Non-small cell lung cancer (NSCLC) is the predominant form of lung cancer. Ferroptosis is a novel therapeutic target against treatment resistance in NSCLC. However, its regulation by m6A RNA modification remains incompletely elucidated. m6A RNA modification mediates mRNA stability, translation, and splicing to target transcripts. Methyltransferase like 7B (METTL7B) has been implicated in tumor progression, but its role in NSCLC ferroptosis via m6A modification have not been reported. We aimed to investigate the mechanism of METTL7B-medaited m6A modification in NSCLC cell ferroptosis. NSCLC cells (SK-MES-1/PC9/H1975/A549) and normal cells (BEAS-2B) were cultured. The expression of METTL7B, long non-coding RNA 02159 (LINC02159), and aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) was determined. After METTL7B knockdown, cell viability was measured by MTT assay; ferroptosis-related factors were analyzed. m6A quantification was performed. m6A enrichment on LINC02159 was analyzed. The interaction between LINC02159 and KAT2A was verified. KAT2A and H3K27ac enrichment on the ARNTL2 promoter was detected. The roles of LINC02159 and ARNTL2 were validated. METTL7B, LINC02159, and ARNTL2 were upregulated in NSCLC cells compared to BEAS-2B cells. METTL7B knockdown increased iron ions, reactive oxygen species, and malondialdehyde levels and decreased cell viability, superoxide dismutase, and glutathione levels. METTL7B potentially upregulate LINC02159 expression through m6A modification. LINC02159 may recruit KAT2A to enhance H3K27ac enrichment on the ARNTL2 promoter, thereby promoting ARNTL2 expression. Overexpression of LINC02159 or ARNTL2 partially reversed the pro-ferroptotic effects of METTL7B knockdown on NSCLC cells. In conclusion, METTL7B inhibits ferroptosis in NSCLC cells via the LINC02159/KAT2A/ARNTL2 axis in an m6A-dependent manner.

Hydroxyacetone was previously detected at high concentrations (up to ∼12 mg/mL) in electronic cigarette (EC) aerosols, including those derived from products associated with adverse health effects. Given the limited understanding of its inhalation toxicology, we investigated hydroxyacetone's impact on human airway epithelial cells. Acute exposures at the air-liquid interface (ALI) using 3D EpiAirway tissues─a surrogate for human tracheobronchial epithelium─were analyzed via proteomics. Differential expression analysis identified numerous affected proteins, with enrichment pointing to alterations in mitochondrial function and actin cytoskeletal disruption as major targets. Ingenuity Pathway Analysis (IPA) highlighted "Mitochondrial Dysfunction" and "NRF2-Mediated Oxidative Stress" among top toxicological categories, and "Nuclear Cytoskeletal Signaling" as a key canonical pathway. To validate and extend these findings, submerged cultures of BEAS-2B cells were exposed to hydroxyacetone (0.01-10 mg/mL) and assessed for mitochondrial activity, oxidative stress, and F-actin integrity. At 1 mg/mL, mitochondrial membrane potential and reactive oxygen species (ROS) increased, with elevated hydrogen peroxide detected in the culture medium. At 10 mg/mL, mitochondrial activity declined significantly, accompanied by cell rounding and apoptotic blebbing within 2 h. F-actin destabilization occurred at 1, 3.33, and 10 mg/mL, with cytoplasmic and perinuclear filaments more affected than cortical actin. Findings from ALI and submerged models were concordant, supporting hydroxyacetone-induced mitochondrial stress, oxidative damage, and cytoskeletal disruption. These results suggest that hydroxyacetone concentrations found in EC aerosols may contribute to respiratory toxicity and warrant further investigation.

MD2 mediates COPD pathogenesis by inducing airway inflammation and ferroptosis through the TLR4/MyD88 pathway.

Modulation of airway inflammation by recombinant Der p 38 mutant immunotherapy in a murine model of allergic asthma.

Zhichuanling oral liquid attenuates airway inflammation in asthma by targeting the STIM1/CHOP/JNK axis.

Problems such as high toxicity, low selectivity, and drug resistance encountered in cancer treatment increase the need for more effective and safe anticancer agents. In this study, the anticancer effects of new compounds consisting of thiazole and 1,3,4-thiadiazole derivatives were investigated. Compound 6e, which showed the strongest cytotoxic effect, was evaluated in detail in human bladder (HTB-9) and lung (A549) cancer cells. According to the WST-1 test results, the IC50 value of compound 6e was determined as 38.9 μM for HTB-9 cells and 82.86 μM for A549 cells. As a result of Annexin V-FITC/PI double staining and flow cytometry analysis, it was determined that compound 6e application significantly increased the apoptotic cell rates in both HTB-9 and A549 cells. It was observed that it significantly induced early apoptosis in HTB-9 cells and late apoptosis in A549 cells (p < 0.0001). Caspase-3/7 activity was significantly increased in HTB-9 cells after compound 6e application compared to the control group and similarly increased in A549 cells (p < 0.0001). In cell cycle analyses, compound 6e caused cell cycle arrest in the G2/M phase in HTB-9 and A549 cells. In the wound healing test, the migration speed in HTB-9 and A549 cells treated with compound 6e after 24 h was significantly decreased (p < 0.0001). Molecular docking revealed strong binding to caspase-3 (PDB ID: 1NMQ, score: -8.2 kcal/mol), identifying key interactions that mechanistically support its pro-apoptotic effects. In addition, the low cytotoxicity of compound 6e in healthy BEAS-2B cells suggests that it has a selective anticancer effect.

Elucidation of the anti-NSCLC mechanism of flavonoid derivative JW4 by an integrative approach of network pharmacology and experimental verification.

Morpholine-modified thiosemicarbazones and thiazolidin-4-ones against Alzheimer's key enzymes: From synthesis to inhibition.

Scutellarin alleviates ferroptosis in cigarette smoke-induced chronic obstructive pulmonary disease via activation of the PI3K/AKT/Nrf2 signaling pathway.

Lonicerae Japonicae Flos (LJF), a traditional Chinese medicine with strong anti-inflammatory and antioxidant effects, was previously shown to suppress ferroptosis in acute lung injury (ALI). This study further aimed to identify its anti-ferroptotic quality markers (Q-markers) and elucidate their mechanisms for ALI therapy. Chemical fingerprints of 22 LJF batches were established, and absorbed constituents were identified through serum pharmacochemistry. Principal component analysis (PCA) and gray correlation analysis (GCA) were applied to link chemical composition with pharmacological effects. Ferroptosis-related indicators were measured in an LPS-induced ALI mouse model after treatment with different extracts. The anti-ferroptotic activity of individual constituents was validated in BEAS-2B cells, leading to the identification of Q-markers. To confirm target engagement, transcriptomic sequencing, protein-protein interaction (PPI) network construction, ferroptosis-target enrichment, real-time quantitative polymerase chain reaction (RT-qPCR), molecular docking, and molecular dynamics (MD) simulations were conducted. 17 candidate constituents with potential anti-ferroptotic and anti-inflammatory activities were identified, of which 9 showed strong correlations with efficacy. Four compounds-protocatechuic acid, loganin, cynaroside, and isochlorogenic acid C-demonstrated significant ferroptosis-inhibitory activity and were designated as Q-markers. Transcriptomic and PPI analyses indicated that these constituents target key ferroptosis-related proteins, including IL-6, Stat3, and Mapk3. Their regulatory effects and binding stability were further validated by RT-qPCR, molecular docking, and MD simulations. LJF exerts anti-inflammatory protection through the synergistic inhibition of ferroptosis by multiple constituents. The identification of protocatechuic acid, loganin, cynaroside, and isochlorogenic acid C as Q-markers provides scientific evidence supporting the therapeutic potential of LJF for ALI.

Hexavalent uranium (U(VI)) is widely found in nature and has an impact on human lung health. In this study, the proteomic changes in lung epithelial BEAS-2B cells exposed to U(VI) were evaluated using DIA (Data-Independent Acquisition) proteomics. BEAS-2B cells cultured in vitro were exposed to 0, 200, 400, and 700 mg/L U(VI) for 24 h, and differential proteins were identified by classification, KEGG pathway enrichment, and GO enrichment analysis. Furthermore, oxidative stress levels were measured, and five proteins were screened for validation. The results indicated that the number of differential proteins increased with the increase of the U(VI) dose. The differentially expressed proteins (DEPs) identified in the GJL vs Control comparison were significantly enriched in several KEGG pathways, including the PI3K-Akt signaling pathway, pathways in cancer, cell cycle, lysosome, and JAK-STAT signaling pathway. The DEPs related to the nucleoplasm, nucleus, and cytoskeleton were found to be enriched in several biological processes, including the cell cycle, positive regulation of transcription by RNA polymerase II, cell division, and cell migration. Differential proteins involve multiple organelles, and their functions are mostly related to protein binding. Furthermore, the ROS level increased, and the GSH was reduced. The expressions of STAT3, N-cadherin, and CDK2 proteins were down-regulated, and the expressions of GPX3 and TNFSF10B were up-regulated. This study provides a comprehensive understanding of the molecular mechanisms underlying U(VI)-induced pulmonary epithelial cytotoxicity.

Non-small-cell lung cancer (NSCLC) is one of the most prevalent cancer types and accounts for the majority of cancer-related deaths worldwide. Tanshinone and its derivatives exhibit diverse biological activities, and their prominent antitumor potential has been well documented. In this study, we rationally designed a series of tanshinone derivatives with a scaffold-hopping strategy. Thirty-five tanshinone derivatives were synthesized, and their cytotoxic activities against the NSCLC cell lines A549 and H838 were investigated. Concurrently, their safety profile was assessed in BEAS-2B cells. The results showed that compounds S2-1, S2-4, and S2-8 exhibited superior inhibitory activity against A549 cells compared with the positive control, β-lapachone. Meanwhile, compounds S2-1, S2-3, S2-4, S2-8, S2-13, and S2-14 exhibited similar or increased antiproliferation activity against H838 cells. Compounds S2-4 (0.58 ± 0.07 μM) and S2-8 (0.42 ± 0.04 μM) demonstrated the greatest potency towards H838 cells; compounds S2-13 (1.28 ± 0.13 μM) and S2-14 (1.80 ± 0.24 μM) exhibited potent and selective activity towards H838 cells. Molecular docking studies of S2-4/NLRP3 and S2-14/STAT3, combined with the structure–activity relationship (SAR) analysis, indicated that the benzofuran core containing an ortho-quinone, along with an amide linkage and a 1,2,3-triazole group introduced at the C-2 position of the furan ring, is an effective chemical scaffold for enhancing the anti-NSCLC activity of tanshinone derivatives.

Transcription factor TFAP2A drives EMT progress by activating BDKRB1 transcription: The potential mechanism by which TFAP2A promotes idiopathic pulmonary fibrosis.

Long-term exposure to silica nanoparticles induces DNA damage by activating ferritinophagy in the lungs.

ABSTRACT Background Fatty acid oxidation (FAO) is implicated in lung diseases, but its role in bronchial asthma is not fully understood. We investigated its effect on airway epithelial barrier integrity. Methods Using a house dust mite (HDM)-induced murine asthma model and HDM, IL-4, IL-13, or TNF-α stimulated human primary bronchial epithelial cells (BECs) and bronchial epithelial (Beas-2b) cells, we modulated FAO with L-carnitine (agonist) and Etomoxir (inhibitor). BECs and Beas-2b cells were infected with lentivirus-mediated CPT1A shRNA prior to stimulation. Barrier function, mitochondrial oxidative stress, inflammation, and metabolism were assessed. Results FAO level in lungs negatively correlated with increased inflammation and tissue injury in HDM-induced asthmatic mice (all p < 0.05), while positively regulating tight junction protein expression. In BECs and Beas-2b cells, Etomoxir treatment and CPT1A knockdown exacerbated the impairment of FAO caused by various stimulants (all p < 0.05). Furthermore, FAO negatively regulated HDM/cytokine-induced epithelial barrier damage, hyperactive inflammatory response, and mitochondrial dysfunction in Beas-2b cells (all p < 0.05). In contrast, treatment with L-carnitine significantly alleviated these pathophysiological features in both in vivo and in vitro models. Conclusion FAO plays a protective role in the occurrence and development of asthma by maintaining airway epithelial cell homeostasis and barrier function.

Effects of chloromethylisothiazolinone/methylisothiazolinone on cytotoxicity and mitochondrial dysfunction in bronchial epithelial cells.

Intratracheal perfluorooctane sulfonate induces pulmonary injury via TLRs signaling and disrupts sex steroidogenesis through systemic translocation.

Epithelial-mesenchymal transition (EMT) is amajor pathological characteristic of airway remodellingin severe asthma. Interleukin (IL)-36 belongs to the IL-1 family and is associated with allergic disease, but the role of IL-36 in airway remodelling in asthma remains unclear. We aimed to explore the effect of IL-36 on EMT and to verify whether blocking IL-36-induced EMT can alleviate the airway remodeling in severe asthma. In this study, BEAS-2B cells were stimulated with IL-36 receptor (IL-36R) agonist. The expression of epithelial‒mesenchymal transition (EMT) markers and the migration capacity of cells were determined. A chronic asthma mouse model was established to evaluate the effects of IL-36 signalling on airway inflammation and remodelling. In vitro, EMT and cell migration in BEAS-2BcellswereinducedbyIL-36. In addition, IL-36 facilitated the phosphorylation of NF-κB and STAT3. In vivo, blocking IL-36R via treatment with an IL-36 receptor antagonist (IL-36Ra) inhibited the infiltration of inflammatory cells, decreased airway hyper-responsiveness (AHR) and alleviated airway remodelling (by inhibiting processes, such as EMT) in asthmatic mice. Compared with the administration of IL-36Ra alone, the coadministration of IL-36R agonist with IL-36Ra restored pathological changes related to airway remodelling. These data indicated that IL-36 signalling may participate in airway remodelling by inducing EMT. IL-36 may be a new therapeutic target for airway remodelling in severe asthma.

Airway remodeling is a critical cause of chronic asthma that is difficult to control. Cell death contributes to the development and progression of chronic asthma. However, the novel copper-dependent cell death, cuproptosis, and especially cuproptosis of bronchial epithelial cells, its role, and underlying mechanisms in airway remodeling are unclear. Repetitive OVA exposure was used to establish a mouse model of chronic asthma. The human bronchial epithelial cell line BEAS-2B (BEAS-2B cells) was incubated with recombinant human IL-4 (rhIL-4) and TGF-β1 to simulated airway remodeling in vitro. Cuproptosis increased after repetitive OVA exposure in chronic asthmatic mice, evidenced by increased Cu2+ levels in bronchoalveolar lavage fluid (BALF) and increased protein expression of cuproptosis-related genes (FDX-1, LIAS, and DLAT), followed by increased airway responsiveness, lung inflammation, area of subepithelial fibrosis and mucus hypersecretion and expression of epithelial-mesenchymal transition (EMT)-related proteins (MMP-2, MMP-9, N-cadherin, vimentin and α-SMA). However, a cuproptosis blocker, the mitochondrion-targeted antioxidant, Szeto-Schiller (SS)-31, substantially inhibited the above mentioned processes. Meanwhile, we observed that proteins of the key regulator of cuproptosis (ferredoxin-1, FDX-1) and bronchial epithelial marker, Keratin 8/18, were partially colocalized in bronchial epithelial which demonstrated that OVA may mediate airway remodeling through cuproptosis of bronchial epithelial. Next, we simulated airway remodeling in vitro through coincubation of rhIL-4 and TGFβ1 in BEAS-2B cells and found that cuproptosis increased after rhIL-4 and TGFβ1 mediation, indicated by increased Cu2+ levels in supernatant and cytoplasm and increased protein expression of FDX-1, LIAS, and DLAT, whereas addition of SS-31 (10 ng/mL) 30 min before rhIL-4 and TGFβ1 treatment attenuated cuproptosis. Moreover, our results revealed increased cell migration and protein expression of above EMT-related proteins in response to induction of rhIL-4 and TGFβ1. Furthermore, silencing FDX-1 significantly inhibited above mentioned responses. Cuproptosis of bronchial epithelial cells participates in airway remodeling in chronic asthma by EMT induction through FDX-1 regulation and may be a therapeutic target in chronic asthma.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-34574-3.

This study aims to investigate the presence of NUF2 component of NDC80 kinetochore complex (NUF2) in tissues of lung adenocarcinoma (LUAD) and its correlation with infiltration of immune cells, clinical features, and prognosis of patients. A variety of online tools and websites were used to explore the role of NUF2 in LUAD. Verified by cellular and immunohistochemistry. The expression of NUF2 messenger RNA (mRNA) is notably elevated in LUAD, and its levels significantly influence the prognosis of patients with this condition. Additionally, NUF2 expression levels were observed to be associated with survival outcomes across different subgroups, including TNM stage, pathological stage, gender, age, and smoking behavior. We discovered 80 key genes linked to NUF2-associated genes, which play a crucial role in the organelle fission pathway in individuals with NUF2. Furthermore, methylation of NUF2 demonstrates a positive relationship with the levels of chemokines, their receptors, immunoinhibitors, and immunostimulators in LUAD. At the single-cell level, NUF2 expression ranges from highest in spermatocytes, followed by oocytes, and is lowest in erythroid cells. The predominant mutations observed in NUF2 within LUAD cases include amplification and other mutations. Moreover, evaluations utilizing the receiver operating characteristic (ROC) curve, along with time-dependent ROC analysis, indicated that the predictive accuracy of NUF2 is significantly enhanced. The prognosis for LUAD correlates with both immune cell infiltration and the expression levels of NUF2. In vitro studies with A549 cells revealed considerably higher mRNA expression levels when compared to BEAS-2B cells. Immunohistochemical assessments confirmed the presence of elevated NUF2 protein expression in human LUAD samples. NUF2 exhibits high expression levels in tissues and cells of LUAD, and is associated with the infiltration of immune cells within the tumor microenvironment as well as patient outcomes. Thus, NUF2 represents a promising target for the clinical treatment of LUAD.