Cell Biology and Toxicology最新文献

{"title":"KMT2D/ZNF460-induced COL9A1-mediated extracellular matrix stiffness maintains the cancer stem cell pool to promote colorectal cancer progression.","authors":"Chengxin Song, Jingmin Xue, Wenjie Song, Xinyu Yue, Yixiu Xia, Peng Han","doi":"10.1007/s10565-025-10053-3","DOIUrl":"10.1007/s10565-025-10053-3","url":null,"abstract":"<p><p>Collagen is a central component of the extracellular matrix (ECM) in tissues, and ECM can promote tumor cell immune evasion. Our research aimed to expound the biological function of the collagen alpha-1(IX) chain (COL9A1) in colorectal cancer (CRC) and the upstream mechanism regarding KMT2D/ZNF460. COL9A1 contributed to maintaining colorectal cancer stem cells (CCSC) self-renewal and proliferative capacity, and COL9A1 knockdown attenuated CCSC stemness, which was activated by 20.0 kPa polyacrylamide gels. Silencing of COL9A1 hampered tumor growth and stemness in mice induced by AOM/DSS and improved the tumor microenvironment (TME) in xenograft-bearing mice. Mechanistically, KMT2D promoted COL9A1 expression by mediating H3K4me1 modification of the enhancer and recruiting ZNF460. In the presence of attenuated KMT2D signaling, its effect on CCSC stemness and CRC progression was similar to that of knockdown of COL9A1, both of which have therapeutic benefits for CRC tumors. Again, the reactivation of COL9A1 reversed this trend. In conclusion, KMT2D mediates H3K4me1 modification of enhancers and recruits ZNF460 to activate COL9A1, which enhances ECM stiffness and self-renewal of CCSC to remodel TME, contributing to CRC progression.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"111"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12213864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539099","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":"YTHDF1 promotes p53 translation and induces ferroptosis during acute cerebral ischemia/reperfusion through m⁶A-dependent binding.","authors":"Xinyu Chang, Bingwu Li, Wanxu Huang, Aixia Chen, Shengmin Zhu, Yueyang Liu, Xiaoling Liu, Jingyu Yang, Dan Ohtan Wang","doi":"10.1007/s10565-025-10061-3","DOIUrl":"10.1007/s10565-025-10061-3","url":null,"abstract":"<p><p>The rapid escalation of oxidative and nitrosative stress during ischemia/reperfusion (I/R) triggers neuronal damage, leading to severe neurological deficits and long-term disability. N6-methyladenosine (m⁶A), a highly abundant RNA modification in the brain, undergoes dynamic changes following acute I/R injury, and regulates stroke pathogenesis and neurological outcomes. However, the molecular mechanisms by which m⁶A influences acute I/R injury responses remain elusive. Our study reveals that the expression of key I/R pathogenesis pathways positively correlates with the expression of m⁶A reader proteins. Modulating expression of YTHDF1, a neuron-enriched reader protein of m⁶A, results in bidirectional changes in oxidative stress response and neuronal viability under I/R conditions. We have identified p53 mRNA as a critical target of m⁶A methylation and YTHDF1, driving the translation of p53 protein in a context- and m⁶A-dependent manner, which exacerbates oxidative stress and ferroptosis. This novel mechanism suggests the potential of targeting the m⁶A reader protein as a strategic avenue for developing neuroprotective therapies to mitigate I/R injury.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"112"},"PeriodicalIF":5.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12213927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539102","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":"NGR-modified curcumin nanovesicles reverse immunotherapy resistance in triple-negative breast cancer via TLR9 and mTOR pathway modulation.","authors":"Shuo Wang, Xiaoou Wang, Xinyu Zheng, Haiyang Jiang, Lu Liu, Ningye Ma, Xiaoshen Dong","doi":"10.1007/s10565-025-10055-1","DOIUrl":"10.1007/s10565-025-10055-1","url":null,"abstract":"<p><p>Curcumin (Cur), a natural bioactive compound extracted from Curcuma longa, has garnered extensive interest due to its modulation of inflammation, antioxidant, and anti-tumor properties. However, its therapeutic translation remains constrained by limited systemic bioavailability. Triple-negative breast cancer (TNBC), an aggressive variant of breast malignancies, exhibits strong resistance to conventional therapies and poor prognosis. The present study was designed to clarify the mechanism through which NGR-modified nanovesicles loaded with Cur (NGR-NVs@Cur) reverse immunotherapy resistance in TNBC. Using transcriptomic and network pharmacology analysis, we identified key genes involved in TNBC development and immunotherapy resistance to determine the targets of Cur. In vitro experiments, including SA-β-gal staining, flow cytometry, and glycolysis analysis, validated that TNBC cells induce glycolysis and CD8⁺ T cell senescence. NGR-NVs@Cur were successfully constructed and marked by transmission electron microscopy (TEM), dynamic light scattering (DLS), pH-responsive release, and cellular uptake assays. Further cell-based studies demonstrated that NGR-NVs@Cur suppressed TNBC cell proliferation, migration, glycolysis, and reversed CD8⁺ T cell senescence. In vivo, both subcutaneous xenograft and adoptive T cell transfer models were developed to evaluate the therapeutic effects of NGR-NVs@Cur in combination with immune checkpoint inhibitors (ICIs, e.g., J43). The results revealed that Cur inhibited TNBC cell glycolysis and T cell senescence by activating TLR9 and suppressing the mTOR pathway, and that NGR-NVs@Cur enhanced targeted Cur delivery and effectively reversed immunotherapy resistance. This study demonstrated a novel strategy by which Cur, delivered via tumor-targeted nanovesicles, modulates glycolysis and CD8⁺ T cell senescence through the TLR9-mTOR axis, offering promising insights into overcoming immune resistance in TNBC.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"109"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539100","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":"TEAD4-mediated upregulation of LPAR3 augments hepatic stellate cell activation in portal hypertension.","authors":"Ruizhao Qi, Zhengyao Chang, Wenlei Zhao, Yuxuan Qiu, Weihua Chang, Ying Zhang, Xinglong Hu, Zhiwei Li","doi":"10.1007/s10565-025-10063-1","DOIUrl":"10.1007/s10565-025-10063-1","url":null,"abstract":"<p><p>Based on bioinformatics insights, this study investigates the functions of lysophosphatidic acid receptor 3 (LPAR3) and TEA domain transcription factor 4 (TEAD4) in hepatic stellate cell (HSC) activation and portal hypertension (PHT) progression. LPAR3 exhibited heightened expression in transforming growth factor beta 1-activated human HSCs (LX-2) and in the liver of carbon tetrachloride-challenged mice. Knockdown of LPAR3 alleviated activation and contractile activity of LX-2 cells, as well as ameliorated liver injury and fibrosis in PHT mice, achieved through deactivation of the p38 MAPK and PI3K/AKT signaling. TEAD4, which was enhanced in the activated LX-2 cells and the liver of PHT mice, was identified to bind to the promoter of LPAR3 to promote its transcription. Silencing of TEAD4 similarly inactivated the p38 MAPK and PI3K/AKT pathways by repressing LPAR3, thus alleviating LX-2 cell activation and liver fibrosis in PHT mice. However, these effects were negated by LPAR3 overexpression. In summary, this investigation suggests that TEAD4-mediated upregulation of LPAR3 augments HSC activation and liver fibrosis in PHT by inducing the p38 MAPK and PI3K/AKT axis.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"110"},"PeriodicalIF":5.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539101","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":"Therapeutic targeting of PRSS3 to alleviate kidney damage in DKD.","authors":"Rui Yang, Rongping Chen, Ningning Xu, Xiaoyan Yang, Hong Chen","doi":"10.1007/s10565-025-10060-4","DOIUrl":"10.1007/s10565-025-10060-4","url":null,"abstract":"<p><strong>Background: </strong>As a primary contributor to end-stage renal disease, diabetic kidney disease (DKD) is characterized by metabolic and inflammatory disturbances. Emerging evidence highlights the gut microbiota's contribution to DKD through metabolite interactions. This study investigates the role of the gut microbiota-derived metabolite trimethylamine-N-oxide (TMAO) and its inhibition of the protease serine 3 (PRSS3) gene in DKD progression.</p><p><strong>Methods: </strong>Fecal and blood samples from 22 DKD and 22 non-diabetic kidney disease (NDKD) patients were analyzed using 16S rRNA sequencing and LC/MS-based metabolomics. Differential gene expression was analyzed using public datasets. Molecular docking assessed TMAO-PRSS3 interactions. In vitro studies employed high-glucose treatments and TMAO exposure in HK-2 renal epithelial cells, while in vivo DKD models were induced in mice using streptozotocin. Functional roles of PRSS3 were validated through lentiviral overexpression and adeno-associated virus delivery.</p><p><strong>Results: </strong>Gut microbiota analysis revealed reduced diversity and abundance in DKD patients, with altered bacterial taxa associated with increased TMAO production. Metabolomics identified TMAO as a significant metabolite, targeting PRSS3 and reducing its expression in renal cells. Molecular docking confirmed direct TMAO-PRSS3 binding. PRSS3 overexpression mitigated high-glucose- and TMAO-induced renal cell damage and inflammation in vitro and fibrosis in DKD mouse models. However, TMAO partially attenuated PRSS3's protective effects.</p><p><strong>Conclusions: </strong>This study identifies TMAO as a key mediator of DKD progression through PRSS3 inhibition. Enhancing PRSS3 expression protects against renal damage, highlighting its potential as a therapeutic target. Modulating gut microbiota and TMAO levels offers promising avenues for DKD management.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"108"},"PeriodicalIF":5.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494751","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":"ADT increases prostate cancer cell invasion via altering AR/SALL4/SOX2-OCT4 stem cell signaling.","authors":"Changcheng Guo, Aimaitiaji Kadier, Zhijin Zhang, Shiyu Mao, Bin Yang, Junhua Zheng, Xudong Yao","doi":"10.1007/s10565-025-10046-2","DOIUrl":"10.1007/s10565-025-10046-2","url":null,"abstract":"<p><p>Early studies indicated that the androgen-deprivation-therapy with antiandrogen Enzalutamide (Enz) could increase prostate cancer patients' survival by an average of 4.8 months. Yet Enz might also have some adverse effects via increasing the prostate cancer (PCa) cell invasion. Here we found Enz treatment could increase SALL4 expression to increase the cancer stem cells-like (CSC-like) population that resulted in increasing the PCa cell invasion. Mechanism dissection revealed that Enz could function via androgen receptor (AR) to transcriptionally regulate the SALL4 expression via direct binding on the SALL4 5'-promoter. The consequences of such Enz/AR/SALL4 axis could upregulate the SOX2-OCT4 expression to increase the CSC-like population and the PCa cells invasion. Together, results from multiple in vitro and in vivo experiments all conclude that Enz may induce the adverse effect of increasing PCa cells invasion via altering the AR/SALL4/SOX2-OCT4 signaling to increase the CSC-like population, and targeting SALL4 may decrease this adverse effect for further suppress the PCa progression.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"107"},"PeriodicalIF":5.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12176959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324502","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":"The role of lncRNA HUPCOS in androgen metabolism and follicle growth arrest in polycystic ovary syndrome.","authors":"Jun Xie, Xiao Xu, Yuning Chen, Yongning Lu, Miao Liu, Yi Feng, Che Qi, Suying Liu","doi":"10.1007/s10565-025-10047-1","DOIUrl":"10.1007/s10565-025-10047-1","url":null,"abstract":"<p><strong>Background: </strong>Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and follicular growth arrest. This study investigates the role of a newly identified long non-coding RNA, lncRNA-ZSCAN2-5:15 (HUPCOS), in the dysregulation of androgen metabolism and ovulatory function.</p><p><strong>Methods: </strong>Clinical samples from 47 PCOS patients and 68 controls undergoing intracytoplasmic sperm injection were analyzed. Follicular fluid hormone levels and granulosa cell expression of HUPCOS, CYP19 A1, and SMAD4 were measured. A PCOS-like mouse model was established via DHEA injection, and Hupcos overexpression was induced by AAV9, with estrous cycles, hormone levels, and ovarian histology examined. Mechanistic studies in KGN cells included overexpression and knockdown assays, immunoprecipitation, ubiquitination, and dual-luciferase reporter assays.</p><p><strong>Results: </strong>PCOS patients showed higher HUPCOS expression (p < 0.01) and testosterone levels (p < 0.0001), and reduced CYP19 A1 in granulosa cells. Hupcos-overexpressing mice showed PCOS-like symptoms, including estrous cycle disturbances and hormonal imbalances. In vitro, HUPCOS overexpression suppressed aromatase expression and estradiol production, while enhancing androstenedione accumulation. Mechanistically, HUPCOS promoted RBPMS ubiquitination, reduced its interaction with SMAD4, and downregulated CYP19 A1 transcription. Co-overexpression of RBPMS and HUPCOS reversed these effects.</p><p><strong>Conclusions: </strong>HUPCOS impairs estrogen biosynthesis in PCOS by enhancing RBPMS degradation and disrupting SMAD4-mediated transcription of CYP19 A1. These findings highlight a novel lncRNA-mediated mechanism contributing to hyperandrogenemia and follicular arrest, offering potential targets for PCOS therapy.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"105"},"PeriodicalIF":5.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309588","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":"Single-cell spatial proteomics of non-relapse small cell lung cancer identifies tumor microenvironment determinants of survival.","authors":"Yin Li, Liliang Xia, Hui Wang, Xinghao Ai, Ying Wang, Qingquan Luo, Yuchen Han, Shun Lu, Xinghua Cheng","doi":"10.1007/s10565-025-10056-0","DOIUrl":"10.1007/s10565-025-10056-0","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is characterized by high malignancy and early propensity for metastasis, and modest response to immunotherapy due to the immunosuppressive microenvironment. Surgical intervention has shown benefits in treating early-stage SCLC. However, most patients experience recurrence after surgery. The factors associated with relapse free survival in these patients remain unclear. We collected operation specimens from ten early-stage SCLC patients (N0M0), conducted long-term follow-up, and grouped them based on disease status. Subsequently, we performed a retrospective analysis using single-cell spatial imaging mass cytometry to explore the characteristics of tumor cells and differences in the tumor microenvironment, especially the single-cell constitute of immune cells, between the two groups. We found that, in early-stage SCLC, tumor cells display pronounced heterogeneity, both intra-group and inter-group. Patients with early recurrence are characterized by a distinct subpopulation of tumor cells with high Ki-67 expression. Non-relapse patients demonstrate better infiltration of M1 macrophages and stromal cells. Neighborhood analysis suggested that positive interactions between macrophages, stromal cells, and T cells with tumor cells may benefit patient prognosis. Additionally, recurrent tumor cells might enhance their metastatic capacity and remodel the microenvironment through upregulation of GranzymeB or reduction of c-Myc expression. In conclusion, SCLC tumor cells demonstrate tumor heterogeneity and microenvironmental changes in the early clinical stages. A higher proportion of M1 macrophages is associated with prolonged postoperative survival in early-stage SCLC patients. This research provides novel insights and evidence for treating and preventing postoperative recurrence in SCLC.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"106"},"PeriodicalIF":5.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315963","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":"GelMA hydrogel-loaded extracellular vesicles derived from keratinocytes promote skin microvasculature regeneration and wound healing in diabetic mice through activation of the PDGF-induced PI3K/AKT pathway.","authors":"Qian Li, Leilei Zhou, Wenqiang Li, Weiheng Zhao, Weimin Chen, Mohammed S AlQranei, Jiarui Bi, Ping Huang","doi":"10.1007/s10565-025-10062-2","DOIUrl":"10.1007/s10565-025-10062-2","url":null,"abstract":"<p><strong>Objective: </strong>This study explores how extracellular vesicles (EVs) derived from keratinocytes cultured in Gelatin Methacryloyl (GelMA) hydrogels facilitate microvascular regeneration and enhance wound repair in diabetic skin ulcers.</p><p><strong>Methods: </strong>EVs were harvested from keratinocyte cultures via ultracentrifugation and ultrafiltration, followed by characterization. Their uptake and angiogenic effects on human umbilical vein endothelial cells (HUVECs) were assessed in the following experimentations. Transcriptomic profiling of EV-treated HUVECs identified angiogenesis-related gene expression changes. A diabetic murine wound model was established and validated via glycemic profiling and pancreatic histology. In vivo effects of GelMA-EVs were evaluated through wound closure rates, histology (re-epithelialization, vascularization, collagen deposition), CD31 staining, and microvascular imaging.</p><p><strong>Results: </strong>Keratinocyte-derived EVs significantly enhanced HUVEC proliferation, migration, and tube formation. Mechanistic studies reported elevated PDGF expression, activating the PI3K/AKT pathway. In vivo experiments validated that GelMA hydrogel-loaded EVs increased PDGF expression in wound tissues, promoting microvascular reconstruction and accelerating wound healing in diabetic mouse skin ulcers.</p><p><strong>Conclusion: </strong>GelMA hydrogel-loaded EVs derived from keratinocytes upregulate PDGF, activating the PI3K/AKT pathway to promote microvascular network reconstruction and enhance wound healing in diabetic mouse skin ulcers.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"103"},"PeriodicalIF":5.3,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12167351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293373","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":"From neurotoxicity to neuroprotection: Rethinking GABA_AR-targeting anesthetics.","authors":"Yubao Li, Hongliang Yang, Lu Liu, Lulu Jiang, Peilin Xie, Xiaoling Wang, Xuhui Cong, Ruilou Zhu, Zhongyuan Lu, Mingyang Sun, Jiaqiang Zhang","doi":"10.1007/s10565-025-10057-z","DOIUrl":"10.1007/s10565-025-10057-z","url":null,"abstract":"<p><p>The brain growth spurt (BGS) represents a pivotal window in neurodevelopment, defined by rapid neurogenesis, heightened synaptogenesis, and the dynamic establishment of neural networks. During this phase, heightened brain plasticity significantly enhances learning and memory abilities, while also increasing the brain's susceptibility to disruptions. Anesthetics, particularly those targeting γ-aminobutyric acid type A receptors (GABA_ARs), interfere with GABAergic and glutamatergic systems, disrupt brain-derived neurotrophic factor (BDNF) signaling, and exacerbate neurotoxic effects. These agents activate glial cells, induce inflammation, and contribute to oxidative stress, while also disrupting calcium homeostasis and triggering endoplasmic reticulum stress. Furthermore, anesthetics alter the expression of non-coding RNAs, which affects gene regulation and long-term memory formation. The extent of neurotoxic effects is contingent upon a constellation of factors, including the timing, dosage, and frequency of anesthetic exposure, as well as individual susceptibility. Notably, perioperative administration of anesthetic agents has been implicated in long-term cognitive dysfunction, thereby emphasizing the critical importance of precisely modulated dosing regimens and temporally optimized delivery strategies to mitigate potential neurodevelopmental risks. In contrast, neuroactive steroids demonstrate promising neuroprotective potential by modulating GABA_AR activity, enhancing BDNF release, and regulating oxidative stress and inflammation. New strategies for preventing and reversing anesthetic-induced neurotoxicity could include novel anesthetic combinations, anti-apoptotic agents, antioxidants, or nutritional supplements. These findings underscore the complex and multifactorial effects of anesthetic agents on the developing brain and emphasize the urgent need to establish and refine anesthetic strategies that safeguard neural integrity during vulnerable windows of neurodevelopment.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"104"},"PeriodicalIF":5.3,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12167312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293372","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}