Cell Biology and Toxicology最新文献

{"title":"Lipotoxicity, lipid peroxidation and ferroptosis: a dilemma in cancer therapy.","authors":"Chuhan Ma, Huixin Hu, Hao Liu, Chongli Zhong, Baokang Wu, Chao Lv, Yu Tian","doi":"10.1007/s10565-025-10025-7","DOIUrl":"https://doi.org/10.1007/s10565-025-10025-7","url":null,"abstract":"<p><p>The vulnerability of tumor cells to lipid peroxidation, driven by redox imbalance and lipid overabundance within the tumor microenvironment (TME), has become a focal point for novel antitumor strategies. Ferroptosis, a form of regulated cell death predicated on lipid peroxidation, is emerging as a promising approach. Beyond their role in directly eliminating tumor cells, lipid peroxidation and its products, such as 4-hydroxynonenal (HNE), exert an additional influence by damaging DNA and shaping an environment conducive to tumor growth and metastasis. This process polarizes macrophages towards a pro-inflammatory phenotype, dampens the antigen-presenting capacity of dendritic cells (DCs), and undermines the cytotoxic functions of T and NK cells. Furthermore, it transforms neutrophils into pro-tumorigenic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). The lipid peroxidation of stroma cells also contributes to tumor progression. Although advanced nanotherapies have shown the ability to target tumor cells precisely, they often overlook the nuanced effects of lipid peroxidation products. In this review, we highlight a synergistic mechanism in which lipid peroxidation products and ferroptosis contribute to an immunosuppressive state that is temporally distinct from cell death. This insight broadens our understanding of ferroptosis-derived immunosuppression, encompassing all types of immune cells within the TME. This review aims to catalyze further research in this underexplored area, emphasizing the potential of lipid peroxidation products to hinder the clinical translation of ferroptosis-based therapies.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"75"},"PeriodicalIF":5.3,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12033115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitin-specific peptidase 10 attenuates bleomycin-induced pulmonary fibrosis via modulating autophagy depending on sirtuin 6-mediated AKT/mTOR.","authors":"Shitao Mao, Na Yu, Wei Wang, Yikai Mao, Ying Du, Qihe Zhao, Xiu Gu, Jian Kang","doi":"10.1007/s10565-025-10031-9","DOIUrl":"10.1007/s10565-025-10031-9","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF), characterized by fibroblast activation and collagen deposition, is a progressive lung disease that lacks effective interventions. Ubiquitin-specific peptidase 10 (USP10) acts as a multifunctional player in inflammatory response and progression of cancers, the effect on pulmonary fibrosis is unknown. Here, we demonstrated downregulated expression of USP10 in fibrotic lung tissues of IPF patients. In the current study, lung tissues were collected at the end of weeks 1, 2, or 3 post bleomycin (BLM)-intratracheal delivery. Consistently, USP10 expression levels were reduced after BLM challenge in a time-dependent manner. Mice treated with lentivirus overexpressing USP10 exhibited mitigative lung injury and reduced collagen deposition. USP10 overexpression enhanced autophagy in BLM-treated mouse lungs. Interestingly, the protective effect of USP10 was attenuated as the pulmonary autophagy flux was blocked by autophagy inhibitor 3-methyladenine (3-MA). Primary human and mouse lung fibroblasts were treated with pro-fibrotic TGF-β1 to verify the role of USP10 in vitro. Mechanically, the deubiquitinating enzyme USP10 interacted with Sirtuin 6 (Sirt6) and inhibited its degradation. Furthermore, USP10 overexpression inhibited the activation of Sirt6-mediated AKT/mTOR pathway in both lung tissues and fibroblasts. Our findings suggest that USP10 might attenuate pulmonary fibrosis through the promotion of Sirt6/AKT/mTOR-mediated autophagy. These data prioritize USP10 as a therapeutic target for treating IPF.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"73"},"PeriodicalIF":5.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12031808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning-based identification of cuproptosis-related lncRNA biomarkers in diffuse large B-cell lymphoma.","authors":"Wenhao Ouyang, Zijia Lai, Hong Huang, Li Ling","doi":"10.1007/s10565-025-10030-w","DOIUrl":"https://doi.org/10.1007/s10565-025-10030-w","url":null,"abstract":"<p><p>Multiple machine learning techniques were employed to identify key long non-coding RNA (lncRNA) biomarkers associated with cuproptosis in Diffuse Large B-Cell Lymphoma (DLBCL). Data from the TCGA and GEO databases facilitated the identification of 126 significant cuproptosis-related lncRNAs. Various feature selection methods, such as Univariate Filtering, Lasso, Boruta, and Random Forest, were integrated with a Transformer-based model to develop a robust prognostic tool. This model, validated through fivefold cross-validation, demonstrated high accuracy and robustness in predicting risk scores. MALAT1 was pinpointed using permutation feature importance from machine learning methods and was further validated in DLBCL cell lines, confirming its substantial role in cell proliferation. Knockdown experiments on MALAT1 led to reduced cell proliferation, underscoring its potential as a therapeutic target. This integrated approach not only enhances the precision of biomarker identification but also provides a robust prognostic model for DLBCL, demonstrating the utility of these lncRNAs in personalized treatment strategies. This study highlights the critical role of combining diverse machine learning methods to advance DLBCL research and develop targeted cancer therapies.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"72"},"PeriodicalIF":5.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12011908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Npc1 gene mutation impairs multilineage differentiation potential of hepatic telocytes in murine models.","authors":"Jichao Yang, Yuqiao Chang, Liang Qiao, Ganesh Dama, Yongli Lou, Juntang Lin","doi":"10.1007/s10565-025-10018-6","DOIUrl":"https://doi.org/10.1007/s10565-025-10018-6","url":null,"abstract":"<p><strong>Objective: </strong>To investigate the effect of the Npc1 gene on the biological activity of Telocytes (TCs) in the liver and to provide theoretical support for further research on the biological activity of TCs.</p><p><strong>Methods: </strong>Primary liver tissue cultures (TCs) from neonatal Npc1^+/+ and Npc1^-/- mice were extracted and cultured using an optimized type II collagenase-digestion protocol, and subsequently purified through a differential adhesion method. The growth state of TCs in both Npc1^+/+ and Npc1^-/- groups was regularly observed under an inverted microscope, and the morphology of TCs under normal growth conditions was documented. The TCs were identified using scanning electron microscopy and immunofluorescence staining. To investigate the impact of the Npc1 gene on the multilineage differentiation potential of TCs, liver TCs from Npc1^+/+ and Npc1^-/- groups were induced with adipogenic, osteogenic, and cardiomyoblastic differentiation solutions, respectively.</p><p><strong>Results: </strong>TCs cell surface markers such as co-expression of vimentin/CD34, vimentin/PDGF-α, and vimentin/c-Kit in Npc1^+/+ and Npc1^-/- groups. \"Combined light and scanning electron microscopy revealed that the cellular structure of TCs from Npc1^+/+ and Npc1^-/- groups was mainly composed of cell bodies and Telopodes (Tps). TCs exhibited small somata with fusiform, stellate, or spindle-shaped nuclei, depending on the number of Tps. The surface of TCs cell membrane was uneven, and there was no difference in morphology between the two groups. TCs had multilineage differentiation potential, and the positive rate of TCs induced in Npc1^-/- group was significantly lower than that in the Npc1^+/+ group.</p><p><strong>Conclusion: </strong>Our findings demonstrate that NPC1 deficiency markedly attenuates hepatic TCs' multipotency of liver TCs to differentiate into adipocytes, osteoblasts, and cardiocytes, suggesting that NPC1 protein might affect the pluripotency of TCs by regulating the lipid transport pathway. This finding provides novel insights into TC-mediated mechanisms in NPC pathology and lays a theoretical foundation for regenerative medicine strategies targeting TCs.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"71"},"PeriodicalIF":5.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12011650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143966485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Based exploration of the diagnostic value of oxidative stress-related key genes in chronic obstructive pulmonary disease.","authors":"Shenglan Wang, MingFeng Zhong, Xiaoli Deng, Chen Liu, Yan Tan, Baojiang Qian, MingMei Zhong","doi":"10.1007/s10565-025-10019-5","DOIUrl":"https://doi.org/10.1007/s10565-025-10019-5","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) ranks as the third most common contributor to global mortality. Oxidative stress has been recognized as a critical driver of multiple interacting mechanisms in COPD development. This research investigated the potential of oxidative stress-related genes (OSRGs) biomarkers and their potential molecular mechanisms for COPD clinical diagnosis and treatment through bioinformatics analyses. As a result, 5 hub genes, CA3, PPP1R15B, MAPT, MMP9, and ECT2, were yielded by LASSO, Boruta, and SVM-RFE, and the performance of the nomogram constructed based on hub genes was favorable. Correlation analyses between hub genes and oxidative stress biomarkers showed that MMP9 and MAPT genes had a high association with oxidative stress biomarkers. Immune cell infiltration identified follicular helper T cells, _Γδ T cells, M0 macrophages, and CD8 T cells as significantly different in COPD. ROC of ECT2 and MMP9 showed a higher capability to discriminate COPD patients from normal samples. In addition, we collected clinical samples and analyzed the core gene expression, which revealed that the hub genes ECT2 and MMP9 had high discriminatory ability in the COPD samples. The epistasis of ECT2 and MMP9 was further verified by constructing animal models, pathological sections, qPCR, immunoblotting, immunohistochemistry, etc. The data indicated the crucial function of MMP9 in CSC-induced oxidative stress injury. Deprivation of MMP9 attenuated CSC-induced injury and promoted macrophage polarisation to M2 macrophages. MMP9 deprivation protected against CSC-induced injury, mainly related to the reduction of cell apoptosis, cell inflammation, and ROS injury in BEAS-2B. It promoted macrophage polarization from M1 to M2. In summary, we found ECT2 and MMP9 are related to oxidative stress in COPD, and MMP9 was related to cell apoptosis, cell inflammation, and ROS injury in BEAS-2B, and the macrophage polarization from M1 to M2.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"69"},"PeriodicalIF":5.3,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11991958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of the MIAT/microRNA 130a-3p/Pdgfra axis on retinal microglia activation in mice with chronic retinal hypoperfusion injury.","authors":"Qingqing Sun, Lei Zhang, Guanghua Zhou, Zhicong Wen, Xiaomei Deng, Xiaoshan Lin, Qian Shi, Lvhong Deng","doi":"10.1007/s10565-025-10017-7","DOIUrl":"https://doi.org/10.1007/s10565-025-10017-7","url":null,"abstract":"<p><p>This paper aimed to address the function of the MIAT/miR-130a-3p/Pdgfra axis in retinal microglia activation in chronic retinal hypoperfusion injury (CRHI) mice. CRHI mouse models were constructed through bilateral common carotid artery occlusion (BCCAO). MIAT, Pdgfra, and miR-130a-3p expression levels in retinal tissues and cells were assessed. The expression of genes linked to the Nlrp3 inflammatory vesicle pathway (Gsdmd, Asc, Tlr4, Casp1, and Casp8) was assessed. Serum contents of inflammatory cytokines IL-18 and IL-1β were determined. Iba-1/Casp1/Csdmd expression was tested. Moreover, the interplay between miR-130a-3p and MIAT, as well as associations between Pdgfra and miR-130a-3p were verified. MIAT and Pdgfra expression was enhanced and miR-130a-3p diminished in BCCAO mouse models. MIAT downregulation reduced IL-18 and IL-1β contents and repressed microglia activation in BCCAO mice, and histopathological results also displayed raised mouse retinal thickness and diminished apoptosis. Both inhibiting miR-130a-3p and overexpressing Pdgfra can reverse the delayed effects of MIAT interference on CRHI. MIAT regulates miR-130a-3p to stimulate the expression of Pdgfra, thereby further promoting retinal microglia activation in CRHI mice. This provides potential targets for the development of innovative treatment approaches for retinal disorders.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"70"},"PeriodicalIF":5.3,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11991966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of the circ-Hdac4/miR-30c/RBPJ axis in decidua impairs placental function in preeclampsia.","authors":"Yan Su, Jing Long, Jiani Diao, Weike Li, Xuemei Chen, Jiujiang Liao, Chao Tong, Liping Tan, Shuang Zhang, Fangfang Li, Junlin He, Yingxiong Wang, Chunli Li, Rufei Gao","doi":"10.1007/s10565-025-10016-8","DOIUrl":"https://doi.org/10.1007/s10565-025-10016-8","url":null,"abstract":"<p><p>Embryo implantation relies on complex mother-fetus interactions. Abnormal decidualization can cause various pregnancy complications such as placental abnormalities, preeclampsia, and fetal growth restriction. circRNAs play a key role in various cellular processes. This study focuses on the role of circ-Hdac4, a circRNA derived from the Hdac4 gene, in decidualization and placental function. Mouse models revealed a spatiotemporally regulated expression of circ-Hdac4 in the endometrium during early pregnancy, with enhanced expression surrounding implantation sites. In vitro and in vivo assays confirmed that circ-Hdac4 is crucial for stromal cell decidualization, as its knockdown resulted in reduced expression of decidualization markers and disrupted endometrial architecture. Furthermore, we found that circ-Hdac4 functions as a microRNA sponge for miR-30c, which negatively regulates RBPJ, a critical protein for decidual remodeling. Proteomic analysis revealed that RBPJ was downregulated upon circ-Hdac4 silencing, and we validated the direct interaction between miR-30c and RBPJ using luciferase reporter assays. A mouse preeclampsia model showed that downregulation of circ-Hdac4 during decidualization exacerbated preeclampsia-related phenotypes, including reduced fetal counts, weights, and placental weights. In addition, we observed decreased expression of circ-Hdac4 and RBPJ in the decidual surface of placental tissues from preeclampsia patients, further supporting our findings in the mouse model. Collectively, our study provides evidence that circ-Hdac4 regulates decidualization through the miR-30c-RBPJ axis and that its abnormal expression during decidualization contributes to placental dysfunction in preeclampsia. This research offers novel insights into the molecular mechanisms underlying pregnancy complications and potential therapeutic targets for their prevention and treatment.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"68"},"PeriodicalIF":5.3,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11985660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lamin A/C regulates cerebellar granule cell maturation.","authors":"Laura Vilardo, Ingrid Cifola, Marta Nardella, Paride Pelucchi, Maria Teresa Ciotti, Andrea Bianchi, Arianna Rinaldi, Ivan Arisi, Rossella Brandi, Mara d'Onofrio, Nicola Galvanetto, Giuliana Gatti, Myriam Catalano, Chiara Lanzuolo, Loredana Guglielmi, Igea D'Agnano","doi":"10.1007/s10565-025-10011-z","DOIUrl":"10.1007/s10565-025-10011-z","url":null,"abstract":"<p><p>Lamin A/C is a nuclear type V intermediate filament protein part of the meshwork structure underlying the inner nuclear membrane (nuclear lamina), which plays numerous roles, including maintenance of nuclear shape, heterochromatin organization, and transcriptional regulation. Our group has demonstrated the role of Lamin A/C in different pathophysiological conditions. Here, we investigated for the first time how Lamin A/C affects neuronal maturation in rat cerebellar granule cells (GCs). Primary rat cerebellar GCs where we silenced the Lmna gene constituted our key model; this provided a rather homogeneous cellular system showing a neuronal population in vitro. We then validated our findings in another in vivo murine model with knock-out of the Lmna gene and in an in vitro human neuronal model with silencing of the LMNA gene. We observed across three different models that Lamin A/C down-regulation affects neurons maturation by protecting the cells from glutamate-evoked excitotoxicity and correlates with an inhibition of calcium influxes and a down-regulation of pro-inflammatory cytokine pathways. Consistent with previous findings from our group, this study corroborates that Lamin A/C plays a key role in neural development and opens new significant implications for a better comprehension of the mechanisms involved in neurodegenerative diseases, where changes in the nuclear envelope are linked to neuroinflammatory processes and damage.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"66"},"PeriodicalIF":5.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting B4GALT3 in BMSCs-EVs for Therapeutic Control of HCC via NF-κB pathway inhibition.","authors":"Juncheng Guo, Kaiqiong Wang, Qigang Sun, Jun Liu, Jinfang Zheng","doi":"10.1007/s10565-025-10013-x","DOIUrl":"10.1007/s10565-025-10013-x","url":null,"abstract":"<p><p>Examining the communications in the tumor microenvironment (TME) specific to hepatocellular carcinoma (HCC), this exploration looks into the role played by beta-1,4-Galactosyltransferase III (B4GALT3) in bone marrow mesenchymal stromal cell-derived extracellular vesicles (BMSCs-EVs) regarding the NF-κB pathway and the triggering of cancer-associated fibroblasts (CAF). Through a multidisciplinary approach combining transcriptome sequencing, bioinformatic analysis, and various experimental models, the involvement of B4GALT3 in regulating CAF activity by modulating NF-κB signaling was brought to light in our study. The outcomes suggest that targeting B4GALT3 could impede HCC cell migration and invasion, promote apoptosis, and dampen tumor progression and metastasis, offering novel insights into potential therapeutic strategies for combating HCC.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"67"},"PeriodicalIF":5.3,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early endolysosomal dysfunction is a contributing factor to gadolinium-based contrast agent mouse renal proximal tubule epithelial cell injury.","authors":"Joshua DeAguero, Tamara Howard, G Patricia Escobar, Karol Dokladny, Brent Wagner","doi":"10.1007/s10565-025-10014-w","DOIUrl":"10.1007/s10565-025-10014-w","url":null,"abstract":"<p><p>The prevalence of contrast-enhanced magnetic resonance imaging (MRI) examinations and the absence of safer alternatives to gadolinium-based contrast agents (GBCAs) make the associated adverse effects of GBCAs much more concerning. Safety concerns arise from the toxic behavior of heavy metal gadolinium (Gd³⁺) and the potential release of the metal from the chelating ligand. Renal insufficiency and other patient factors increase the susceptibility to the toxic effects of GBCAs. It is, therefore, imperative that the molecular and cellular mechanisms underlying GBCA toxicity be defined. This study aims to determine GBCA-induced endolysosomal dysfunction in mouse renal proximal tubule epithelial cells. Loss of cell viability was agent- and time-dependent, and proximal tubule injury was detectable following 24 h linear GBCA exposure. Both classes of GBCAs displayed lysosomotropic behaviors, characterized by early lysosomal enlargement and lysosomal injury. Hijacking of the endolysosomal system by these agents inhibited cathepsin processing by blocking the transport and maturation of cathepsin B (CTSB) and cathepsin D (CTSD). Lysosomal enlargement coincided with the translocation of CTSB and CTSD from the lysosomal lumen to the cytosol, suggesting lysosomal membrane destabilization. Even though both agents displayed a similar response, linear exposures appeared to exhibit a greater effect. Disturbance of mitochondrial activity and loss of cell viability occurs downstream of early lysosome damage. This effect was partially restored by lysosomal protease inhibitor co-treatment. This data suggests that GBCA exposures induce a lysosomal stress response, and partial LMP occurs upstream of mitochondrial dysfunction and resultant cellular injury.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"65"},"PeriodicalIF":5.3,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}