Bronchopulmonary dysplasia (BPD) is a chronic lung disease primarily affecting preterm infants, characterised by impaired alveolar development and persistent inflammation, particularly associated with ventilator-induced lung injury due to mechanical ventilation. In this study, we performed an integrated bioinformatic analysis of multiple datasets (GSE108754 and GSE39840) and identified 203 differentially expressed genes (DEGs) between BPD and control samples. Functional enrichment analysis revealed significant involvement in cytokine-mediated signalling, response to lipopolysaccharide and regulation of interferon-beta production. Using machine learning algorithms (LASSO, SVM-RFE and Random Forest), we identified three hub genes (IL6, TFRC and PIEZO1) with high diagnostic accuracy for BPD. Immune infiltration analysis indicated altered immune cell proportions in BPD, with PIEZO1 expression positively correlated with neutrophil infiltration. Experimental validation confirmed elevated NETosis markers (PADI4, MPO, dsDNA) in BPD patients and further demonstrated that PIEZO1 overexpression promotes NET formation via calcium overload, which was inhibited by verapamil. Additionally, using a co-culture system, we showed that PIEZO1-induced NETosis exacerbates pulmonary fibrosis in lung epithelial cells. These findings highlight PIEZO1 as a key regulator of NETosis in BPD and a promising therapeutic target for mitigating lung injury and fibrosis.

Tumor-associated macrophages (TAMs) enriched in tumor microenvironment (TME) promote immune evasion and poor prognosis. Mitochondrial dysfunction, especially branched-chain amino acid (BCAA) metabolic reprogramming, has been confirmed to be involved in regulating TAMs function. The mitochondria-related protein MTFR2 was significantly upregulated in LUAD and closely associated with reduced survival. We conducted flow cytometry, multiplex immunofluorescence, immunohistochemistry on LUAD tissues, combined with analysis of public single-cell sequencing datasets, to characterize the TME features under MTFR2 dysregulation. Transcriptomics, metabolomics, and proteomics analyses revealed BCAA metabolic reprogramming, which was driven by MTFR2 binding to Leu125 within the β8 strand of VDAC1 and promoting its oligomerization. This interaction triggered mtDNA release into the cytoplasm, activating the TLR9-NF-κB pathway to upregulate BCAT1. Elevated concentrations of BCAA metabolites such as α-ketoisocaproate (KIC) and α-keto-β-methylvalerate (KMV) in the TME promoted M2 polarization and infiltration of TAMs by in vitro co-culture, 3D spheroid, and organoid models, and polarized M2 macrophages reciprocally promoted LUAD progression. Our findings establish a LUAD associated MTFR2-VDAC1-BCAT1 axis regulating the BCKAs-M2 axis in TAMs. Notably, targeting BCAT1 or depleting macrophages blocked this loop, offering a potential combination therapy for LUAD.

Background:Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. While identifying drivers of tumor progression is critical, the molecular alterations specifically associated with T-stage advancement remain poorly understood. This study aimed to investigate genes linked to T-stage progression in PM using The Cancer Genome Atlas (TCGA) data, with a focus on the previously unreported roles of PRR11 and HEPACAM in this disease. Methods:RNA-sequencing data and clinical information for 87 PM patients were obtained from the TCGA database. After excluding patients with missing survival data, 43 patients were included in the survival analysis. Differential expression analysis was performed between advanced (T3-T4) and early (T1-T2) T-stage tumors using DESeq2. Survival analysis was conducted using Kaplan-Meier curves and multivariate Cox proportional hazards models. Associations between gene expression and T stage were evaluated, and the correlation between PRR11 and HEPACAM was assessed using Spearman correlation analysis. Results:A total of 116 differentially expressed genes (DEGs) were identified between T3-T4 and T1-T2 tumors. While PRR11 was the most significantly upregulated gene in the overall DEGs analysis (log2FC =5.87), its expression showed no significant difference when directly comparing T3-T4 to T1-T2 groups (P=0.44). However, in multivariate analysis, high PRR11 expression emerged as an independent prognostic factor for worse overall survival (OS) [hazard ratio (HR) =2.74, P=0.005]. In contrast, HEPACAM, identified as the most significantly downregulated gene in the DEG analysis (log2FC =-5.10), exhibited paradoxically higher expression in advanced T-stage tumors compared to early-stage tumors (P=0.01). HEPACAM expression showed no significant association with OS (log-rank P=0.3). Notably, a significant negative correlation was observed between PRR11 and HEPACAM expression (Spearman's ρ =-0.375, P=0.01). Conclusions:This study reveals divergent roles for PRR11 and HEPACAM in PM. PRR11 is a robust independent prognostic biomarker, despite its lack of correlation with local tumor invasion as defined by T stage. HEPACAM demonstrates a complex, stage-dependent expression pattern, suggesting a potential context-dependent role in late-stage tumor biology. The inverse correlation between these genes may reflect opposing cellular programs in PM progression. These findings provide new insights into the molecular heterogeneity of PM and highlight the importance of integrating multiple analytical approaches when interpreting transcriptomic data.

Fungal metabolites represent a valuable but underexplored source of anticancer agents, in part due to poorly defined mechanisms of action. Kojic acid (KA) is a fungal secondary metabolite with reported anti-melanoma activity, but its mechanism of action remains unclear. Here, we show that KA inhibits melanoma progression by disrupting MYC-driven transcriptional programs. KA treatment reduced proliferation and induced apoptosis in melanoma cells in vitro, and suppressed tumor growth in xenograft models. Transcriptomic profiling revealed a dose-dependent repression of MYC target genes, with CCNA2 and KPNA2 identified as key effectors. Both genes were validated as direct MYC targets and were associated with poor prognosis in the melanoma cohort (TCGA-SKCM). KA did not alter MYC expression but impaired its promoter binding and transcriptional activation of CCNA2 and KPNA2. Single-cell analysis further localized this axis to a proliferative mitotic subpopulation, promoting melanoma progression. These findings uncover a previously unrecognized mechanism by which KA inhibits melanoma growth and suggest that targeting the MYC-CCNA2/KPNA2 pathway may provide a therapeutic strategy for melanoma.

Introduction This study explores the role of Major Facilitator Superfamily Domain-containing Protein 9 (MFSD9) in lung adenocarcinoma (LUAD) using bioinformatics and experimental validation, aiming to identify its potential as a biomarker and therapeutic target.Methods Comprehensive analysis of MFSD9 expression across cancers, particularly LUAD, was carried out using The Cancer Genome Atlas (TCGA) dataset. Correlations between MFSD9 expression and clinical outcomes, immune infiltration, immune checkpoint genes, tumor mutational burden (TMB), microsatellite instability (MSI), mRNA expression-stemness index (mRNAsi), and drug sensitivity were examined. Validation was performed using the Human Protein Atlas (HPA), Gene Expression Omnibus (GEO) databases, and qRT-PCR in LUAD cell lines.Results MFSD9 was significantly overexpressed in LUAD, correlating with reduced overall survival (OS) and progression-free survival (PFS) (p = 0.044 and p = 0.026, respectively). It was found to be an independent prognosis factor (p = 0.046). MFSD9 expression was associated with immune cell infiltration, immune checkpoint genes, TMB, MSI, and mRNAsi, and inversely correlated with sensitivity to certain drugs, including zygosporin A and lovastatin.Discussion MFSD9 shows promise as a prognostic biomarker and therapeutic target in LUAD. Its role in immune modulation and tumor progression highlights its potential for immunotherapy. However, further experimental validation is needed to address study limitations.Conclusion MFSD9 is a potential biomarker and therapeutic target in LUAD, with significant implications for prognosis and treatment response. Future studies should focus on functional validation and clinical application.

Objective:To investigate the effects of metabolic syndrome (MetS) and its interaction with genetic factors on lung cancer incidence and mortality. Methods:The cohort analysis included 355,344 participants from the UK Biobank. MetS was defined using the modified National Cholesterol Education Program Adult Treatment Panel III criteria. Cox proportional hazards models were used to evaluate the associations between MetS-related variables, their interactions with genetic factors, and lung cancer outcomes (incidence and mortality). Results:MetS was associated with increased risks of lung cancer incidence (hazard ratio [ HR]: 1.31, 95% confidence interval [ CI]: 1.22-1.42) and mortality ( HR: 1.35, 95% CI: 1.24-1.48). Risk increased proportionally to the number of metabolic abnormalities. Increased waist circumference, reduced high-density lipoprotein cholesterol, and elevated glycated hemoglobin were independently associated with both outcomes. Participants with both high genetic risk and MetS had the highest risk of lung cancer incidence ( HR: 2.07, 95% CI: 1.82-2.35) and mortality ( HR: 2.12, 95% CI: 1.83-2.45) compared with those with low genetic risk and no MetS. A significant positive additive interaction was observed between waist circumference and genetic risk. Conclusion:Metabolic abnormalities are important modifiable risk factors for lung cancer. Integrating metabolic health assessment with genetic risk profiling may improve risk stratification and targeted prevention of lung cancer.

Hepatitis C virus (HCV) infection induces hyperinsulinemia and is associated with various extrahepatic manifestations, including effects on pancreatic β cells. However, the specific impact of HCV infection on β-cell function remains unclear. This study elucidates the mechanisms of hyperinsulinemia in HCV-infected individuals and its clinical significance in the era of direct-acting antiviral (DAA) therapy. Analysis of 118 non-diabetic HCV-positive patients demonstrated significantly elevated basal insulin levels and C-peptide concentrations compared with 30 healthy controls, with serum/hepatic HCV RNA load positively correlating with insulin secretion. In vitro investigations revealed regulatory effect of HCV on insulin secretion: stimulation under low-glucose conditions via nitric oxide (NO)-dependent pathways, and inhibition under high-glucose conditions. Mechanistically, HCV infection activated the TLR3/TRIF/NF-κB signaling axis to upregulate inducible nitric oxide synthase (iNOS), leading to enhanced NO production that promoted basal insulin release. Pharmacological inhibition of NO or iNOS abrogated HCV-induced insulin hypersecretion without compromising viral replication. Clinically, these findings establish hyperinsulinemia as a pre-diabetic marker in HCV infection and identify the NF-kB/iNOS/NO pathway as a therapeutic target for metabolic comorbidity prevention. Despite HCV curability with DAAs, this work highlights persistent virus-induced β-cell dysfunction and informs integrated strategies for antiviral and metabolic intervention to optimize long-term patient outcomes.

Lipin proteins, including Lipin 1, Lipin 2 and Lipin3, play a vital role in lipid metabolism. Despite their significance, there is limited understanding of the involvement of Lipin proteins in kidney diseases. This study aims to elucidate the specific functions of Lipin 3 in the context of acute kidney injury (AKI). In the present study, Lipin3 levels were analyzed in AKI public database, kidney tissues from AKI patients and cisplatin induced mice models, as well as cisplatin induced HK2 cells. A Lipin3 knockout (Lipin3-KO) mouse model was generated to investigate the pathophysiological roles of Lipin3 in the kidneys. The underlying mechanisms were further examined in primary tubular epithelial cells (PTECs) and HK2 cells in vitro. The findings indicated that (1) Lipin3 was obviously increased in AKI patients, as well as cisplatin induced mice and cells; (2) Lipin3-null mice presented with more severe AKI symptoms compared to WT mice after cisplatin treatment; (3) Lipin3 played crucial role in regulating cell death and mitochondrial function after cisplatin treatment; (4) In terms of mechanism, Lipin3 regulated these phenotypes through its interaction with Sirt1, which activated the p21-Caspase 3-GSDME pathway. Our study suggests that Lipin3 could be pivotal in pyroptosis and AKI. Decreased Lipin3 levels in the kidney may potentially contribute as a risk factor for exacerbating AKI.

Background: HER2 mutations are rare driver events in advanced NSCLC, with limited relief from current targeted therapies. This study aimed to characterize the molecular features of HER2-mutant NSCLC and to evaluate the clinical efficacy of pyrotinib-based combination therapy as a first-line treatment, providing evidence for optimizing treatment strategies. Methods: NSCLC patients diagnosed at Jiangsu Province People’s Hospital from 2016 to 2024 were enrolled. HER2-positive cases were screened by IHC/FISH and further profiled by NGS. Treatment response was assessed by RECIST 1.1, and survival analysis was performed using Kaplan–Meier and log-rank tests. Results: Among 144 HER2-mutant NSCLC cases confirmed by NGS, 10 insertion mutations, 26 missense mutations, and 2 fusion mutations were identified. The most common mutation was the exon 20 p.A775_G776insYVMA (47.9%), and TP53 was the most frequent co-mutation (10.4%). In terms of efficacy, the pyrotinib-based combination therapy demonstrated significant clinical benefit, with an ORR of 33.3%, DCR of 95.2%, median PFS (mPFS) of 11.3 months (95% CI: 10.27–12.26), and median OS (mOS) of 21.0 months (95% CI: 18.00–23.94). Subgroup analysis revealed no significant impact of mutation subtype or co-mutation status on the treatment efficacy, but patients with brain metastases had a significantly worse prognosis than those without metastasis (mPFS: 5.1 vs. 12.9 months, p < 0.01; mOS: 9.3 vs. 26.5 months, p < 0.01). All TRAEs were grade 1–3 (any grade: 90.5%; grade 3: 14.3%), with the most common TRAE being diarrhea (any grade: 85.7%; grade 3: 9.5%). Conclusions: Pyrotinib-based combination therapy is a feasible first-line treatment for HER2-mutant NSCLC, demonstrating significant survival benefits and manageable toxicity. However, brain metastasis patients require enhanced comprehensive management.

PINK1/Parkin-mediated ubiquitin-dependent mitophagy is a critical negative regulatory machinery for browning in the inguinal white adipose tissue (iWAT). However, the precise regulatory mechanism underlying PINK1/Parkin-mediated mitophagy during browning of iWAT remains largely unknown. Here we report that PNPLA7, an Endoplasmic Reticulum and mitochondria-associated membrane (MAM) protein, inhibits browning of iWAT by promoting PINK1/Parkin-mediated mitophagy upon cold challenge or β3-adrenergic receptor agonist treatment. With genetic manipulation in mice, we show that adipose tissue overexpressing PNPLA7 induces mitophagy, abolishes iWAT browning and interrupts adaptive thermogenesis. Conversely, conditional ablation of PNPLA7 in adipose tissue promotes browning of iWAT, resulting in enhanced adaptive thermogenesis. Mechanistically, PNPLA7 interacts with Parkin to promote mitochondrial recruitment of Parkin for mitophagy activation and mitochondria degradation by disrupting PKA-induced phosphorylation of Parkin under cold challenge. Taken together, our findings suggest that PNPLA7 is a critical regulator of mitophagy that resists cold-induced browning of iWAT, thus providing a direct mechanistic link between mitophagy and browning of iWAT.

Alterations in the mesenchymal-epithelial transition factor (MET) gene are critical drivers of non-small cell lung cancer (NSCLC). In recent years advances in precision therapies targeting MET alterations have significantly expanded treatment options for NSCLC patients. These alterations include MET exon 14 skipping mutations (MET exon 14 skipping), MET gene amplifications, MET point mutations (primarily kinase domain mutations), and MET protein overexpression. Accurate identification of these alterations and appropriate selection of patient populations and targeted therapies are essential for improving clinical outcomes. The East China Lung Cancer Group, Youth Committee (ECLUNG YOUNG, Yangtze River Delta Lung Cancer Cooperation Group) has synthesized insights from China’s innovative drug development landscape and clinical practice to formulate an expert consensus on the diagnosis and treatment of NSCLC patients with MET alterations. This consensus addresses key areas, such as optimal testing timing, testing methods, testing strategies, quality control measures, and treatment approaches. By offering standardized recommendations, this guidance aims to streamline diagnostic and therapeutic processes and enhance clinical decision-making for NSCLC with MET alterations.

BACKGROUND:The abnormal expression and overactivation of the epidermal growth factor receptor (EGFR), a typical cancer marker for non-small cell lung cancer (NSCLC), are closely related to the tumorigenesis and progression of NSCLC. However, the endocytosis mechanism of EGFR in lung cancer is not yet known. Epsin3 (EPN3), a member of the endocytic adaptor protein family, is essential for the endocytosis of multiple receptors. In this study, we aimed to investigate the role of EPN3 in modulating EGFR function, its effects on NSCLC progression, and its potential involvement in tyrosine kinase inhibitor (TKI) resistance, which remains a significant hurdle in NSCLC treatment. RESULTS:Our findings revealed that the expression of EPN3 is significantly up-regulated in NSCLC patients. Elevated EPN3 expression was proportional to shorter overall survival in patients with NSCLC. Functional analyses revealed that EPN3 directly interacts with EGFR, enhancing its recycling to the plasma membrane and preventing its degradation via the lysosomal pathway. This stabilization of EGFR led to sustained downstream signalling, promoting NSCLC cell proliferation and migration. Notably, mutations in the EGFR tyrosine kinase domain, which typically confer resistance to TKIs, did not alter the regulatory effect of EPN3. CONCLUSIONS:EPN3 enhances EGFR signalling by promoting its recycling and stability, contributing to NSCLC progression and TKI resistance. Targeting EPN3 could offer a novel therapeutic strategy to overcome drug resistance in EGFR-driven NSCLC.

Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus. This study investigated the effects of alogliptin on DCM and its underlying mechanisms. A DCM model was constructed and treated with alogliptin. Downstream targets of alogliptin were screened using bioinformatics analysis. An in vitro DCM model was constructed using mouse cardiomyocytes with a high concentration of glucose. Echocardiography was performed to measure the heart function parameters. Myocardial damage, collagenous fibrosis, and apoptosis of cardiomyocytes in mouse heart tissues were assessed using cardiac histological staining. AURKB and NLGN2 levels, ROS levels, MDA levels, SOD activity, and cardiomyocyte viability were determined. Alogliptin ameliorated DCM in mice. Bioinformatics analysis revealed that the target of alogliptin was AURKB, and the downstream target of AURKB was NLGN2. AURKB and NLGN2 levels were reduced in the heart tissues of streptozotocin-induced mice. Combined knockdown of AURKB and NLGN2 inhibited the therapeutic effect of alogliptin in DCM mice. Alogliptin attenuated oxidative stress, increased viability, and decreased apoptosis in cardiomyocytes treated with high glucose, which were reversed by combined knockdown of AURKB and NLGN2. Overall, alogliptin ameliorated oxidative stress in cardiomyocytes and DCM in mice by promoting AURKB expression to transcriptionally activate NLGN2.

e20636 Background: Nimotuzumab (a humanized monoclonal antibody) has shown antitumor activity in lung adenocarcinoma. We aimed to evaluate the efficacy and safety of nimotuzumab plus chemotherapy for lung adenocarcinoma with third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) resistance. Methods: Patients with stage IV, metastatic, EGFR-mutated, posterior line therapy failed, and EGFR-TKIs resistant lung adenocarcinoma were collected from Nov, 2018 to Dec, 2023. All patients received nimotuzumab (600 mg every 3 weeks) plus chemotherapy. Overall survival (OS) was the primary endpoint. The second endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Results: A total of 19 patients were screened. As of Sep 20, 2024, the median follow-up was 30.4 months (95% CI: 18.7, not evaluable). The median age was 61.0 years with a range of 42-79. 19 (100.0%) patients had EGFR mutation, 1 (5.3%) patient was treated with second-line treatment, 18 (94.7%) patients with third-line and above treatment. ORR was 26.3% (95% CI: 9.1, 51.2), and DCR was 89.5% (95% CI: 66.9, 98.7). 1-year OS rate was 57.9% (95% CI: 33.2, 76.3) and 2-year OS rate was 23.7% (95% CI: 7.2, 45.5), with the median OS was 12.8 months (95% CI: 5.7, 20.1). 1-year PFS rate was 26.3% (95% CI: 9.6, 46.8), with the median PFS was 4.4 months (95% CI: 3.3, 10.2). Subgroup analysis exhibited that patients with nimotuzumab treatment ≥5 cycles (median PFS=12.39 months, 95% CI: 4.44, 12.91) and no brain metastasis (median PFS=9.23 months, 95% CI: 3.48, NA) have a trend of survival benefit of PFS. Compared to the brain metastasis population, no brain metastasis population had higher 1-year OS rate (66.67% vs. 53.85%, P = 0.09) and 1-year PFS rate (50.00% vs. 15.38%, P = 0.06). The intracranial efficacy after receiving nimotuzumab showed partial response in 7.7% (1/13), stable disease in 76.9% (10/13), and progressive disease in 15.4% (2/13), with an ORR of 7.7% and a DCR of 84.6%. The most frequent Grade 3-4 treatment-related adverse events (AEs) included leukopenia, myelosuppression, neutropenia, thrombopenia, vomiting, nausea, and gastrointestinal reaction. No serious AEs or deaths were monitored. Conclusions: This combination therapy indicated a favorable clinical benefit and tolerable toxicity in the posterior line treatment of patients with third-generation EGFR-TKIs resistant lung adenocarcinoma.

Ubiquitination plays important roles in various biological processes and diseases by affecting the subcellular localization, function, and degradation of substrates. Multiple ubiquitin-associated enzymes jointly mediate the binding of ubiquitin to substrates. Over the past few decades, numerous E3 ubiquitin ligases, including RING finger protein 114 (RNF114), have been well studied. Research has revealed the involvement of RNF114 in various biological processes, including embryonic development, the cell cycle, genome stability, the immune response, and osteoclastogenesis. Additionally, RNF114 is implicated in multiple diseases, such as viral infections, psoriasis, liver fibrosis, and cancer. This review recapitulates the most recent advances regarding RNF114 and provides possible directions for future research.

Background Patients with breast cancer exhibit different tumor shrinkage patterns (TSPs) after neoadjuvant therapy (NAT), making accurate TSP prediction essential for breast-conserving surgery planning. The intratumoral microbiome influences treatment response, and related imaging features may improve TSP prediction. Purpose To develop an intratumoral microbiome-related MRI model that accurately predicts TSP following NAT. Materials and Methods This retrospective study included patients with breast cancer who underwent NAT followed by surgery at 12 institutions between July 2015 and April 2023. Patients were allocated to training (n = 671), internal validation (n = 335), and external validation (n = 1243) sets. Pre-NAT and mid-NAT MRI scans were collected for model development and validation. Five models integrating three-dimensional U-Net automated segmentation, habitat radiomic and/or deep learning (ResNet-50) features, and histologic intratumoral microbiome data were developed: pre-NAT habitat, mid-NAT habitat, pre-NAT ResNet-50, mid-NAT ResNet-50, and a fusion model. Models were validated across molecular subtypes and tumor stages using receiver operating characteristic curves, confusion matrices, and diagnostic metrics. Shapley additive explanations were used to interpret model output. Results Among 2249 women with breast cancer (median age, 49 years [IQR, 42-56 years]), 1238 (55%) experienced concentric shrinkage. Tumors with concentric shrinkage had increased microbiome abundance (P < .001). The three-dimensional U-Net achieved Dice coefficients of 0.96, 0.92, and 0.91 on pre-NAT MRI scans and 0.96, 0.90, and 0.88 on mid-NAT MRI scans in the training, internal validation, and external validation sets, respectively. The fusion model outperformed single-time point models in the internal validation set (area under the receiver operating characteristic curve [AUC], 0.89 vs 0.80-0.83; all P < .05) and external validation set (AUC, 0.87 vs 0.74-0.81; all P < .001), remaining robust across molecular subtypes (AUC range, 0.85-0.91) and tumor stages (AUC range, 0.84-0.89). Shapley additive explanations confirmed that each imaging feature independently predicted TSP. Conclusion An intratumoral microbiome-related MRI model enabled precise TSP prediction. © The Author(s) 2025. Published by the Radiological Society of North America under a CC BY 4.0 license. Supplemental material is available for this article.

Background:Gastric signet ring cell carcinoma (GSRCC) is a highly lethal malignancy. Serpin family E member 2 (SERPINE2) is a pro-tumorigenic factor in cancer. Here, we sought to define the role of SERPINE2 in the pathogenesis of GSRCC. Methods:Messenger RNA (mRNA) expression was analyzed by quantitative polymerase chain reaction (PCR). Protein expression was tested by immunohistochemistry (IHC) and immunoblot assays. Proliferation was assessed by 5-ethynyl-2'-deoxyuridine (EdU) assay, and invasion and migration were detected by transwell assay. Tube formation assay was used to test the influence on angiogenesis. Cell apoptosis and M2 macrophage polarization were evaluated by flow cytometry. The methyltransferase-like 3 (METTL3)-SERPINE2 relationship was analyzed by RNA immunoprecipitation (RIP), luciferase, and mRNA stabilization assays. Xenograft experiments were used for assessment of METTL3's influence on tumorigenicity of GSRCC cells. Results:SERPINE2 and METTL3 levels were upregulated in human GSRCC. Functionally, SERPINE2 depletion enhanced apoptosis of GSRCC cells and diminished their proliferative, migratory and invasive capacities in vitro. Moreover, SERPINE2 depletion suppressed tube formation ability of human umbilical vein endothelial cells (HUVECs) and M2 polarization of THP-1-derived macrophages. Mechanistically, METTL3 induced SERPINE2 upregulation by enhancing SERPINE2 mRNA stabilization. Our rescue experiments indicated that the effects of METTL3 depletion on cell phenotypes were due to the reduction of SERPINE2 expression. Additionally, METTL3 deficiency inhibited GSRCC xenograft growth in vivo. Conclusions:Our study defines the significant roles of the METTL3/SERPINE2 axis as an epigenetic mechanism in GSRCC progression. Our work may have diagnostic and/or therapeutic applications in GSRCC.

Drug resistance in tumors constitutes a significant obstacle to tumor therapy. Head and neck squamous cell carcinoma (HNSCC) presents a major challenge due to its deep anatomical location, limited space, and complex structure. These factors complicate surgical procedures and hinder the effectiveness of chemoradiotherapy, leading to poor prognosis and reduced quality of life. However, there is hope in the form of circular RNAs (circRNAs), non-coding RNA molecules with a closed-loop structure that exhibits superior stability and resistance to degradation compared to linear RNAs. Recent advances in high-throughput sequencing and bioinformatics technology revealed that circRNAs participate in tumor proliferation, invasion, migration, and drug resistance. This review aims to summarize current research progress on the involvement of circRNAs in drug resistance of HNSCC and provide valuable insights for the prevention and mitigation of drug resistance in HNSCC.

Dysregulation in lipid metabolism is among the most prominent metabolic alterations in cancer. Stimulated by retinoic acid 6 (STRA6), a vitamin A transporter has shown to be involved in the pathogenesis of cancers. Nevertheless, the function of STRA6 in non-small cell lung cancer (NSCLC) progression remains undefined. We obtained cancer and adjacent tissues from NSCLC patients and conducted functional experiments on STRA6 on NSCLC cell lines and mice. High STRA6 expression is correlated with poor prognosis in patients with NSCLC. Results from in vitro and in vivo animal studies showed that STRA6 knockdown suppressed the proliferation, migration, and invasion of NSCLC cells in vitro and tumor growth in vivo through regulation of lipid synthesis. Mechanistically, STRA6 activated a Janus kinase 2/signal transducer and activator of transcription 3 (JAK2-STAT3) signaling cascade which inducing the expression of STAT3 target gene. By inducing the expression of the target gene of STAT3, sterol regulatory element binding protein 1 (SREBP-1), STRA6 promotes SREBP-1-mediated adipogenesis and provides energy for NSCLC cell growth. Our study uncovers a novel STRA6/STAT3/SREBP-1 regulatory axis that enhances NSCLC metastasis by reprogramming of lipid metabolism. These results demonstrate the potential use of STRA6 as a biomarker for diagnosing NSCLC, which may therefore potentially serve as a therapeutic target for NSCLC.