Frontiers in Molecular Biosciences最新文献

{"title":"Investigation of sphingolipid-related genes in lung adenocarcinoma.","authors":"Jibin Mao, Li Li, Hui Sun, Jie Han, Jinqiao Li, Chang-Sheng Dong, Hongyu Zhao","doi":"10.3389/fmolb.2025.1548655","DOIUrl":"10.3389/fmolb.2025.1548655","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) is responsible for majority cases of lung cancer and considered to be the primary cause of cancer-related mortality. The imbalance of cellular proliferation and apoptosis is critically implicated in the pathogenesis and progression of LUAD. Sphingomyelin, a vital lipid component, is integral to the regulation of tumor cell growth and apoptosis, and has garnered significant attention as a target in novel anticancer therapies. The pivotal molecules involved in sphingomyelin metabolism are crucial in modulating tumor cell behavior, thereby influencing clinical outcomes.</p><p><strong>Methods: </strong>A comprehensive consensus clustering analysis was conducted by collecting clinical LUAD figures from the TCGA and GEO databases. By employing Cox regression and Lasso regression analysis, a prognostic model for LUAD patients was established by identifying seven sphingolipid-related genes (SRGs), and validated in the GEO database. The study also delved into the clinical relevance, functional capabilities, and immune implications of prognostic signals associated with sphingolipid metabolism. Finally, experiments conducted <i>in vitro</i> confirmed the imbalance of sphingolipid-associated genes in LUAD.</p><p><strong>Results: </strong>Using the prognostic model, lung adenocarcinoma (LUAD) patients can be divided into high-risk and low-risk groups. Meanwhile, we can observe marked disparities in survival times among these groups. Additionally, the model demonstrates high predictive accuracy in external validation cohorts. Research on the immune microenvironment and immunotherapy points to this risk stratification as a useful reference for immunotherapeutic strategies in LUAD. Finally, our hypothesis was corroborated through <i>in vitro</i> experiments.</p><p><strong>Conclusion: </strong>This study demonstrates that sphingolipid-related gene prognostic characteristics correlate with tumor progression and recurrence, long-term prognosis, and immune infiltration in LUAD patients. The outcomes of our study could help shape innovative strategies for early intervention and prognosis prediction in lung adenocarcinoma.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1548655"},"PeriodicalIF":3.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Metabolomics perspectives for clinical medicine, volume II.","authors":"Danuta Dudzik, Julia Kuligowski, Víctor González-Ruiz, Hector Gallart-Ayala","doi":"10.3389/fmolb.2025.1577050","DOIUrl":"10.3389/fmolb.2025.1577050","url":null,"abstract":"","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1577050"},"PeriodicalIF":3.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A dual-reporter LDLR system integrating fluorescence and luminescence for understanding LDLR regulation and facilitating drug discovery.","authors":"Peng Jiao, Na Yang, Qianfeng Jia, Baozhen Fan, Ke Feng, Jian Yu, Shengtian Zhao","doi":"10.3389/fmolb.2025.1552085","DOIUrl":"10.3389/fmolb.2025.1552085","url":null,"abstract":"<p><strong>Introduction: </strong>The low-density lipoprotein receptor (LDLR) is integral to cholesterol metabolism and cardiovascular health. Enhancing LDLR expression is a promising strategy for treating hyperlipidemia and reducing the risk of atherosclerosis. However, current LDLR reporter systems have limitations in detecting both transcriptional and translational regulation. To address this, we developed a novel dual-reporter LDLR system incorporating Enhanced Green Fluorescent Protein (EGFP) and Gaussia luciferase (Gluc) to enable precise monitoring of LDLR expression and function.</p><p><strong>Methods: </strong>A CRISPR/Cas9-mediated knock-in strategy was used to integrate EGFP and Gluc upstream of the stop codon located in exon 18 of the LDLR gene in HEK293 cells. The dual-reporter system allows real-time visualization of LDLR expression via EGFP fluorescence and quantitative assessment through secreted Gluc activity. The system was validated using western blotting, immunofluorescence, and functional assays, including DiI-LDL uptake and drug response analyses with statins and PCSK9 inhibitors.</p><p><strong>Results: </strong>The established LDLR-EGFP-Gluc knock-in cell line faithfully recapitulates endogenous LDLR expression and function. EGFP fluorescence accurately reflects LDLR expression dynamics, while Gluc activity provides a highly sensitive and quantitative readout. Functional assays confirmed that LDLR expression responds appropriately to statins and PCSK9 inhibitors. Additionally, screening for transcriptional regulators identified FOXP3 and CREB as novel modulators of LDLR expression, with CREB-mediated regulation involving the sterol regulatory element-binding protein 2 (SREBP2) pathway.</p><p><strong>Discussion: </strong>This dual-reporter system enables complementary monitoring of LDLR dynamics, providing enhanced sensitivity, accuracy, and versatility for studying LDLR regulation and function, as well as facilitating drug discovery targeting hyperlipidemia and cardiovascular diseases.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1552085"},"PeriodicalIF":3.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network pharmacology combined with untargeted metabolomics reveals the intervention mechanism and compatibility of chenpi-rougui herb pair in nonalcoholic fatty liver disease.","authors":"Jinlin Xu, Sen Li, Yuehui Jin, Huiwen Yao, Xu Hu, Shan Cao, Huimin Zhou","doi":"10.3389/fmolb.2025.1553162","DOIUrl":"10.3389/fmolb.2025.1553162","url":null,"abstract":"<p><strong>Background: </strong>Chenpi (the dried mature peel of <i>Citrus reticulata</i> Blanco) and Rougui (the dried bark of <i>Cinnamomum cassia</i> Presl) are both edible and medicinal plants, which have therapeutic effects on nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanisms necessitate further exploration. This study evaluated the prevention effect of Chenpi-Rougui herb pair (CRP) on NAFLD using an integrated strategy that combined network pharmacology with metabolomics.</p><p><strong>Methods: </strong>Initially, the components in CRP decoction were characterized by UPLC-QTOF-MS/MS. Subsequently, a high-fat diet induced NAFLD mouse model was used to assess the efficacy of CRP and its individual constituent, Chenpi and Rougui. Additionally, synergetic pathways and crucial targets for CRP therapy in NAFLD were identified using network pharmacology and serum metabolomics. Finally, real-time polymerase chain reaction (RT-PCR) was utilized to validate relevant genes.</p><p><strong>Results: </strong>CRP exerted a more extensive prevention effect on NAFLD mice compared to the individual herb of Chenpi and Rougui. A total of 105 compounds were characterized from CRP, which were linked to 70 potential therapeutic targets for NAFLD. Thirty-two differential metabolites were identified by metabolomics, which were co-regulated by Chenpi, Rougui and CRP. Pathways associated with the intervention of herb pair in NAFLD included energy metabolism, fatty acid metabolism, glycerophospholipid metabolism, sphingolipids metabolism, arachidonic acid metabolism, sterol and bile acid metabolism. Finally, eight targets were screened through conjoint analysis and experimental verification showed that six of them including FASN, AKT1, CASP3, F2, PTGS2 and PRKCA, could be modulated by CRP in NAFLD mice. Besides, Chenpi primarily regulated FASN, AKT1, CASP3 and PRKCA, which were associated with reducing apoptosis in hepatocytes, while Rougui exceled in regulating F2 and PTGS2, closely linked to its anti-inflammatory properties. The combination of Chenpi and Rougui resulted in a broader influence on metabolites, pathways, and primary targets compared to their individual application.</p><p><strong>Conclusion: </strong>These results provided valuable insights into the compatibility mechanism of CRP for treating NAFLD, and could also improve the value of its forthcoming application and development as a natural liver protective agent.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1553162"},"PeriodicalIF":3.9,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Molecular basis of the energy management in cells: implications in health and disease.","authors":"Vanessa Checchetto, Simona Reina, Francesca Maria Garino, Marianna Flora Tomasello","doi":"10.3389/fmolb.2025.1578972","DOIUrl":"https://doi.org/10.3389/fmolb.2025.1578972","url":null,"abstract":"","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1578972"},"PeriodicalIF":3.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression and distribution of activin-follistatin-inhibin axis in the urinary bladder.","authors":"Weipu Mao, Tracy Zhang, Huan Chen, Sagar Barge, Zongwei Wang, Aria Olumi, Seth Alper, Weiqun Yu","doi":"10.3389/fmolb.2025.1519977","DOIUrl":"10.3389/fmolb.2025.1519977","url":null,"abstract":"<p><p>The activin-follistatin-inhibin (AFI) axis plays a crucial role in sexual development and reproduction. Recently it was demonstrated that these proteins are also synthesized by many local tissues and regulate different biological activities, including tissue regeneration and cancer metastasis. However, little is known about the expression profile of the AFI axis in the bladder and its role in bladder function and dysfunction. We have examined the expression profile of 11 AFI family members in the mouse bladder. INHA, INHBA, and follistatin are the major ligand subunits detected among the six examined in the bladder. ACVR1, ACVR1B, and ACVR2B are the major receptor subunits detected among the five examined in the bladder. Immunolocalization studies reveal unique cellular distributions of these ligands and receptors within the bladder. The urothelial-localized ACVR2B/ACVR1B receptor complex suggests a role of activin signaling in urothelial function. The stimulatory activin A is present only in a subset of interstitial cells, separated from the urothelial activin receptor ACVR2B/ACVR1B by a basement membrane containing accumulated inhibitory ligand FST and by a layer of activin-negative myofibroblasts. This spatial information on AFI signal molecules suggests that activin A-positive interstitial cells might regulate urothelial cell function via paracrine signaling through activin A-ACVR2B/ACVR1B interaction. Further analysis of the human bladder confirmed the expression profile of the AFI axis, and revealed significantly upregulated expression of INHBA-ACVR2B in bladder cancer. These data suggest roles for these molecules in the growth and metastasis of bladder cancer, and highlight their potential as diagnostic and prognostic biomarkers.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1519977"},"PeriodicalIF":3.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative multi-omics analysis and machine learning refine global histone modification features in prostate cancer.","authors":"XiaoFeng He, QinTao Ge, WenYang Zhao, Chao Yu, HuiMing Bai, XiaoTong Wu, Jing Tao, WenHao Xu, Yunhua Qiu, Lei Chen, JianFeng Yang","doi":"10.3389/fmolb.2025.1557843","DOIUrl":"10.3389/fmolb.2025.1557843","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer (PCa) is a major cause of cancer-related mortality in men, characterized by significant heterogeneity in clinical behavior and treatment response. Histone modifications play key roles in tumor progression and treatment resistance, but their regulatory effects in PCa remain poorly understood.</p><p><strong>Methods: </strong>We utilized integrative multi-omics analysis and machine learning to explore histone modification-driven heterogeneity in PCa. The Comprehensive Machine Learning Histone Modification Score (CMLHMS) was developed to classify PCa into two distinct subtypes based on histone modification patterns. Single-cell RNA sequencing was performed, and drug sensitivity analysis identified potential therapeutic vulnerabilities.</p><p><strong>Results: </strong>High-CMLHMS tumors exhibited elevated histone modification activity, enriched proliferative and metabolic pathways, and were strongly associated with progression to castration-resistant prostate cancer (CRPC). Low-CMLHMS tumors showed stress-adaptive and immune-regulatory phenotypes. Single-cell RNA sequencing revealed distinct differentiation trajectories related to tumor aggressiveness and histone modification patterns. Drug sensitivity analysis showed that high-CMLHMS tumors were more responsive to growth factor and kinase inhibitors (e.g., PI3K, EGFR inhibitors), while low-CMLHMS tumors demonstrated greater sensitivity to cytoskeletal and DNA damage repair-targeting agents (e.g., Paclitaxel, Gemcitabine).</p><p><strong>Conclusion: </strong>The CMLHMS model effectively stratifies PCa into distinct subtypes with unique biological and clinical characteristics. This study provides new insights into histone modification-driven heterogeneity in PCa and suggests potential therapeutic targets, contributing to precision oncology strategies for advanced PCa.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1557843"},"PeriodicalIF":3.9,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11936803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational electrostatic engineering of nanobodies for enhanced SARS-CoV-2 receptor binding domain recognition.","authors":"Zafar Iqbal, Muhammad Asim, Umair Ahmad Khan, Neelam Sultan, Irfan Ali","doi":"10.3389/fmolb.2025.1512788","DOIUrl":"10.3389/fmolb.2025.1512788","url":null,"abstract":"<p><p>This study presents a novel computational approach for engineering nanobodies (Nbs) for improved interaction with receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Using Protein Structure Reliability reports, RBD (7VYR_R) was selected and refined for subsequent Nb-RBD interactions. By leveraging electrostatic complementarity (EC) analysis, we engineered and characterized five Electrostatically Complementary Nbs (ECSb1-ECSb5) based on the CeVICA library's SR6c3 Nb. Through targeted modifications in the complementarity-determining regions (CDR) and framework regions (FR), we optimized electrostatic interactions to improve binding affinity and specificity. The engineered Nbs (ECSb3, ECSb4, and ECSb5) demonstrated high binding specificity for AS3, CA1, and CA2 epitopes. Interestingly, ECSb1 and ECSb2 selectively engaged with AS3 and CA1 instead of AS1 and AS2, respectively, due to a preference for residues that conferred superior binding complementarities. Furthermore, ECSbs significantly outperformed SR6c3 Nb in MM/GBSA results, notably, ECSb4 and ECSb3 exhibited superior binding free energies of -182.58 kcal.mol^-1 and -119.07 kcal.mol^-1, respectively, compared to SR6c3 (-105.50 kcal.mol^-1). ECSbs exhibited significantly higher thermostability (100.4-148.3 kcal·mol⁻¹) compared to SR6c3 (62.6 kcal·mol⁻¹). Similarly, enhanced electrostatic complementarity was also observed for ECSb4-RBD and ECSb3-RBD (0.305 and 0.390, respectively) relative to SR6c3-RBD (0.233). Surface analyses confirmed optimized electrostatic patches and reduced aggregation propensity in the engineered Nb. This integrated EC and structural engineering approach successfully developed engineered Nbs with enhanced binding specificity, increased thermostability, and reduced aggregation, laying the groundwork for novel therapeutic applications targeting the SARS-CoV-2 spike protein.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1512788"},"PeriodicalIF":3.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated transcriptomic and metabolomic analysis reveals the effects of EMMPRIN on nucleotide metabolism and 1C metabolism in AS mouse BMDMs.","authors":"Yun Zhang, Diyuan Zhang, Zulong Xie, Tianli Xia, Lili Zou, Tao Wang, Li Zhong, Zhuo Zeng, Lingying Wang, Guozhu Chen, Xing Liang","doi":"10.3389/fmolb.2024.1460186","DOIUrl":"10.3389/fmolb.2024.1460186","url":null,"abstract":"<p><strong>Background: </strong>Extracellular matrix metalloproteinase inducer (EMMPRIN) has been considered as a key promoting factor in atherosclerosis (AS). Some studies have shown that regulating EMMPRIN expression in bone marrow-derived macrophages (BMDMs) of ApoE-/- mice can affect plaque stability, but the mechanism was not clear.</p><p><strong>Methods: </strong>AS model mice were built from high-fat-feeding ApoE -/- mice, and were divided into siE group and CON group. The BMDMs and aortas from AS mice were harvested following <i>in vivo</i> treatment with either EMMPRIN short interfering (si)RNA (siEMMPRIN) or negative control siRNA. Transcriptomic and metabolomic profiles were analyzed using RNA-sequencing and Liquid chromatography-tandem mass spectrometry (LC-MS/MS), respectively. The efficacy of siEMMPRIN was assessed through real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting (WB). Immunofluorescence staining was employed to measure EMMPRIN expression within aortic atherosclerotic plaques. Cell proliferation was monitored using the Cell Counting Kit-8 (CCK8), while flow cytometry was utilized to analyze the cell cycle. Additionally, seahorse analysis and oil red O staining were conducted to verify glucose and lipid metabolism, respectively.</p><p><strong>Results: </strong>A total of 3,282 differentially expressed metabolites (DEMs) and 16,138 differentially expressed genes (DEGs) were identified between the CON group and siE group. The nucleotide metabolism and one-carbon (1C) metabolism were identified as major altered pathways at both the transcriptional and metabolic levels. Metabolomic results identified increased levels of glycine, serine, betaine and S-adenosyl-L-methionine (SAM) to S-adenosyl-L-homocysteine (SAH) ratio and decreased levels of dimethylglycine (DMG) and SAH in 1C metabolism, accompanied by the accumulation of nucleotides, nucleosides, and bases in nucleotide metabolism. Transcriptomics results shown that Dnmt, Mthfd2 and Dhfr were downregulated, while Mthfr were upregulated in 1C metabolism. And numerous genes involved in <i>de novo</i> nucleotide synthesis, pentose phosphate pathway (PPP) and dNTP production were significantly inhibited, which may be associated with decreased BMDMs proliferation and cell cycle arrest in the G0/G1 phase in siE group. Multi-omics results also showed changes in glucose and lipid metabolism. Seahorse assay confirmed reduced glycolysis and oxidative phosphorylation (OXPHOS) levels and the Oil Red O staining confirmed the decrease of lipid droplets in siE group.</p><p><strong>Conclusion: </strong>The integrated metabolomic and transcriptomic analysis suggested that nucleotide metabolism and 1C metabolism may be major metabolic pathways affected by siEMMPRIN in AS mouse BMDMs. Our study contributes to a better understanding of the role of EMMPRIN in AS development.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"11 ","pages":"1460186"},"PeriodicalIF":3.9,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapamycin combined with osimertinib alleviated non-small cell lung cancer by regulating the PARP, Akt/mTOR, and MAPK/ERK signaling pathways.","authors":"Qingrong Ma, Kai Chen, Haiping Xiao","doi":"10.3389/fmolb.2025.1548810","DOIUrl":"10.3389/fmolb.2025.1548810","url":null,"abstract":"<p><strong>Backgrounds: </strong>Non-small cell lung cancer (NSCLC), one kind of common malignant tumor, is accompanied by high morbidity and mortality. The effects and related mechanisms of rapamycin (Rapa) combined with osimertinib (Osi) in treating NSCLC are still unclear. Therefore, this study aims to investigate the effects and related mechanisms of Rapa combined with Osi on NSCLC.</p><p><strong>Methods: </strong>In A549 and PC-9 cells, the Cell Counting Kit-8 (CCK-8) assay was used to select the optimal administrative concentrations of Rapa and Osi and evaluate the cell viability. The Transwell assay and flow cytometry were used to determine the migration, cell cycle, apoptosis, and the level of Reactive Oxygen Species (ROS), respectively. The protein and mRNA expression level of Matrix Metalloproteinase-9 (MMP9), Caspase-3, Microtubule-Associated Protein 1 Light Chain 3 II/I (LC3 II/I), beclin1, Sequestosome 1 (p62), Poly (ADP-ribose) Polymerase (PARP), Mitogen-Activated Protein Kinase (MAPK), Extracellular Signal-Regulated Kinase (ERK), Protein Kinase B (Akt), and Mammalian Target of Rapamycin (mTOR) was determined by Western blot and Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR).</p><p><strong>Results: </strong>The optimal administrative concentrations of Rapa and Osi were 0.5 μM and 1 μM, respectively. Rapamycin combined with Osimertinib significantly decreased the viability of cells, the quantity of migrated cells, the levels of ROS, as well as the mRNA and protein expression levels of MMP9 and p62, Caspase-3, LC3 II/I, beclin1. The combination of the two drugs is markedly more effective than the use of drugs alone.</p><p><strong>Conclusion: </strong>In conclusion, the study demonstrated that Rapamycin combined with Osimertinib can inhibit the cell migration, regulate the cell cycle, promote the autophagy and apoptosis, increase the ROS level and regulate the PARP, MAPK/EKR, and Akt/mTOR pathways in A549 and PC-9 cells, providing a novel theoretical basis for their clinical treatment of NSCLC.</p>","PeriodicalId":12465,"journal":{"name":"Frontiers in Molecular Biosciences","volume":"12 ","pages":"1548810"},"PeriodicalIF":3.9,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}