Journal of Biochemical and Molecular Toxicology最新文献

{"title":"Mechanism of Nano-Microplastics Exposure-Induced Myocardial Fibrosis: DKK3-Mediated Mitophagy Dysfunction and Pyroptosis","authors":"Liang Xiong,&nbsp;Ziyi Xiong,&nbsp;Juan Hua,&nbsp;Qi Chen,&nbsp;Dandan Wang","doi":"10.1002/jbt.70245","DOIUrl":"https://doi.org/10.1002/jbt.70245","url":null,"abstract":"<div>\u0000 \u0000 <p>Nano-microplastics (NMPs), as environmental pollutants, are widely present in nature and pose potential threats to biological health. This study aims to investigate the mechanisms by which NMPs inhibit mitophagy through the suppression of dickkopf-related protein 3 (DKK3) expression, leading to NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-mediated cardiomyocyte pyroptosis and promoting myocardial fibrosis. Healthy adult male C57BL/6 mice were administered NMP solution via gavage, and their cardiac function was monitored. The results showed that NMP exposure significantly reduced left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) and increased the extent of myocardial fibrosis. Transcriptome sequencing identified 14 differentially expressed genes (DEGs), including MYL7. Using the random forest algorithm and functional enrichment analysis, DKK3 was identified as a key gene. In Vitro experiments further confirmed that NMPs downregulate DKK3 expression, thereby inhibiting mitophagy and promoting cardiomyocyte pyroptosis. This study elucidates the molecular mechanisms by which NMPs induce myocardial fibrosis and provides new theoretical bases and molecular targets for the diagnosis and treatment of heart diseases.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143861586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resveratrol—A Herbal Immunomodulator, Ameliorates Experimental Autoimmune Myasthenia Gravis by Regulating the Foxo1-Foxp3 Pathway","authors":"Heyun Cheng,&nbsp;Yunan Shan,&nbsp;Xiaoyue Shen,&nbsp;Yanbin Li","doi":"10.1002/jbt.70265","DOIUrl":"https://doi.org/10.1002/jbt.70265","url":null,"abstract":"<div>\u0000 \u0000 <p>Resveratrol (RES), extracted from traditional Chinese medicinal plants, demonstrates notable potential in managing autoimmune diseases by modulating multiple pathways and targeting various immune cell subsets with minimal adverse effects. Current treatments for a novel form of myasthenia gravis (MG) face challenges such as inconsistent efficacy and numerous side effects. The exact mechanisms by which RES affects MG progression remain unclear. To investigate RES's impact on MG, an experimental model was created using <i>Lewis female mice</i> immunized with an antigenic emulsion from the 97–116 region of the <i>rat AChR alpha subunit</i> (R97-116 peptide). RES was administered orally in varying doses. Following treatment, the experimental autoimmune myasthenia gravis (EAMG) model was assessed through several metrics, including EAMG score, autoantibody levels, and antibody affinity via ELISA. Network pharmacology was employed to construct the RES action pathway. Validation of RES effects on immune cell pathways in immune organs was performed using Western blot, real-time PCR, immunofluorescence, and immunohistochemistry, with dendritic cells (DCs) in vitro confirming the pathway. Flow cytometry was used for immunophenotyping. RES mitigated EAMG clinical symptoms and reduced both autoantibody content and affinity in serum. Network pharmacology identified the Foxo1/Foxp3 pathway as integral to RES's therapeutic effects on MG. In the RES-treated group, Foxo1 and Foxp3 expression levels were elevated in the spleen, lymph nodes, and thymus. In vitro experiments indicated decreased Foxp3 expression following Foxo1 inhibition in DCs. Flow cytometry revealed an increase in regulatory DCs, reduced DC activation, and diminished lymphocyte proliferation stimulation. Concurrently, Treg levels increased while germinal center B cells decreased. RES can serve as a potential drug for the treatment of MG, as it can regulate DC cells and other immune cells by affecting the Foxo1/Foxp3 pathway.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143861584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HHLA3 Silencing Suppresses KRAS-Mutant Non-Small-Cell Lung Cancer Cell Progression Through Triggering MYEOV-Mediated Ferroptosis","authors":"Zhimiao Tang,&nbsp;Jia Ye,&nbsp;Dong Chen","doi":"10.1002/jbt.70271","DOIUrl":"https://doi.org/10.1002/jbt.70271","url":null,"abstract":"<div>\u0000 \u0000 <p>KRAS mutation is one of the most common mutational events in non-small-cell lung cancer (NSCLC). However, due to the complex signaling pathways and high biological heterogeneity of KRAS-mutant NSCLC, the current clinical treatment for patients with KRAS mutations still faces many difficulties. The oncogenic effector in KRAS-mutant NSCLC was screened using GEO data sets. CCK-8, colony formation, transwell, and flow cytometry were conducted to assess the malignant phenotype of KRAS-mutant NSCLC cells. The indicators intracellular Fe²⁺, ROS, GSH, and MDA levels were employed to reflect the ferroptosis of cells. The mechanism of myeloma overexpressed (MYEOV) in KRAS-mutant NSCLC was explored from the perspective of noncoding RNA (ncRNA) and validated by rescue experiments. MYEOV presented a high expression trend in KRAS-mutant NSCLC specimens. MYEOV silencing effectively repressed the malignant phenotype and promoted ferroptosis of NSCLC cells carrying KRAS mutations. Based on bioinformation analysis and a series of rescue experiments, we established the HHLA3/miR-139-5p/MYEOV regulatory network in KRAS-mutant NSCLC cells and disclosed that HHLA3 served as a molecular sponge for miR-139-5p to regulate MYEOV expression. The mechanism of MYEOV and its ncRNA network affecting the progression of KRAS-mutant NSCLC revealed in this study intends to provide a theoretical basis for KRAS-mutant NSCLC treatment.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143861585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Newly Synthesized PW06 Induced Cell Apoptosis in Human Glioblastoma Multiforme GBM 8401 Cells Through Caspase- and Mitochondria-Dependent Pathways","authors":"Jin-Cherng Lien,&nbsp;Sheng-Yao Hsu,&nbsp;Fu-Shin Chueh,&nbsp;Yi-Shih Ma,&nbsp;Yung-Lin Chu,&nbsp;Yu-Cheng Chou,&nbsp;Kuang-Chi Lai,&nbsp;Jaw-Chyun Chen,&nbsp;Yi-Ping Huang,&nbsp;Rick Sai-Chuen Wu","doi":"10.1002/jbt.70264","DOIUrl":"https://doi.org/10.1002/jbt.70264","url":null,"abstract":"<div>\u0000 \u0000 <p>Glioblastoma multiforme (GBM) is the most common, aggressive, and dangerous lethal tumor in the brain, which develops in adults. Currently, the efficiency of chemotherapy treatment for GBM patients is still unsatisfactory. PW06 was synthesized by Dr. Lien's laboratory (China Medical University, Taichung, Taiwan), and it was demonstrated to induce cancer cell apoptosis in human pancreatic carcinoma MIA PaCa-2 cells. However, the anti-cancer activities of PW06 on human GBM cancer cells are not reported. Thus, herein, PW06 was investigated on the anticancer activity on human glioblastoma multiforme GBM 8401 cells. Both PI exclusion and Annexin V/PI double staining methods were conducted for investing cell viability and apoptosis in GBM 8401 cells, respectively; they were analyzed with flow cytometer assay. Results showed that PW06 decreased total viable cell number with the process of cell apoptosis in GBM 8401 cells. Both productions of reactive oxygen species (ROS) and Ca²⁺, affect mitochondria membrane potential (ΔΨm) levels, and activities of caspase-3, -8, and -9 in GBM 8401 cells after exposure with PW06 were assayed by flow cytometer. Results showed that PW06 promoted ROS production and Ca²⁺ release from ER but lowered the levels of ΔΨm, and it also induced higher activities in caspase-3, -8, and -9 in GBM 8401 cells. Evaluation of protein expressions associated with apoptosis in GBM 8401 cells after being incubated with PW06 were conducted by Western blot analysis. Results show that PW06 increased GADD153, BiP, ATF-6α, ATF-6β, eIF2α, eIF2α^pSer51, CHOP, and caspase-4, and they are associated with ER stress-associated protein expression. However, it induced higher pro-apoptotic proteins (Bax and Bad) expression and inhibited anti-apoptotic proteins (Bcl-2, Bcl-xl, and Mcl-1) expression, even promoting higher cleaved caspase-8, -9, and -3 protein expression and increased EndoG and AIF in GBM 8401 cells. Collectively, it may suggest PW06 exits anti-GBM activity to process cell apoptosis in the human GBM 8401 cells in vitro.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin-Stimulated Mesenchymal Stem Cells-Derived Exosomes Carrying LINC00052 Alleviate Hyperoxic Lung Injury by Promoting miR-152-3p-KLF4-Nrf2 Pathway","authors":"Nan Li,&nbsp;DeYu Fang,&nbsp;Feng Ge,&nbsp;Lin Zhang,&nbsp;Ying Liu,&nbsp;Yan Gao,&nbsp;HongXu Jin","doi":"10.1002/jbt.70241","DOIUrl":"https://doi.org/10.1002/jbt.70241","url":null,"abstract":"<div>\u0000 \u0000 <p>Exposure of the lungs to high O2 levels, can lead to a noninfectious lung damage known as hyperoxia-induced lung injury (HILI). Melatonin stimulation can enhance the efficacy of stem cells in some diseases. This study aims to investigate the mechanism of exosomes secreted by mesenchymal stem cells (MSCs) stimulated by melatonin in HILI. The MSCs-derived exosomes were isolated and identified after stimulation with melatonin, and the neonatal rat model of HILI was constructed. After injection of exosomes and related lentiviruses, the ratio of wet lung to dry lung was calculated to evaluate pulmonary edema. Inflammatory factors in medium or serum were measured by ELISA. HE staining was used to evaluate the pathological status of lung tissue. Masson staining was used to evaluate collagen deposition in lung tissue. Lung cell apoptosis was detected by Tunel staining. In vitro model of HILI was established, CCK-8 and EDU staining were used to detect cell viability and proliferation, and flow cytometry was used to detect cell apoptosis. The binding relationship between LINC00052, miR-152-3p, and KLF4 was verified through bioinformatics websites, dual luciferase reporter experiments, RIP experiments, and RNA pull down experiments. Melatonin-stimulated MSCs-derived exosomes could alleviate HILI. Exosomes had a therapeutic effect on HILI neonatal rats by carrying LINC00052. Inhibition of LINC00052 reversed the therapeutic effect of exosomes on HILI, while low expression of miR-152-3p or inducing KLF4 negated the effect of sh-LINC00052. LINC00052 bound to miR-152-3p. miR-152-3p targeted KLF4. In vitro, melatonin-stimulated MSC-derived exosomes alleviated the cytotoxicity and cell viability inhibition of AEC-II cells induced by hyperoxia. KLF4 overexpression activated NRF2 signaling in AEC-II cells. LINC00052 in MSCs-derived exosomes stimulated by melatonin activates the Nrf2 pathway through the miR-152-3p/KLF4 axis to alleviate HILI, which may be a potential therapeutic approach for HILI.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the Role of Scd1 in OSAHS-Induced Vascular Changes","authors":"Jing Yang,&nbsp;Hui Zhang,&nbsp;Lulu Yang,&nbsp;Shen Yi,&nbsp;Ting Zhang","doi":"10.1002/jbt.70221","DOIUrl":"https://doi.org/10.1002/jbt.70221","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 <p>This study investigates the role of Stearoyl-CoA Desaturase-1 (Scd1) in vascular remodeling associated with Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) using multi-omics analysis. Transcriptomic and metabolomic datasets of OSAHS mouse models were analyzed to identify differentially expressed genes and metabolites, followed by functional enrichment analysis. Key genes were screened using weighted gene correlation network analysis (WGCNA) and machine learning, and a PPI network was constructed. An OSAHS mouse model was developed via intermittent hypoxia exposure. Human aortic smooth muscle cells (HASMCs) were subjected to hypoxia/reoxygenation cycles to simulate OSAHS in vitro. Blood pressure, plasma lipid profiles, histological changes in the thoracic aorta, and Scd1 protein expression were assessed. CCK-8 and Transwell assays evaluated HASMC proliferation and migration. Scd1 was identified as a critical factor in OSAHS-related vascular remodeling, with its expression significantly upregulated in vascular tissues of OSAHS mice. Metabolomic analysis revealed changes in fatty acid metabolism. Scd1 knockdown reduced blood pressure, lipid levels, aortic wall thickness, collagen deposition, elastic fiber accumulation, and mucin deposition in vivo. In vitro, hypoxia/reoxygenation cycles elevated Scd1 expression, while Scd1 knockdown inhibited HASMC proliferation and migration. Multi-omics analyses highlight Scd1 as a key regulator in OSAHS-associated vascular remodeling, driving pathological changes through its upregulation. These findings suggest Scd1 as a potential therapeutic target for managing OSAHS-related vascular pathologies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of AMPK/mTOR Autophagic Pathway Using Dapagliflozin Protects Against Cadmium-Induced Testicular and Renal Injury in Rats","authors":"Doha M. Dagher,&nbsp;Marwa S. Zaghloul,&nbsp;Ghada M. Suddek","doi":"10.1002/jbt.70257","DOIUrl":"https://doi.org/10.1002/jbt.70257","url":null,"abstract":"<div>\u0000 \u0000 <p>Cadmium is a widely distributed heavy metal found in the environment that poses serious hazards to human health. Dapagliflozin (DAPA), a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, exhibited antioxidant, antiapoptotic, and anti-inflammatory properties. Our data assessed the effect of DAPA against Cd-triggered renal and testicular impairment in rats, as well as the underlying mechanisms. Cd (30 mg/kg) and DAPA (5 and 10 mg/kg) were administrated by oral gavage to rats and continued for 21 days. DAPA attenuated Cd-triggered renal and testicular injury as shown by diminishing serum creatinine, BUN, and urinary total protein concentration in addition to increasing creatinine clearance, urinary creatinine, and serum testosterone. Moreover, it diminished renal and testicular histopathological alterations induced by Cd. DAPA stimulated the impaired autophagy flux as seen by significantly elevating the p-AMPK/total AMPK, decreasing p-mTOR/total mTOR ratios, and diminishing p62 &amp; LC3 protein levels. Additionally, DAPA significantly lowered MDA content, increased GSH level and SOD activity. Moreover, it augmented the cytoprotective Nrf2/HO-1 signaling pathway. Furthermore, it attenuated renal and testicular apoptotic cell death via decreasing caspase-3 expression. Conclusion: Boosting autophagic events and combating oxidative stress and apoptosis by DAPA were engaged in alleviating Cd-induced renal and testicular impairment. This was accomplished by modulating the AMPK/mTOR and enhancing the Nrf2/HO-1 pathways.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell RNA Sequencing Contributes to the Treatment of Acute Myeloid Leukaemia With Hematopoietic Stem Cell Transplantation, Chemotherapy, and Immunotherapy","authors":"Raed Obaid Saleh,&nbsp;Ahmed Hjazi,&nbsp;Safia Obaidur Rab,&nbsp;Subasini Uthirapathy,&nbsp;Subbulakshmi Ganesan,&nbsp;Aman Shankhyan,&nbsp;M. Ravi Kumar,&nbsp;Girish Chandra Sharma,&nbsp;Muthena Kariem,&nbsp;Jawad Kadhim Ahmed","doi":"10.1002/jbt.70218","DOIUrl":"https://doi.org/10.1002/jbt.70218","url":null,"abstract":"<div>\u0000 \u0000 <p>Acute myeloid leukemia (AML) is caused by altered maturation and differentiation of myeloid blasts, as well as transcriptional/epigenetic alterations and impaired apoptosis, all of which lead to excessive proliferation of malignant blood cells in the bone marrow. It is these mutations that cause tumor heterogeneity, which is linked to a higher risk of relapse and death and makes anti-AML treatments like HSCT, chemotherapy, and immunotherapy (ICI, CAR T-cell-based therapies, and cancer vaccines) less effective. Single-cell RNA sequencing (scRNA-seq) also makes it possible to find cellular subclones and profile tumors, which opens up new diagnostic and therapeutic targets for better AML management. The HSCT process works better when genetic and transcriptional information about the patient and donor stem cells is collected. This saves time and lowers the risk of harmful side effects happening in the body.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of Novel Isoindolinones: Carbonic Anhydrase Inhibition Profiles, Antioxidant Potential, Antimicrobial Effect, Cytotoxicity and Anticancer Activity","authors":"Yusuf Serdar Yazıcıoğlu,&nbsp;Şeydanur Elmas,&nbsp;Zeynep Kılıç,&nbsp;Murat Çelik,&nbsp;Buket Bakan,&nbsp;Ufuk Atmaca,&nbsp;Songül Bayrak","doi":"10.1002/jbt.70261","DOIUrl":"https://doi.org/10.1002/jbt.70261","url":null,"abstract":"<p>An efficient one-pot method has been developed for synthesizing novel isoindolinone derivatives from 2-benzoylbenzoic acid using chlorosulfonyl isocyanate and alcohols. This reaction occurs under mild, metal-free conditions, rendering it a sustainable and effective approach for isoindolinone synthesis. The inhibitory potential of the synthesized compounds against human carbonic anhydrase (hCA) I and II isozymes was evaluated and compared with the standard inhibitor, acetazolamide (AAZ). Additionally, their antimicrobial and antioxidant activities were assessed using various bioanalytical methods, with results benchmarked against standard reference compounds. Furthermore, cytotoxicity and anticancer activity were investigated in L929 and A549 cell lines via the WST-1 assay following a 24 h exposure. Among the synthesized derivatives, compounds <b>2c</b> and <b>2f</b> exhibited superior inhibitory effects on hCA I and II compared to AAZ, with Ki values ranging from 11.48 ± 4.18 to 16.09 ± 4.14 nM for hCA I and 9.32 ± 2.35 to 14.87 ± 3.25 nM for hCA II. These findings indicate that compounds <b>2c</b> and <b>2f</b> have a high affinity for the enzyme's active site, resulting in more effective inhibition of its catalytic activity. Compound 2e emerged as the most promising candidate, demonstrating potent carbonic anhydrase inhibition and significant antioxidant and antimicrobial properties. None of the synthesized compounds displayed cytotoxic effects on healthy cells at the tested concentrations. Additionally, compound <b>2a</b> exhibited dose-dependent anticancer activity against A549 cells. These results suggest that isoindolinone derivatives, particularly <b>2f</b>, hold substantial potential for further pharmaceutical development as multifunctional bioactive agents.</p>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbt.70261","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KAT3B Promotes the Glycolysis and Malignant Progression of Lung Cancer by Mediating the Succinylation Modification of PKM2","authors":"Zhifeng Guo,&nbsp;Yan Hui,&nbsp;Siqi Sun,&nbsp;Fanlong Kong","doi":"10.1002/jbt.70259","DOIUrl":"https://doi.org/10.1002/jbt.70259","url":null,"abstract":"<div>\u0000 \u0000 <p>Lysine succinyltransferase KAT3B plays a critical role in the progression of various cancers by modulating key metabolic pathways, including glycolysis. However, the function and underlying mechanism of KAT3B in glycolysis and lung cancer (LC) progression remain to be further studied. We determined mRNA expression levels of lysine succinyl-modifying enzymes through qRT-PCR. Protein expression and succinylation status of glycolysis-related proteins PKM2, LDHA, and ENO1 were analyzed via Western blot. Co-immunoprecipitation and immunofluorescence microscopy were employed to verify the interaction between KAT3B and PKM2. Bioinformatics analysis predicted succinylation sites on PKM2, which were subsequently validated through site-directed mutagenesis. The effects of KAT3B and PKM2 on LC cell malignancy and glycolysis were evaluated using CCK-8, transwell migration, glucose uptake, lactate production, ECAR, and OCR assays. A xenograft tumor model was utilized to assess the impact of KAT3B on LC tumor growth. We confirmed the augmentation of KAT3B in LC, which also was correlated with advanced TNM stages and elevated T stages of LC patients. Conversely, KAT3B knockdown suppressed the growth, metastasis, and glycolytic activity of LC cells in vitro, while also inhibiting tumor growth in vivo. KAT3B mediated succinylation at PKM2 K298, and the suppression of LC cell malignancy and glycolysis upon KAT3B downregulation was largely reversed by upregulation of PKM2. The KAT3B/PKM2 axis may be a novel target for LC therapy.</p></div>","PeriodicalId":15151,"journal":{"name":"Journal of Biochemical and Molecular Toxicology","volume":"39 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}