Chemico-biological interactions最新文献

{"title":"Discovery of a new function of human butyrylcholinesterase and the catalytic activity of its natural variants toward homocysteine thiolactone hydrolysis.","authors":"Xiabin Chen, Xiaoxuan Li, Huan Liu, Jianzhuang Yao, Yishuang Li, Hualing Li, Zelin Wu, Yun Zhang, Tingjun Hou, Jiye Wang, Shurong Hou","doi":"10.1016/j.cbi.2025.111683","DOIUrl":"10.1016/j.cbi.2025.111683","url":null,"abstract":"<p><p>Abnormal activity level of human butyrylcholinesterase (BChE) was detected in patients with cardiovascular disease and neurodegenerative disorders, however, the specific role of BChE in the pathology of these diseases are not known yet. Homocysteine thiolactone (HTL) is a toxic thioester metabolite of homocysteine in conditions of hyperhomocysteinemia (HHcy). Experimental evidences suggest that HTL and resultant N-Hcy proteins that disrupt normal protein function, are associated with the pathology of HHcy-related complications such as cardiovascular diseases. Given the abundance of BChE in the blood and its esterase capacity, it is worthy to investigate the hydrolytic ability of BChE and its genetic polymorphism effects towards the endogenous toxic HTL in order to delineate its function in the complex disease network. In this study, human BChE and acetylcholinesterase were examined for their ability in HTL hydrolysis, and BChE demonstrates higher catalytic efficiency than reported serum paraoxonase 1. Furthermore, the catalytic mechanism uncovered by Quantum mechanics/Molecular mechanics molecular dynamics method helps to understand and substantiate the function of BChE in HTL metabolism. Six frequent BChE nonsynonymous coding single nucleotide polymorphisms (SNPs) variants were recombinantly produced and their catalytic activity was assessed. Differential catalytic efficiency toward HTL was observed among these variants, suggesting their distinct metabolic capability in vivo. These findings highlight the potential protection role of BChE against HTL-induced toxicity, and pave a way for future investigation into BChE's contribution in HTL metabolism and the possible correlation between specific BChE SNPs and susceptibility for developing HTL-associated diseases.</p>","PeriodicalId":93932,"journal":{"name":"Chemico-biological interactions","volume":" ","pages":"111683"},"PeriodicalIF":5.4,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cigarette smoke-induced glycerophospholipid DLPC promotes macrophage ferroptosis through the USP7/GPX4 regulatory axis in chronic obstructive pulmonary disease.","authors":"Weibin Ruan, Zhimin Peng, Mingsi Huang, Hui Zhang, Xiaohua Li, Tingting Ma, Jiehua Deng, Mianluan Pan, Ziqing Mai, Xia Meng, Jianquan Zhang","doi":"10.1016/j.cbi.2025.111697","DOIUrl":"10.1016/j.cbi.2025.111697","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD), a smoking-associated chronic inflammatory disorder, involves macrophage-mediated inflammation and cell death, yet the mechanisms linking cigarette smoke (CS) to macrophage ferroptosis remain unclear. Through integrated transcriptomic and metabolomic analyses of CS-exposed macrophages, we identified activation of the ferroptosis pathway accompanied by dysregulated glycerophospholipid metabolism. Notably, phosphatidylcholine species enriched in polyunsaturated fatty acids (PUFA-PC), particularly 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), were markedly elevated. Functional studies revealed that DLPC exacerbated lipid peroxidation and triggered ferroptosis in macrophages. Mechanistically, DLPC downregulated the deubiquitinase ubiquitin-specific peptidase 7 (USP7), which normally stabilizes glutathione peroxidase 4 (GPX4) through TRAF/CAT domain-mediated binding and deubiquitination activity. This suppression accelerated GPX4 ubiquitination and subsequent proteasomal degradation. Furthermore, CS upregulated glycerol-3-phosphate acyltransferase 3 (GPAT3), whose genetic ablation diminished PUFA-PC (including DLPC) synthesis, attenuated lipid reactive oxygen species (ROS) accumulation, and inhibited ferroptosis in CS-stimulated macrophages. In vivo, adeno-associated virus-mediated GPAT3 knockdown in murine lung tissues mitigated ROS production, ferroptosis, and emphysema in an experimental emphysema murine model. Collectively, our findings delineate a CS-GPAT3-DLPC axis that drives macrophage ferroptosis via USP7/GPX4 dysregulation, offering novel mechanistic insights into COPD pathogenesis and identifying DLPC and GPAT3 as potential therapeutic targets.</p>","PeriodicalId":93932,"journal":{"name":"Chemico-biological interactions","volume":" ","pages":"111697"},"PeriodicalIF":5.4,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144796334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effects of Co-exposure of tobacco smoke with Dibenzo[a,l]pyrene diol epoxide on molecular targets and immune cells in the mouse oral cavity.","authors":"Todd D Schell, Zachary T Bitzer, Kun-Ming Chen, Cesar Aliaga, Yuan-Wan Sun, Dhimant Desai, Matthew Lanza, Jiafen Hu, Neil Christensen, Karam El-Bayoumy","doi":"10.1016/j.cbi.2025.111694","DOIUrl":"10.1016/j.cbi.2025.111694","url":null,"abstract":"<p><p>Tobacco smoking (TS) is an established etiological factor in the development of head and neck squamous cell carcinoma (HNSCC). We previously developed a mouse model using a select tobacco carcinogen, dibenzo[a,l]pyrene (DB[a,l]P, and its ultimate carcinogenic metabolite diol-epoxide (DB[a,l]PDE) to induce oral squamous cell carcinoma (OSCC) in mice; the molecular characteristics and histological changes observed in the mouse oral cavity mimic those found in human HNSCC. In the present study, using our mouse model, we examined for the first time the co-carcinogenic effects of TS with DB[a,l]PDE on DNA damage, histology, molecular targets, and immune cell regulation. We observed a non-significant increase of the levels of DB[a,l]PDE-DNA adduct in the oral cavity of mice exposed to TS as compared to those exposed to compressed air. Histologically, we observed significant increases in epithelial hyperplasia and epithelial single cell necrosis in TS treated mice. TS significantly enhanced protein expression of NF-κB and Ki67 while the enhancement of COX-2 did not reach significance but p53 expression was significantly decreased. We analyzed immune cell regulation in both spleen and tongue (target organ). No significant changes were observed in the spleen; however, in the tongue, we observed a significantly reduced frequency of CD3+T cells that included reductions of both CD4 and CD8 T cells and a corresponding increase was observed for multiple myeloid cell populations. While preliminary, our results offer the foundation for future research using this mouse model to explore the impact of co-carcinogens/tumor promotors other than TS on critical factors involved in the development of HNSCC.</p>","PeriodicalId":93932,"journal":{"name":"Chemico-biological interactions","volume":" ","pages":"111694"},"PeriodicalIF":5.4,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12392687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring human sperm nuclear basic protein-DNA interactions: could hexavalent chromium play an interfering role?","authors":"Gennaro Lettieri, Carmen Di Giovanni, Simona Amore, Rosanna Del Gaudio, Giancarlo Palumbo, Luigi Montano, Ferdinando Febbraio, Marina Piscopo","doi":"10.1016/j.cbi.2025.111768","DOIUrl":"10.1016/j.cbi.2025.111768","url":null,"abstract":"<p><p>In human, sperm nuclear basic proteins (SNBP) are protamines (∼85 %, P1 and P2) and histones (∼15 %). The interaction with DNA is prevalently mediated by protamines, through guanidinium-phosphate salt bridges, being these proteins very arginine rich. In this work, the binding of SNBP to DNA was investigated in the presence of hexavalent chromium [Cr(VI)], a known disruptor of reproductive function. With Cr(VI) treatment, electrophoretic mobility shift assays indicated markedly impaired of SNBP-DNA complex, SDS and native-PAGE showed SNBP aggregation and fluorescence spectroscopy analyses revealed significant rearrangements in the polar surface exposition. To further probe the role of arginine, SNBP were deguanidinated with hydrazine, producing changes in DNA-binding similar to those caused by Cr(VI). The combination of deguanidinated derivatives of SNBP with Cr(VI) resulted in a worsening of the DNA-binding. All this emphasizes the importance of arginine integrity in the function of SNBP. In silico molecular docking revealed that Cr(III), the most stable reduced form of Cr(VI), forms coordination complexes with the guanidinium groups of arginine residues, thereby affecting DNA binding. These Cr(III) complexes are the primary agents responsible for the genotoxic effects on DNA. Additionally, this approach showed that Cr(III) can form stable bonds with guanine bases in GC-rich sequences and less stable bonds with AT-rich sequences, consistent with available experimental data reported in the literature. All results highlight the importance of a correct SNBP-DNA binding for sperm chromatin organisation and human reproductive health.</p>","PeriodicalId":93932,"journal":{"name":"Chemico-biological interactions","volume":" ","pages":"111768"},"PeriodicalIF":5.4,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sevoflurane suppresses growth and metastasis of bladder cancer cells via inducing ferroptosis and antitumor microenvironment through Akt/mTOR/SREBP1 signaling.","authors":"Lin Lin, Li Kong, Xiaohui Dong, Songmei Ma","doi":"10.1016/j.cbi.2025.111766","DOIUrl":"https://doi.org/10.1016/j.cbi.2025.111766","url":null,"abstract":"<p><p>Sevoflurane is a volatile anesthetic commonly used in clinics, and whether prolonged and repeated exposure to sevoflurane has a potential influence on bladder cancer progression is uncertain. Cell viability assays, transwell assays, flow cytometry, animal models, immunohistochemistry (IHC) staining, western blotting, and reverse transcription-quantitative PCR (RT-qPCR) were performed to evaluate the potential influence of sevoflurane on bladder cancer cells. Multiple rounds of sevoflurane treatment inhibited growth and metastasis and promoted reactive oxidative species (ROS) generation and ferroptosis in bladder cancer cells. In immunocompetent mice, repeated sevoflurane exposure induces an antitumor immune response in bladder cancer xenografts in vivo, whereas inhibition of ferroptosis abrogates this effect. Mechanistically, multiple rounds of sevoflurane exposure modulated lipid oxidation and lipogenesis in bladder cancer cells via the inhibition of Akt/mTOR/SREBP1 signaling, and reactivation of this signaling abrogated the influence of sevoflurane on ferroptosis and bladder cancer progression. Our results indicate that long-term and repeated exposure to sevoflurane suppresses the growth and metastasis of bladder cancer cells by inducing ferroptosis and the antitumor microenvironment by suppressing Akt/mTOR/SREBP1 signaling. Our data suggest a novel role of sevoflurane in bladder cancer progression and treatment.</p>","PeriodicalId":93932,"journal":{"name":"Chemico-biological interactions","volume":" ","pages":"111766"},"PeriodicalIF":5.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145226484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cordiaquinone B induces cytotoxicity and oxidative stress-mediated apoptosis in human colorectal cancer cells invitro and invivo.","authors":"Stéphanie Aguiar de Negreiros Matos Silva, Fabrício Dos Santos Machado, Luciano de Souza Santos, Maria Victoria Lima de Castro, Mateus Lima Nogueira, Milena Botelho Pereira Soares, Simone Alves Serafim Rocha, Renata Mendonça Araújo, Rosane Borges Dias, Daniel Pereira Bezerra, Ana Jérsia Araújo, José Delano Barreto Marinho Filho","doi":"10.1016/j.cbi.2025.111764","DOIUrl":"10.1016/j.cbi.2025.111764","url":null,"abstract":"<p><p>Cordiaquinones are natural molecules derived from the Varronia and Cordia genera with diverse biological potential. In this work, the effects of Cordiaquinone B were initially evaluated in a panel of cancer cell lines. Subsequently, it was first-hand investigated both in vitro and in vivo in human colorectal adenocarcinoma (HCT-116) cells. Experiments were conducted using two-dimensional (2D) and three-dimensional (3D) cell cultures and in the HCT-116 xenograft model in immunodeficient CB17-SCID mice. Cordiaquinone B inhibited the viability of both adherent and non-adherent cancer cell lines without inducing hemolysis in human erythrocytes. In Cordiaquinone B-treated HCT-116 cells, morphological changes and alterations in apoptosis-related protein levels were observed, indicating an apoptotic mechanism associated with mitochondrial oxidative stress. This was supported by an increased mitochondrial superoxide content and prevention of observed cytotoxic and apoptotic effects by N-acetylcysteine (NAC) pretreatment. In the 3D tumor model of HCT-116 spheroids, Cordiaquinone B treatment led to a spheroid size reduction. Additionally, in CB17-SCID mice, a dose of 3 mg/kg/day inhibited HCT-116 tumor growth by 42.6 % without causing severe organ toxicity or alterations in hematological parameters, except for mild to moderate hepatic and pulmonary alterations. These results demonstrate the efficacy of Cordiaquinone B and highlight its potential as a promising candidate for colorectal cancer therapy.</p>","PeriodicalId":93932,"journal":{"name":"Chemico-biological interactions","volume":" ","pages":"111764"},"PeriodicalIF":5.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ionizing zwitterionic oxime antidote attenuates gliosis in mice exposed to sarin.","authors":"Nikolina Maček Hrvat, Borna Puljko, Rakesh K Sit, Katarina Ilić, Dora Kolić, Kristina Mlinac-Jerkovic, Svjetlana Kalanj-Bognar, Zoran Radić, Barry K Sharpless, Palmer Taylor, Zrinka Kovarik","doi":"10.1016/j.cbi.2025.111767","DOIUrl":"10.1016/j.cbi.2025.111767","url":null,"abstract":"<p><p>Toxic organophosphates like the nerve agent sarin readily cross the blood-brain barrier (BBB) and inhibit acetylcholinesterase (AChE), a pivotal enzyme in regulating neurotransmission by hydrolysis of acetylcholine (ACh). Elevated levels and prolonged residence time of ACh initiate seizures and activation of glial cells leading to neuroinflammation. Furthermore, AChE inhibition induces life-threatening symptoms if not treated promptly with atropine and an oxime reactivator of inhibited AChE. The oximes approved for therapy (e.g. 2-PAM) poorly cross the BBB due to their permanent positive charge and do not restore synaptic AChE activity, leaving the brain vulnerable to long-term damage. In this study, we investigated whether treatment with the centrally-active oxime RS194B acts protectively on the brain of mice exposed to sarin. We compared the levels of specific proteins expressed in neuronal and glial cells of mice treated with RS194B after sarin exposure with those of sarin-exposed mice, mice treated with 2-PAM, and untreated control mice. The level of Iba-1 protein was investigated as a measure of microgliosis, and GFAP of astrogliosis, whereas neuronal cell viability was assessed by detecting NeuN immunoreactivity. Our results indicated that sarin-induced gliosis was suppressed in mice treated with RS194B, in contrast to mice treated with 2-PAM. Treatment with RS194B re-established the physiological function of AChE, thus correcting the neurochemical imbalance of ACh that initiates seizures and leads to neuroinflammation. Overall, our results highlight the significance of restoring synaptic AChE activity extending beyond merely mitigating cholinergic crisis.</p>","PeriodicalId":93932,"journal":{"name":"Chemico-biological interactions","volume":" ","pages":"111767"},"PeriodicalIF":5.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outlining the A-Series of Organophosphorus Compounds: Cholinesterase Inhibition, Reactivation, Cytotoxicity, and Acute Toxicity in Mice.","authors":"Zrinka Kovarik, Dora Kolić, Tena Čadež, Goran Šinko, Petra Tuksar, Tamara Zorbaz, Christophe Curty, Nikolina Maček Hrvat","doi":"10.1016/j.cbi.2025.111762","DOIUrl":"https://doi.org/10.1016/j.cbi.2025.111762","url":null,"abstract":"<p><p>Given the scarcity of experimental studies on A-series nerve agents (NAs), this paper provides ground-breaking insights and, for the first time, describes the inhibition and reactivation of human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibited by these NAs using standard oximes. Furthermore, we present a detailed assessment of the toxicity profile of A-series NAs, based on both in vitro and in vivo studies. Our findings demonstrate that A-230, A-232, and A-234 are the most potent inhibitors of AChE and BChE among the A-series, with inhibitory potency comparable to the G-series NAs cyclosarin and soman. A-242 and A-262 inhibited both enzymes with potency similar to that of tabun and VX. Reactivation assays identified HI-6 oxime as the most effective reactivator in mitigating A-230-AChE conjugate-induced toxicity, achieving complete restoration of AChE activity within 4 hours. Obidoxime and TMB-4 showed moderate reactivation capacity over 24 hours, while 2-PAM was ineffective, indicating limited reactivation potential for counteracting A-230-inhibited AChE. These results confirm that both inhibition and reactivation are finely tuned processes, dependent on the structural characteristics of all reactants. In other words, while standard oximes show reasonable potency in reactivating AChE inhibited by agents like sarin and VX, they lack universal efficacy across different NA-AChE conjugates. The reactivation of BChE inhibited by A-agents was negligible when using standard oximes. Additionally, we modelled a near-attack conformation of HI-6 within AChE phosphylated by A-230, providing insights into the structural requirements necessary for more effective reactivation. Beyond enzyme studies, we also assessed hepatotoxicity and neurotoxicity in vitro, and evaluated the acute subcutaneous toxicity of A-series agents in mice. The toxicity of A-230, A-232, and A-234 was comparable to VX, while A-242 and A-262 were similar in toxicity to sarin. These findings significantly advance our understanding of the toxicological properties of phosphoramidates and underscore the urgent need to develop more effective medical countermeasures against A-agents exposure.</p>","PeriodicalId":93932,"journal":{"name":"Chemico-biological interactions","volume":" ","pages":"111762"},"PeriodicalIF":5.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ginsenoside Rk1 suppresses the epithelial-mesenchymal transition of hepatic stellate cells via PFKFB2-mediated aerobic glycolysis.","authors":"Mengyuan Li, Tingdi Zhu, Feng Jiang, Weizhi Zhang, Yuxiang Gao, Mengting Shen, Jinglu Yu, Jianjian Zheng","doi":"10.1016/j.cbi.2025.111760","DOIUrl":"10.1016/j.cbi.2025.111760","url":null,"abstract":"<p><p>Liver fibrosis may progress to cirrhosis or hepatoma without treatment. Hepatic stellate cell (HSC) activation, which could be promoted by epithelial-mesenchymal transition (EMT) process, is crucial for liver fibrosis progression. Ginsenoside Rk1 (GRk1) is a ginsenoside with properties against inflammatory and tumor. Nonetheless, its effects on fibrosis remain unclear. In this study, the suppressive effects of GRk1 on HSC activation as well as liver fibrosis and its underlying mechanism were explored in CCl₄-treated liver fibrosis mice and primary HSCs. Molecular docking analysis verified the interaction between PFKFB2 and GRk1. In addition, RNA-sequence analysis and proteomic lactylation analysis were performed in GRk1-treated HSCs. The results showed that GRk1 attenuated CCl₄-induced liver fibrosis and HSC activation, with suppressed HSC EMT. Notably, it was revealed that GRk1 inhibited aerobic glycolysis and its production lactate via targeting PFKFB2, which was reversed by PFKFB2 overexpression. In addition, it was found that STAT3 lactylation participated in GRk1-inhibited HSC EMT and activation. Further experiments demonstrated that K161 site of STAT3 was responsible for GRk1-inhibited STAT3 lactylation. Moreover, GRk1 treatment led to reduced STAT3 nuclear expression, decreasing TGF-β1 expression and suppressing EMT process, ultimately inhibiting HSC activation. To sum up, this study reveals that GRk1 inhibits aerobic glycolysis via directly targeting PFKFB2, leading to the inhibition of STAT3 lactylation and nuclear translocation, which finally contributes to HSC EMT inhibition and inactivation.</p>","PeriodicalId":93932,"journal":{"name":"Chemico-biological interactions","volume":" ","pages":"111760"},"PeriodicalIF":5.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HFPO-TA exposure triggers hepatomegaly and lipid peroxidation via Nrf2/keap1 antioxidant dysregulation and ferroptosis activation in the liver.","authors":"Xu Fang, Zhonghua Fan, Mengjiao Li, Zhi Li, Lin Cheng, Yuanyuan Wu, Li Wang, Hui Liu","doi":"10.1016/j.cbi.2025.111765","DOIUrl":"https://doi.org/10.1016/j.cbi.2025.111765","url":null,"abstract":"<p><p>As an alternative to perfluorooctanoic acid (PFOA), Hexafluoropropylene oxide trimer acid (HFPO-TA), is currently utilized across various industries and national life, and now, has been detected in all surroundings. Due to its widespread environmental presence and potential biological toxicity, it may adversely affect human health. Studies have shown that HFPO-TA exposure exhibits hepatotoxicity, however, the underlying mechanisms remain unclear. This study investigated the mechanisms of HFPO-TA induced hepatic oxidative stress and lipid peroxidation leading to hepatotoxicity and ferroptosis through in vivo and in vitro experiments. In the in vivo experiments, mice were exposed to 0.02, 0.1 and 0.5 mg/kg/d of HFPO-TA for 14 days, which induced hepatic oxidative stress, mitochondrial morphological changes and lipid peroxidation, leading to hepatocyte ferroptosis. In vitro experiments with AML12 cells demonstrated that HFPO-TA exposure resulted in the accumulation of reactive oxygen species (ROS), a decrease in mitochondrial membrane potential, and subsequent lipid peroxidation and cell membrane damage, ultimately causing ferroptosis. In conclusion, both in vivo and in vitro experiments provide preliminary evidence implicating the p62/Keap1/Nrf2 pathway in HFPO-TA-induced oxidative stress, increases the accumulation of lipid peroxidation products, and leads to the injury of liver tissue and AML12 cells. This study provides new insights into the hepatotoxic effects of HFPO-TA.</p>","PeriodicalId":93932,"journal":{"name":"Chemico-biological interactions","volume":" ","pages":"111765"},"PeriodicalIF":5.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}