Gennaro Lettieri , Carmen Di Giovanni , Simona Amore , Rosanna del Gaudio , Giancarlo Palumbo , Luigi Montano , Ferdinando Febbraio , Marina Piscopo
{"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":"<div><div>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. <em>In silico</em> 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<em>.</em> All results highlight the importance of a correct SNBP-DNA binding for sperm chromatin organisation and human reproductive health.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 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":2,"RegionCategory":"医学","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":"10.1016/j.cbi.2025.111766","url":null,"abstract":"<div><div><strong>S</strong>evoflurane 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 <em>in vivo</em>, 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.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 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":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
{"title":"Cordiaquinone B induces cytotoxicity and oxidative stress-mediated apoptosis in human colorectal cancer cells in vitro and in vivo","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":"<div><div>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 <em>in vitro</em> and <em>in vivo</em> 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 <em>N</em>-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.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 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":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jianing Liu , Yiyang Liu , Qi Zhang , Runnan Luo , Jiajia He , Hong Su , Liyan Hou , Qinghui Wang , Qingshan Wang
{"title":"Rotenone induces ferroptosis and neurotoxicity through inhibition of SIRT1-Nrf2-ferroportin 1/GPX4 pathways in SH-SY5Y cells and mice","authors":"Jianing Liu , Yiyang Liu , Qi Zhang , Runnan Luo , Jiajia He , Hong Su , Liyan Hou , Qinghui Wang , Qingshan Wang","doi":"10.1016/j.cbi.2025.111763","DOIUrl":"10.1016/j.cbi.2025.111763","url":null,"abstract":"<div><div>Rotenone is a pesticide that causes damage to dopaminergic neurons and contributes to Parkinson's disease (PD) with prolonged exposure. Recent evidence suggested that ferroptosis contributes to rotenone-induced dopaminergic neurotoxicity. However, the underlying mechanisms remain unclear. SIRT1 and downstream nuclear factor Nrf2 play critical roles in regulating cell survival in pathological conditions. In this stidu, we revealed the role of SIRT1-Nrf2 axis in rotenone-induced neuron ferroptosis. Results showed that in SH-SY5Y cells, rotenone exposure decreased cell viability, which was associated with iron accumulation, lipid peroxidation, glutathione depletion and alterations of ferroptosis-related markers. Ferrostatin-1 and lipostain-1, prevented rotenone-induced neuronal damage as iron chelator and ferroptosis inhibitor, respectively. Furthermore, rotenone treatment blocked the expression and activation of SIRT1-Nrf2 axis and promoted their degradation through proteasome and lysosome. Agonists of SIRT1 and Nrf2 mitigated rotenone-induced iron accumulation, thereby reducing lipid peroxidation and neuron ferroptosis. Mechanistically, the expression of ferroportin 1 (Fpn-1) and glutathione peroxidase 4 (GPX4) was up-regulated by the activation of the SIRT1-Nrf2 axis, which in turn inhibited rotenone-induced iron accumulation and lipid peroxidation responses in cells, respectively. VIT-2763 and RSL4, the inhibitors of Fpn-1 and GPX4, counteracted the protective effects of SIRT1-Nrf2 axis against rotenone-induced ferroptosis. Finally, we revealed reduced expression of SIRT1-Nrf2 axis in rotenone-treated mice and activation SIRT1-Nrf2 by agonists ameliorated rotenone-induced ferroptosis of dopaminergic neuron and improved gait abnormality in mice. Taken together, we revealed that rotenone induced neuron ferroptosis through iron accumulation and lipid peroxidation via inhibition of SIRT1-Nrf2 axis, providing additional evidence for the mechanisms of pesticide-induced neurotoxicity and related PD.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111763"},"PeriodicalIF":5.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
{"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":"<div><div>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.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 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":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"In vitro investigation and mass spectrometric characterization of novel DNA adducts of sesquimustard","authors":"Muharrem Cenk , Havva Bekiroğlu Ataş , Suna Sabuncuoğlu","doi":"10.1016/j.cbi.2025.111761","DOIUrl":"10.1016/j.cbi.2025.111761","url":null,"abstract":"<div><div>Sesquimustard (Q), a potent bifunctional alkylating vesicant, is a significant toxicological concern due to its environmental persistence and capability to induce severe genotoxic effects. It can create several metabolites, some of which can be utilized as biomarkers, and it can extensively alkylate key macromolecules in organisms, including DNA. Although prior research has primarily focused on glutathione and albumin adducts as retrospective biomarkers of Q exposure, no prior studies have identified DNA adducts of Q. This study aimed to fill this critical gap by characterizing, for the first time, Q-induced DNA adducts using advanced mass spectrometric techniques. Three novel DNA adducts -hydroxyethylthioethylthioethyl-adenine (HETETE-Ade), hydroxyethylthioethylthioethyl-guanine (HETETE-Gua), and guanine-ethylthioethylthioethyl-guanine (Gua-ETETE-Gua)- were identified in Q-treated calf thymus DNA via liquid chromatography–high-resolution mass spectrometry (LC-HRMS) and structurally confirmed through high-resolution product ion spectra. Their formation was further demonstrated in a human keratinocyte (HaCaT) cell model using liquid chromatography–tandem mass spectrometry (LC-MS/MS), revealing dose-dependent increases in adduct signal intensities. Compared to protein-based biomarkers, DNA adducts may offer potential advantages in workflow simplicity and direct indication of genotoxic damage. This study provides first molecular insight into Q-induced DNA adducts and lays the groundwork for their future use in toxicological assessment, forensic verification, and biomarker development.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111761"},"PeriodicalIF":5.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zrinka Kovarik , Dora Kolić , Tena Čadež , Goran Šinko , Petra Tuksar , Tamara Zorbaz , Christophe Curty , Nikolina Maček Hrvat
{"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":"10.1016/j.cbi.2025.111762","url":null,"abstract":"<div><div>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 <em>in vitro</em> and <em>in vivo</em> studies.</div><div>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 h. Obidoxime and TMB-4 showed moderate reactivation capacity over 24 h, while 2-PAM was ineffective, indicating limited reactivation potential for counteracting A-230-inhibited AChE. HI-6 also achieved partial reactivation of AChE inhibited by A-232 and A-234. A-242 and A-262-AChE conjugates exhibited minimal susceptibility to oxime reactivation. 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.</div><div>Beyond enzyme studies, we also assessed hepatotoxicity and neurotoxicity <em>in vitro</em>, 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.</div><div>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.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 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":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhenyu Zhu , Chunyan Wang , Shasha Wei , Runtao Wu , Wenxia Zhao , Xinyuan Zhao , Yingjun Li , Ye Yang
{"title":"Benzophenone-3 drives osteoarthritis pathogenesis by regulating chondrocyte senescence","authors":"Zhenyu Zhu , Chunyan Wang , Shasha Wei , Runtao Wu , Wenxia Zhao , Xinyuan Zhao , Yingjun Li , Ye Yang","doi":"10.1016/j.cbi.2025.111757","DOIUrl":"10.1016/j.cbi.2025.111757","url":null,"abstract":"<div><div>Benzophenone-3 (BP-3), a widely used UV absorber, is of increasing concern due to its potential health risks. Recent epidemiological studies have identified a link between BP-3 exposure and osteoarthritis (OA) prevalence, yet its specific role in OA pathogenesis remains incompletely understood. This study reveals that prolonged BP-3 exposure induces OA-like articular cartilage degeneration in rats, marked by structural disorganization, proteoglycan depletion, and critical dysregulation of extracellular matrix (ECM) homeostasis evidenced by up-regulated matrix metalloproteinases (MMPs) and down-regulated type II collagen (Col2a1). Notably, in human C28/I2 chondrocytes, BP-3 significantly disrupted ECM balance evidenced by increased MMPs and decreased Col2a1 content, which corroborates in vivo findings. Mechanistically, transcriptome analysis identified altered expression of genes associated with senescence in BP-3 exposure groups. Subsequent experiments confirmed that BP-3 induced chondrocyte senescence evidenced by elevated Senescence-Associated β-Galactosidase (SA-β-gal) activity and up-regulated p16, p21, and p53. Subsequent cellular transcriptomics further revealed significant changes in Mitogen-activated protein kinase (MAPK) signaling pathways following BP-3 exposure. Crucially, in chondrocytes, BP-3 exposure selectively activated ERK1/2 pathway but not p38 or JNK pathways within the MAPK cascade. Further investigation established that BP-3 drove p21 transcription via dual ERK-dependent mechanism: p53 phosphorylation at Ser15 and phosphorylation/nuclear translocation of the downstream ERK effector Ets-like transcription factor 1 (Elk-1). Strikingly, the ERK-specific inhibitor PD98059 effectively blocked BP-3-induced ERK activation, Elk-1 phosphorylation, chondrocyte senescence, and ECM degradation. Collectively, these findings establish a novel mechanism for BP-3 as an environmental osteoarthritic hazard, in which it triggers chondrocyte senescence and promotes OA pathogenesis through the specific activation of the ERK pathway.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111757"},"PeriodicalIF":5.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","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":"<div><div>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 CCl<sub>4</sub>-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 CCl<sub>4</sub>-induced liver fibrosis and HSC activation<em>,</em> 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.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 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":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xu Fang , Zhonghua Fan , Mengjiao Li , Zhi Li , Lin Cheng , Yuanyuan Wu , Li Wang , Hui Liu
{"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":"10.1016/j.cbi.2025.111765","url":null,"abstract":"<div><div>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 <em>in vivo</em> and <em>in vitro</em> experiments. In the <em>in vivo</em> 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. <em>In vitro</em> 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 <em>in vivo</em> and <em>in vitro</em> 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.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 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":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}