in lung cancer tissues. The CRISPR/Cas9 (clustered regularly interspaced short palindromic repeat) technology was employed to construct stable ARID1B gene knockout (KO) cell lines. The plate colony formation assay was used to detect cell proliferation, and the Transwell cell migration and invasion assays were used to detect changes in cell migration ability. RNA-Seq was utilized for the expression and enrichment analysis of differentially expressed genes. Western blot (WB) was used to verify the knockout effect of the ARID1B gene and to detect the expression changes of epithelial-mesenchymal transition (EMT) markers and mitogen-activated protein kinases (MAPK) signaling pathway-related proteins. Nude mouse tumor models were constructed and the tumorigenic abilities of control and ARID1B-deficient cells were compared. RESULTS: Patients with low ARID1B expression have poor overall survival. ARID1B is differentially expressed in lung cancer and normal tissues, and its expression level being lower in cancer cells. ARID1B-deficient cells had significantly enhanced in vitro proliferation, migration and invasion abilities. In animal experiments, the tumor formation speed of ARID1B gene deficient cells was significantly accelerated. Enrichment analysis of RNA-Seq results revealed that the differentially expressed genes were mainly enriched in MAPK, phosphoinositide 3-kinase-protein kinase B (PI3K/Akt) and other signaling pathways. WB experiments demonstrated that the expressions of E-cadherin, N-cadherin and Vimentin changed in ARID1B gene deficient cells, and the expressions of MAPK and p-MAPK was increased. CONCLUSIONS The A549-ARID1B KO and PC9-ARID1B KO cell lines were successfully established. The ARID1B-deficient cell lines demonstrated high migration, invasion and proliferation potential at both in vitro and in vivo biological behavior levels and at the transcriptome sequencing level. The changes in the expression of EMT markers and the activation of the MAPK signaling pathway suggest possible metastasis mechanisms of ARID1B-deficient NSCLC.
Humans ; Cell Proliferation/genetics* ; Cell Movement/genetics* ; Lung Neoplasms/metabolism* ; Animals ; Carcinoma, Non-Small-Cell Lung/physiopathology* ; Transcription Factors/metabolism* ; Neoplasm Invasiveness ; Mice ; DNA-Binding Proteins/metabolism* ; Gene Deletion ; Cell Line, Tumor ; Epithelial-Mesenchymal Transition ; Mice, Nude ; Gene Expression Regulation, Neoplastic