Toxicology最新文献

{"title":"Mechanism of PISD/SPG7-mediated mPTP opening in necroptosis of inflammatory HaCaT cells induced by nano-zinc oxide.","authors":"Menglei Wang, Qianwen Yang, Wantong Xiao, Yawen Luo, Jiawen Chen, Ziyi Tang, Yu Wei, Haiqing Li, Wanchun You, Yue Zheng, Li Li","doi":"10.1016/j.tox.2025.154258","DOIUrl":"10.1016/j.tox.2025.154258","url":null,"abstract":"<p><p>Zinc oxide nanoparticles (ZNPs) are extensively used in cosmetics and topical medications and are considered safe for normal skin. However, patients with inflammatory dermatoses, who have an impaired skin barrier, may be at increased risk of percutaneous exposure to ZNPs. Limited research currently exists on the percutaneous toxicity of ZNPs in such conditions. Therefore, this study aimed to evaluate the safety of ZNPs in inflammatory dermatoses. ZNP treatment increased inflammatory human immortalised keratinocyte (HaCaT) cell death and significantly elevated phosphorylated mixed lineage kinase domain-like protein (p-MLKL) protein expression in a concentration-dependent manner, showing that ZNPs trigger necroptosis in HaCaT cells. Further exploration revealed that ZNPs induced mitochondrial swelling and rupture and abnormal opening of the mitochondrial permeability transition pore (mPTP) in inflammatory HaCaT cells as well as decreased the expression of spastic paraplegia 7 (SPG7), a critical protein of the mPTP. Furthermore, phosphatidylserine decarboxylase (PISD) expression in the inner mitochondrial membrane (IMM) was significantly reduced. SPG7 overexpression reversed mPTP opening and necroptosis, whereas PISD overexpression directly upregulated SPG7 expression, inhibited mPTP opening, and reversed necroptosis. Our results indicate that ZNPs contribute to mPTP opening and mitochondrial swelling and rupture via the PISD/SPG7 pathway, an important mechanism leading to necroptosis in inflammatory HaCaT cells. Overall, this study highlights the potential hazards of ZNP exposure in patients with inflammatory dermatoses, reveals the mechanism of injury by which ZNPs induce skin toxicity, and provides data for future dermatotoxicological studies on ZNPs.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154258"},"PeriodicalIF":4.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804916","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":"Ex vivo exposure to p,p'-DDE decreases human macrophage polarization to the M1 phenotype.","authors":"José R Palacios-Valladares, Christian D Ortiz-Robles, Lea A Cupul-Uicab, Omar B Rivera-Maya, Luisa C Hernández-Kelly, Rosa M García-Hernández, Rocio Gómez, Mariano E Cebrián, Emma S Calderon-Aranda","doi":"10.1016/j.tox.2025.154259","DOIUrl":"10.1016/j.tox.2025.154259","url":null,"abstract":"<p><p>Evidence from cellular and animal model studies has shown that p,p-dichloro-diphenyl-trichloroethane (p,p'-DDT) and p,p-dichloro-diphenyl-dichloroethylene (p,p'-DDE) negatively affect the macrophage's inflammatory response and resistance to pathogen infections. Still, no evidence is available on the p,p'-DDE effects on human macrophages, even though there is a translational value to human public health. This study aimed to determine p,p'-DDE serum concentrations in human volunteers with non-occupational exposure and to investigate the effect of ex vivo exposure to p,p'-DDE on the polarization of human monocyte-derived macrophages (hMDM) toward the M1 phenotype. p,p'-DDE from thirty healthy male volunteers was quantified by gas chromatography with a micro-electron capture detector. The hMDM were differentiated using GM-CSF. hMDM were exposed to 25-2500 ng/ml p,p'-DDE for 48 h, and after 24 h of exposure, they were activated with LPS+IFN-γ to the M1 phenotype for 24 h. p,p ´ -DDT was detected in 4/30 individuals (mean= 0.54 ± 0.35 ng/ml), and 30/30 had p,p ´ -DDE (mean=0.57 ± 0.34 ng/ml). Ex vivo, p,p ´ -DDE did not affect cell viability but decreased the expression of M1-polarization markers (HLA-DR and CD68). Bivariate and multivariate analyses revealed that in the M1 macrophage phenotype, 25-2500 ng/ml p,p'-DDE, in a concentration-dependent manner, decreased NO^•- -production, IL-1β, TNF-α, and IL-12 secretion, while increasing ROS. Our study showed that humans are still exposed to p,p'-DDE. Experimental results suggest that p,p'-DDE negatively interferes with the polarization of hMDMs toward the M1 phenotype at environmentally relevant concentrations, influencing key inflammatory mediators critical to innate immunity against pathogens and inducing oxidative stress. This study is the first to evaluate the effect of the p,p'-DDE on polarization of hMDMs to the M1-phenotype. It may contribute to addressing studies to determine whether the incidence of pathologies associated with inflammatory macrophage dysfunction is higher in human populations exposed to DDT and its metabolites. These data will be valuable for implementing policy and health intervention strategies in individuals still exposed to this pesticide.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154259"},"PeriodicalIF":4.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812436","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":"Progressive motor dysfunction and loss of cerebellar Purkinje and granule cells in rat offspring after maternal exposure to imidacloprid.","authors":"Xinyu Zou, Yuri Ebizuka, Yuri Sakamaki, Momoka Shobudani, Qian Tang, Mengyuan Luo, Mio Kobayashi, Tetsuhito Kigata, Makoto Shibutani","doi":"10.1016/j.tox.2025.154246","DOIUrl":"10.1016/j.tox.2025.154246","url":null,"abstract":"<p><p>Imidacloprid (IMI), a major neonicotinoid insecticide, raises concerns about neurodevelopmental abnormalities, particularly attention deficit hyperactivity disorder. However, the involvement of cerebellar development in IMI-induced developmental neurotoxicity has not been studied. Here, this study investigated the maternal exposure effects of IMI on the developing cerebellum in rats. Pregnant Sprague-Dawley rats were fed diet containing IMI at 0 (control), 83, 250 or 750 ppm from gestational day 6 through gestation, and dams treated with the diet during lactation until day 21 postpartum. Male offspring were raised without IMI until postnatal day 77. IMI exposure caused progressive changes of impaired motor coordination (≥ 250 ppm IMI groups) and loss of Purkinje cells (≥ 83 ppm) and granule cells (≥ 250 ppm). IMI suppressed granule cell proliferation by inhibiting sonic hedgehog-mediated cell cycle activation by downregulating Pcna, Cdk2, Shh, and Gli and promoted granule cell apoptosis by upregulating Casp3 during IMI exposure. Neuroinflammation and oxidative stress were key contributors to IMI-induced apoptosis in cerebellar neurons by downregulating Sod2 and upregulating Tnf. The obtained results suggest that exposure to even a lowest dose of IMI (83 ppm; 5.5-14.1 mg/kg/day) can lead to cerebellar defects in rat offspring.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154246"},"PeriodicalIF":4.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765577","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":"Phthalate exposure and hepatocellular carcinoma: Unraveling mechanisms through network toxicology.","authors":"Simin Zhan, Chun Li, Kaiyi Zeng, Yanhao Ran, Chenyu Liu, Yunshuo Zhang, Zekai Zeng, Chuntian Wang, Ziqing Yang","doi":"10.1016/j.tox.2025.154243","DOIUrl":"10.1016/j.tox.2025.154243","url":null,"abstract":"<p><p>Phthalates are typical environmental pollutants that, as plasticizers, are released into the environment through waste, accumulate in organisms, and have reproductive toxicity and potential carcinogenic risks. However, the specific regulatory mechanisms by which phthalates induce liver cancer are still unclear. This study investigates the role of CYP2C9 in liver cancer (LIHC) and its interaction with plasticizers such as BBP and DBP. Toxicological analyses reveal that CYP2C9 is significantly downregulated in LIHC, correlating with poorer patient survival rates. Differential expression analysis using TCGA and GTEx databases confirms high CYP2C9 expression in liver cells, negatively associated with immune cell infiltration. Methylation and mutation analyses indicate a significant relationship between CYP2C9 expression and methylation levels. Additionally, molecular dynamics simulations demonstrate strong binding stability between CYP2C9 and BBP. These findings underscore the critical role of CYP2C9 in liver cancer progression and support its potential as a therapeutic target.</p>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":" ","pages":"154243"},"PeriodicalIF":4.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144733432","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":"Involvement of ARTS in bisphenol A-induced apoptosis of mouse Leydig cells","authors":"Ying Yang ,&nbsp;Si Yang ,&nbsp;Meijuan Zhang ,&nbsp;Linlin Xu ,&nbsp;Jiaxiang Chen","doi":"10.1016/j.tox.2025.154297","DOIUrl":"10.1016/j.tox.2025.154297","url":null,"abstract":"<div><div>As a widely used organic chemical raw material in the world, bisphenol A (BPA) can induce apoptosis in mouse Leydig cells, yet the underlying mechanism remains insufficiently elucidated. Herein, we confirmed that BPA could induce apoptosis of TM3 cells, accompanied with the upregulation of apoptosis-related protein in the TGF-β signaling pathway (ARTS). Overexpression of ARTS promoted apoptosis of TM3 cells, while ARTS depletion attenuated BPA-induced apoptosis of the cells, indicating that ARTS plays a key role in BPA-induced apoptosis of mouse Leydig cells. Subsequently, BPA was found to increase the expression of transcription factor p53 in the cells. Interestingly, overexpression of p53 enhanced the expression of ARTS and induced apoptosis of TM3 cells, while knockdown of p53 by siRNA attenuated the upregulation of ARTS and the induction of apoptosis caused by BPA, implying that BPA induces apoptosis of mouse Leydig cells through p53/ARTS signals. In addition, we also found that oxidative stress was involved in BPA-induced apoptosis of TM3 cells through p53/ARTS signals. Taken together, these findings suggest that BPA-triggered oxidative stress activates p53/ARTS signaling pathway, thereby inducing apoptosis of mouse Leydig cells.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154297"},"PeriodicalIF":4.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145227807","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":"Chronic oral exposure to chlorpyrifos disrupts hepatic epigenetic regulation and induces metabolic dysfunction in mice","authors":"Meenakshi Mansukhani ,&nbsp;Nirmalya Ganguli ,&nbsp;Subeer S. Majumdar ,&nbsp;Souvik Sen Sharma","doi":"10.1016/j.tox.2025.154296","DOIUrl":"10.1016/j.tox.2025.154296","url":null,"abstract":"<div><div>Organophosphate pesticides (OPs) have found extensive use in agriculture due to their short half-lives and relatively low persistence in the environment. In recent years, a growing body of evidence has linked OPs, including chlorpyrifos (CPF), to endocrine, reproductive, and metabolic dysfunction, raising significant public health concerns. Although CPF has been linked to various toxic effects, the epigenetic mechanisms underlying CPF-induced hepatotoxicity remain poorly understood. In the present study, mice were orally exposed to CPF (2 or 20 mg/kg body weight), and the effects on hepatic function were assessed. CPF exposure resulted in pronounced hepatotoxicity characterized by increased oxidative stress, impaired mitochondrial function and dysregulated expression of genes involved in oxidative phosphorylation. Notably, CPF exposure significantly depleted hepatic choline levels and downregulated the expression of genes involved in the regulation of DNA methylation, including <em>Dnmt1</em>, <em>Mthfr</em> and <em>Tet2</em>. The decline in hepatic choline was correlated with hypomethylation of the hepatic genome in CPF-exposed mice. CPF also elevated serum corticosterone in mice, reinforcing its role as an endocrine disruptor. This hormonal disruption was associated with dysregulated glucose homeostasis as evidenced by glucose intolerance, elevated hepatic glycogen and altered hepatic expression of the glucose transporter Glut2. Together, the findings from this study provide novel mechanistic insights into the epigenetic and metabolic effects of CPF-induced hepatotoxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154296"},"PeriodicalIF":4.6,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145227808","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":"The correlation between lung surfactant function inhibition in vitro and the effect on breathing of mice during inhalation exposure – A study of spray-formulated engine/brake cleaners and lubricating products","authors":"Jorid B. Sørli ,&nbsp;Sreyoshee Roy Sengupta ,&nbsp;Niels Hadrup","doi":"10.1016/j.tox.2025.154287","DOIUrl":"10.1016/j.tox.2025.154287","url":null,"abstract":"<div><div>Moving parts in motors require maintenance, both lubrication for smooth operation and de-greasing for cleaning and repair. Since these motor parts are hard to reach, cleaning and lubrication products are often applied by spraying. However, the aerosol spray of the product can potentially reach the breathing zone of the worker and end up in the lungs. We investigated eight products and two single ingredients for their acute effects on the lungs. The effects of the aerosolized substances were tested in an in vitro model for lung surfactant function inhibition. The in vitro results were then compared to the effects of the aerosolized substances on the breathing parameters of exposed mice, measured in whole-body plethysmographs. No-observed-adverse–effect-concentrations were set based on the endpoint of reduction in tidal volume. When a reduction in tidal volume was used as the ´true´ result, the in vitro test for lung surfactant inhibition was 80 % accurate at predicting if the substance affected tidal volume in exposed mice. The ranking of test substances were similar between the in vivo and in vitro results with the exception of (2-methoxymethylethoxy)propanol (substance A). This substance did not inhibit lung surfactant function, but was potent at reducing tidal volume in mice. In conclusion, lung surfactant function inhibition in vitro can be used as a screening tool for acute effects of ingredients in- or formulated -spray products on the lungs.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154287"},"PeriodicalIF":4.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193119","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":"2-Ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) triggers Z-DNA-binding protein 1(ZBP1)- (Receptor-interacting serine/threonine-protein kinase 3) RIP3 mediated programmed necrosis in hepatic cells by inducing mitochondrial left-handed helix (Z-DNA) release","authors":"Meng yu ,&nbsp;Li Jinchao ,&nbsp;Liu Jinlai ,&nbsp;Jing Yanyan ,&nbsp;Liao Lili ,&nbsp;Wang Xinpeng","doi":"10.1016/j.tox.2025.154286","DOIUrl":"10.1016/j.tox.2025.154286","url":null,"abstract":"<div><div>Traditional Polybrominated Diphenyl Ethers (PBDEs) have been gradually banned due to their significant health impacts. As a substitute, the novel brominated flame retardant 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB) has been extensively utilized in industrial and consumer products. TBB has been detected in various environmental media, organisms, and humans, suggesting potential health risks. However, existing toxicological studies on TBB are still limited. The liver is one of the most important target organs in toxicological research. Therefore, we explored the toxicological effects of TBB on liver. Therefore, a series of corresponding biochemical experiments were conducted to evaluate the toxicological effects of TBB. Firstly, CCK8 and EdU assays indicated that TBB blocked the proliferation of hepatocytes. Cell cycle analysis demonstrated that TBB inhibited cell cycle progression; Secondly, TBB treatment causes mitochondrial damage by detection of mitochondrial membrane potential. Further work found that TBB led to programmed necrosis, which is mediated by ZBP1. Mechanistically, we found that TBB induced mitochondrial damage, as evidenced by impaired mitochondrial membrane potential, followed by mitochondrial genome instability and subsequent generation/release of mitochondrial Z-DNA, which subsequently drives both cell death and inflammatory responses. In conclusion, this study investigated the toxicological effects of the novel brominated flame retardant (TBB), these findings indicate that limiting TBB usage should be prioritized in future studies.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154286"},"PeriodicalIF":4.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138869","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":"Oral exposure to tire rubber-derived contaminant 6PPD and 6PPD-quinone induces intestinal toxicity in mice","authors":"Liya Fang,&nbsp;Jinhua Xu,&nbsp;Chanlin Fang,&nbsp;Yuanxiang Jin","doi":"10.1016/j.tox.2025.154285","DOIUrl":"10.1016/j.tox.2025.154285","url":null,"abstract":"<div><div>N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) is a commonly used rubber protectant that continuously enters the environment via groundwater. Its oxidation product, N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6PPDQ), has garnered significant concern due to its reported toxicity in animals. This study aims to evaluate the intestinal toxicity and potential metabolic impact of 6PPD and 6PPDQ in mice following oral exposure to various doses. Our results demonstrate that both compounds compromise the intestinal barrier, as evidenced by significant increases in the expression of tight junction proteins (claudin-1 and occludin) and mucin protein (MUC2). These changes suggest an impairment of both the physical and chemical barriers of the intestine. Following exposure, there was a marked increase in pro-inflammatory cytokines (IL-6, IL-22, and NOD-1), indicating an inflammatory response associated with the disruption of lipid metabolism and macrophage polarization. Specifically, the shift from M2 to M1 macrophage polarization correlates with increased expression of M1 markers despite no change in the M1/M2 ratio over prolonged exposure. Furthermore, 6PPD exposure significantly reduced gut microbiota richness and evenness, with more pronounced changes observed in the 6PPDQ-treated group. Correlation analysis suggested that these microbial shifts may influence host carnitine and lipid metabolism pathways. Ultimately, both 6PPD and 6PPDQ exposure led to elevated levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein (LDL) in the bloodstream, attributed to decreased TC esterification. These findings highlight the potential long-term health risks associated with environmental exposure to 6PPD and 6PPDQ, particularly concerning gut integrity and metabolic dysregulation.</div></div><div><h3>Synopsis</h3><div>This study investigates the toxicity of 6PPD and its transformation product 6PPDQ, revealing their detrimental effects on intestinal health, disruption of gut microbiota, and alterations in lipid metabolism, highlighting significant implications for both environmental and human health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"518 ","pages":"Article 154285"},"PeriodicalIF":4.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145104757","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":"Deciphering the quantitative relationship between NRF2 and SRXN1 through semi-mechanistic computational modeling","authors":"Raju Prasad Sharma ,&nbsp;Liesanne Loonstra-Wolters ,&nbsp;Bas ter Braak ,&nbsp;Marije Niemeijer ,&nbsp;Andrew White ,&nbsp;Bob van de Water ,&nbsp;Alistair M. Middleton ,&nbsp;Joost B. Beltman","doi":"10.1016/j.tox.2025.154284","DOIUrl":"10.1016/j.tox.2025.154284","url":null,"abstract":"<div><div>Nuclear factor erythroid 2-related factor 2 (NRF2) plays a vital role in the regulation of various antioxidant response element (ARE) genes, which control physiological processes such as oxidative stress, autophagy, proliferation and apoptosis to maintain cellular homeostasis. It is not understood in detail how the NRF2 program acquires its flexibility with respect to regulation of its downstream targets. Various NRF2 binding partners and cofactors specific to ARE genes are involved in this regulation, and are potentially condition-specific (e.g., type of stressor) and dependent on non-canonical signaling pathways (i.e., crosstalk). Here, we explored the quantitative relationship between NRF2 and sulfiredoxin 1 (SRXN1), a bona fide key NRF2 target gene. We developed a semi-mechanistic mathematical model based on time course experimental data of NRF2 and SRXN1 protein expression in HepG2 cells following single or repeated exposure to NRF2 activating soft electrophiles (sulforaphane, andrographolide, ethacrynic acid or CDDO-me) at a wide concentration range. We showed that a nonlinear mixed effect modeling approach with partially hierarchical parameters accurately captures the observed experimental dynamics. Our analysis highlights that NRF2 requires a cofactor or post-translational modification to regulate its activity as a transcription factor. Moreover, this modulation of the transcription factor activity of NRF2 is time-, compound- and exposure scenario specific. We conclude that a complete understanding of NRF2-mediated ARE genes activation requires detailed dynamic information on NRF2 binding partners and cofactors.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"519 ","pages":"Article 154284"},"PeriodicalIF":4.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092409","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}