Chemico-Biological Interactions最新文献

{"title":"Modulation of dopamine, serotonin, and behavior by lutein carrier nanoparticles in a Drosophila melanogaster model of neurodevelopmental disorders","authors":"Dieniffer Espinosa Janner ,&nbsp;Andriele de Moura Brinck ,&nbsp;Frâncelly Marquez de Figueiredo ,&nbsp;Elize Aparecida Santos Musachio ,&nbsp;Luana Barreto Meichtry ,&nbsp;Eliana Jardim Fernandes ,&nbsp;Pamela Piardi de Almeida ,&nbsp;Carlos Borges Filho ,&nbsp;Magali Kemmerich ,&nbsp;Amarilis Santos De Carvalho ,&nbsp;Odinei Hess Gonçalves ,&nbsp;Fernanda Vitória Leimann ,&nbsp;Rilton Alves de Freitas ,&nbsp;Marina Prigol ,&nbsp;Gustavo Petri Guerra","doi":"10.1016/j.cbi.2025.111500","DOIUrl":"10.1016/j.cbi.2025.111500","url":null,"abstract":"<div><div>Considering that woman's health during pregnancy is crucial to well-being as much maternal and fetal as well as the child's future, supplementation with antioxidant compounds has emerged as a promising strategy to prevent the development of future diseases. Given this context, the study aimed to evaluate the effect of lutein carrier nanoparticles supplementation during the preconception period on the offspring of <em>Drosophila melanogaster</em> subjected to a neurodevelopmental disorder model. Female flies, were exposed to either a standard diet or a diet containing NPs LUT (6 μM) for 24 h. Following this period, the flies were transferred to new experimental vials, and eighteen males were added, resulting in a total of 53 flies per experimental group. The male and female flies were then subdivided into two groups and exposed to either a standard diet or imidacloprid (IMI), for 7 days, to induce the neurodevelopmental disorder model, creating four experimental groups: 1) Control; 2) IMI; 3) NPs LUT; 4) NPs LUT + IMI. The hatched offspring were then used for behavioral and biochemical evaluations. Our results showed that supplementation with lutein carrier nanoparticles was able to prevent decreased activity of enzyme tyrosine hydroxylase (TH), as did neurotransmitters dopamine (DA) and serotonin (5-HT) in the head of flies, and as a consequence it prevented behavioral damages such as hyperactivity, anxiety, social interaction, repetitive movements, learning and memory in the progeny of both sexes. Thus, these findings highlight the relevance of preconception supplementation with lutein carrier nanoparticles as an effective approach to prevent the emergence of symptoms associated with neuropsychiatric disorders, paving the way for future research aimed at investigating the best intervention period to prevent ASD and ADHD-type disorders.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"414 ","pages":"Article 111500"},"PeriodicalIF":4.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826044","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":"Histone lactylation-augmented IRF4 is implicated in arsenite-induced liver fibrosis via modulating Th17 cell differentiation","authors":"Weiyong Chen ,&nbsp;Peiwen Wang ,&nbsp;Yan Xie ,&nbsp;Daxiao Xie ,&nbsp;Hailan Wang ,&nbsp;Ning Bu ,&nbsp;Jiaheng Lin ,&nbsp;Meng Wu ,&nbsp;Haibo Xia ,&nbsp;Cheng Cheng ,&nbsp;Yuanzhong Zhou ,&nbsp;Qizhan Liu","doi":"10.1016/j.cbi.2025.111507","DOIUrl":"10.1016/j.cbi.2025.111507","url":null,"abstract":"<div><div>Arsenic, a ubiquitous environmental toxicant, has been implicated in causing liver fibrosis through chronic exposure. Histone lactylation is involved in various inflammatory diseases, among which liver fibrosis is included, and is also closely related to the regulation of immune cells. This work focuses on the mechanisms of histone lactylation and Th17 cell differentiation in arsenite-induced liver fibrosis through animal and cellular experiments. Chronic arsenite exposure of mice led to liver fibrosis, elevated glycolysis in liver, and increased lactate levels in both serum and liver, which promoted Th17 cell differentiation of CD4⁺ T cells and increased IL-17A secretion. Treatment with oxamate, a lactate dehydrogenase inhibitor, suppressed Th17 cell differentiation and alleviated fibrosis in the liver. For HepG2 cells, arsenite exposure enhanced glycolysis and lactate levels, leading to increased global lactylation (Kla), H3K18la, interferon-regulatory factor 4 (IRF4), retinoic acid receptor-related orphan receptor gamma t (RORγt), and IL-17A expression and secretion in co-cultured Jurkat cells. Furthermore, in Jurkat cells, reducing lactate production and transport decreased these protein levels, suppressed Th17 cell differentiation, decreased IL-17A secretion, and ultimately inhibited the activation of hepatic stellate cells (HSCs). These results indicate that lactate derived from hepatocytes promotes Th17 cell differentiation by upregulating IRF4 through H3K18la, thereby enhancing IL-17A secretion and the activation of HSCs, contributing to arsenite-induced liver fibrosis. Our work reveals a new mechanism of histone lactylation in arsenite-induced liver fibrosis and offers a fresh perspective for the development of strategies for prevention and treatment of this condition.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"414 ","pages":"Article 111507"},"PeriodicalIF":4.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828506","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":"NLRs in tumor chemotherapy resistance: A double-edged sword","authors":"Lili Sun ,&nbsp;Yanmei Zhu ,&nbsp;Yuan Yuan","doi":"10.1016/j.cbi.2025.111499","DOIUrl":"10.1016/j.cbi.2025.111499","url":null,"abstract":"<div><div>Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a numerous family of cytoplasmic proteins. Members of this family not only function as innate immune sensors, but also serve as transcriptional regulators of major histocompatibility complex class II (MHC II) and major histocompatibility complex class I (MHC I) genes to activate adaptive immunity. Furthermore, NLRs are involved in mediating various signaling pathways, including the inflammasome. To date, extensive research has been conducted on the contradictory roles and mechanisms of NLRs in the occurrence, development, invasion, and metastasis of tumors within the tumor microenvironment (TME). The double-edged sword effect (either positive or negative role) of NLRs in the treatment of malignant tumors has attracted increasing attention in recent years, making these a promising bidirectional therapeutic target for such tumors. Rational utilization of the double-edged sword nature of NLRs can provide a feasible solution for improving the efficacy of malignant tumor treatment and overcoming chemotherapy resistance. This article provides a systematic review of the influence of the NLR family on chemosensitivity in different malignant tumors and the regulatory mechanisms of their upstream and downstream signaling pathways. In doing do, we aim to elucidate the dual role of NLRs in promoting and combating tumor chemotherapy resistance, and elucidate their application value in tumor chemotherapy resistance.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"414 ","pages":"Article 111499"},"PeriodicalIF":4.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143768024","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":"Fusobacterium nucleatum-derived 3-indolepropionic acid promotes colorectal cancer progression via aryl hydrocarbon receptor activation in macrophages","authors":"Qi Song ,&nbsp;Zhiliang Jin ,&nbsp;Han Zhang ,&nbsp;Kunqiao Hong ,&nbsp;Beibei Zhu ,&nbsp;Haisen Yin ,&nbsp;Baoping Yu","doi":"10.1016/j.cbi.2025.111495","DOIUrl":"10.1016/j.cbi.2025.111495","url":null,"abstract":"<div><div>An increasing body of research indicates that <em>Fusobacterium nucleatum</em> (<em>F. nucleatum</em>) significantly influences the onset and progression of colorectal cancer (CRC). Our previous study has shown that <em>F. nucleatum</em> exerts pro-tumorigenic effects through aryl hydrocarbon receptor (AhR) activation. However, the role of its microbial metabolites in regulating immune responses remains unclear. Here, we report for the first time that <em>F. nucleatum</em>-derived 3-Indolepropionic acid (IPA) activates AhR in macrophages, driving M2 polarization and tumor-promoting immunosuppression. We discovered that culture supernatant of <em>F. nucleatum</em> (CSF) robustly activates AhR in macrophages. In co-culture systems, CSF upregulated the expression of the M2 marker CD206 and elevated mRNA levels of CD163, TGF-β, IL-10, and VEGF. In a subcutaneous allograft model, CSF induced an elevated number of CD206⁺ macrophages and decreased presence of CD8⁺ T cells within the tumor microenvironment, thereby promoting tumor growth. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed IPA as a novel major AhR-activating metabolite in CSF. Strikingly, IPA recapitulated CSF's effects in promoting tumor cell migration and immunosuppression, both <em>in vitro</em> and <em>in vivo</em>. Critically, the AhR inhibitor CH223191 abolished both IPA-mediated M2 polarization and tumor growth. Our study revealed a novel mechanism by which <em>F. nucleatum</em>-derived IPA reprograms macrophages through AhR activation to fuel CRC progression, providing potential therapeutic targets for CRC treatment and prognosis improvement.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"414 ","pages":"Article 111495"},"PeriodicalIF":4.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775203","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":"Structural and Functional Alterations of Human Serum Albumin (HSA) Induced by TBBPS-BME: A Spectroscopic, Computational, and Molecular Dynamics Study","authors":"Wei Zhang ,&nbsp;Linna Gao ,&nbsp;Shuyuan Zhang ,&nbsp;Jiaqing Luo ,&nbsp;Ruoxuan Yu ,&nbsp;Xiting Li ,&nbsp;Zhili Lu ,&nbsp;Baozhu Chi ,&nbsp;Ying Guo ,&nbsp;Xun Tuo","doi":"10.1016/j.cbi.2025.111498","DOIUrl":"10.1016/j.cbi.2025.111498","url":null,"abstract":"<div><div>Tetrabromobisphenol S Dimethyl Ether (TBBPS-BME) serves as a substitute for Tetrabromobisphenol A (TBBPA). It exhibits a greater potential for bioaccumulation, potentially posing substantial risks to environmental health and human safety. This research utilized a variety of spectroscopic and computational modeling methods to investigate structural and functional alterations of human serum albumin (HSA) induced by TBBPS-BME. The findings revealed that TBBPS-BME induces fluorescence quenching in HSA by binding to site I. The predominant force in this binding process is hydrophobic interaction. The binding constant for this complex is 2.394 ± 0.032 × 10⁴ M^-1 at 298 K, suggesting that they can form complex <em>in vivo</em>. The interaction with TBBPS-BME causes structural alterations in HSA, leading to a decrease in α-helix proportion and an overall enhancement of protein structural flexibility. The esterase-like function of HSA was also impacted by the presence of TBBPS-BME. Computational simulation tests indicate that this may be through interactions with residues Lys199 and Lys195. Molecular dynamics simulations further validated the formation of stable TBBPS-BME-HSA binary complexes, highlighting the critical role of hydrogen bonds in this steadiness. Alanine scanning mutation analysis revealed that Trp214, Phe211, Arg218, Lys199, and His242 are necessary for the assembly of the TBBPS-BME-HSA complex. Overall, this study provides an exhaustive examination of the binding mechanisms between TBBPS-BME and HSA, elucidating the underlying health hazards that may arise from exposure to TBBPS-BME.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111498"},"PeriodicalIF":4.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143767633","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":"Cholinesterase-based inhibitors as multitarget small molecules for the therapy of Alzheimer's disease","authors":"José Luis Marco-Contelles ,&nbsp;María Jesús Oset-Gasque","doi":"10.1016/j.cbi.2025.111497","DOIUrl":"10.1016/j.cbi.2025.111497","url":null,"abstract":"<div><div>Herein, we have summarized the most significant results that we have communicated from our laboratories in the last thirty years, highlighting the most potent and attractive ChEIs based hit(lead)-Multitarget Small Molecules, such as (<em>S</em>)<em>-p</em>-methoxytacripyrine (<strong>1</strong>), ASS234 (<strong>2</strong>), Contilisant (<strong>3</strong>), and Contilistat (<strong>4</strong>), that we have identified in the search for new chemical entities for the therapy of Alzheimer's disease.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111497"},"PeriodicalIF":4.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756465","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":"Pantothenic acid alleviates osteoarthritis progression by inhibiting inflammatory response and ferroptosis through the SIRT1/Nrf2 signaling pathway","authors":"Yi Liu ,&nbsp;Yang Wang ,&nbsp;Shengqi Cheng ,&nbsp;Jie Mu ,&nbsp;Guanchen Yin ,&nbsp;Hang Gao","doi":"10.1016/j.cbi.2025.111494","DOIUrl":"10.1016/j.cbi.2025.111494","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a degenerative joint disease that is a major cause of deformity, swelling, pain and even loss of function in the knee joints of the elderly. Pantothenic acid (PA) plays a protective role in many organs due to its antioxidant and anti-inflammatory properties. Herein, we aimed to assess the protective role of PA on osteoarthritis and investigate the underlying molecular mechanism. The levels of inflammatory factors (IL-1β and TNF-α) in knee tissues were measured by ELISA. The Safranin O-Fast Green staining was used to assess the severity of OA and the H&amp;E staining was used to assess the degree of synovitis. In vitro, the levels of iron, MDA, GSH were measured by the detection kits. Western blotting was used to assess the levels of signaling-related proteins. Our results showed that PA significantly attenuated the degree of cartilage degeneration in the MIA-induced osteoarthritis model. PA also reduced the expression of IL-1β, TNF-α, MMP1 and MMP3. In vitro, PA effectively reduced the concentrations of MMP1 and MMP3 in IL-1β-stimulated chondrocytes. PA decreased the levels of Fe²⁺ and MDA, while increasing GSH production and GPX4 and SLC7A11 expression in IL-1β-induced chondrocytes. Meanwhile, we found that PA was able to inhibit the phosphorylation level of p65, IκB protein in chondrocytes, which effectively blocked the NF-κB signaling pathway. Furthermore, PA also increased the level of SIRT1, Nrf2, and HO-1 protein expression. In addition, the inhibition of PA on IL-1β-induced MMPs production and ferroptosis were inhibited by the SIRT1 inhibitor EX-527. In conclusion, PA inhibited chondrocyte ferroptosis and cartilage destruction in osteoarthritis. The mechanism was through activating SIRT1/Nrf2 signaling pathway.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111494"},"PeriodicalIF":4.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143738251","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":"ADME profile of AP-238 - opioid designer drug (CAS: 140924-11-4): first application of multi-in silico approach methodology for comprehensive prediction of ADME profile (absorption, distribution, metabolism and excretion) important for clinical toxicology and forensic purposes","authors":"Kamil Jurowski ,&nbsp;Alicja Krośniak","doi":"10.1016/j.cbi.2025.111493","DOIUrl":"10.1016/j.cbi.2025.111493","url":null,"abstract":"<div><div>AP-238 is a recently emerged opioid designer drug from the cinnamylpiperazine class, raising increasing concern in forensic and clinical toxicology due to its potential for abuse and limited ADME (absorption, distribution, metabolism, and excretion) profile. This study presents the first comprehensive prediction of the ADME parameters for AP-238 using a multi-<em>in silico</em> approach. Multiple <em>in silico</em> methods (SwissADME, ACD/Percepta, pkCSM, ADMETlab 3.0, ADMET Predictor 12.0, Simulation Plus, XenoSite, and DruMAP) were employed to estimate key ADME parameters. Results indicate high gastrointestinal absorption and blood-brain barrier permeability, suggesting strong psychoactive potential. AP-238 exhibits pH-dependent solubility and interacts variably with P-glycoprotein, which may affect its systemic and central nervous system exposure. Distribution modeling revealed moderate to extensive tissue penetration and significant plasma protein binding. Metabolic simulations identified 11 primary metabolites and involvement of major CYP isoforms (including CYP2B6, CYP2C19, CYP2D6, CYP3A4). Excretion predictions suggest a rapid elimination primarily via hepatic routes. This study provides critical pharmacokinetic insight into AP-238, supporting its early toxicological assessment and prioritization for further investigation. The applied <em>in silico</em> strategy demonstrates a rapid, ethical alternative to traditional ADME testing, particularly valuable in the context of novel synthetic opioids.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"415 ","pages":"Article 111493"},"PeriodicalIF":4.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744677","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":"Enhancing cardiac safety: Liposomal ciprofloxacin mitigates anthracycline-induced cardiotoxicity without compromising anticancer efficacy","authors":"Olga Swiech ,&nbsp;Anna Boguszewska-Czubara","doi":"10.1016/j.cbi.2025.111496","DOIUrl":"10.1016/j.cbi.2025.111496","url":null,"abstract":"<div><div>Anthracyclines, such as doxorubicin and epirubicin (EPI), are integral in the treatment of solid tumors and hematological malignancies but are associated with cardiotoxicity, potentially leading to heart failure. The underlying mechanisms involve the generation of reactive oxygen species (ROS), alterations in iron metabolism, and the inhibition of topoisomerase 2β (Top2β), resulting in mitochondrial dysfunction and cell death. Fluoroquinolones, including ciprofloxacin (CPX), enhance the efficacy of anthracyclines by inhibiting topoisomerase II and inducing apoptosis, thereby indicating a promising combination therapy. This study investigated the impact of environmental pH on the cardiotoxicity and myocardial accumulation of anthracyclines, as well as the cardioprotective and synergistic potential of CPX when co-administered with epirubicin. The findings revealed that only the zwitterionic form of CPX, either free or encapsulated in liposomes, offers significant cardioprotection without compromising the anticancer activity of EPI. Remarkably, the combination of liposomal CPX and EPI completely attenuates EPI's cardiotoxicity. These results suggest that initiating treatment with liposomal CPX prior to EPI administration may optimize cardioprotection while maintaining therapeutic efficacy against cancer.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"414 ","pages":"Article 111496"},"PeriodicalIF":4.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744678","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":"Inhibition of bromodomain and extra-terminal (BET) proteins with JQ1 exacerbates acetaminophen-induced hepatotoxicity by altering detoxification pathways and oxidative stress responses","authors":"A.P. Laddha ,&nbsp;A. Seyednejad ,&nbsp;A.C. Donepudi ,&nbsp;M.J. Goedken ,&nbsp;J.E. Manautou ,&nbsp;G.C. Sartor","doi":"10.1016/j.cbi.2025.111491","DOIUrl":"10.1016/j.cbi.2025.111491","url":null,"abstract":"<div><div>Acetaminophen (APAP) is a widely used over-the-counter drug for the treatment of fever and pain. At therapeutic doses, APAP has a relatively safe profile. However, at supratherapeutic doses it can produce liver injury and even fatal hepatotoxicity. Antioxidant genes regulated by the Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor, erythroid 2-like 2 (NRF2) pathway play a crucial role in hepatoprotection against APAP-induced hepatotoxicity and oxidative stress. Recent studies suggest that bromodomain and extra-terminal motif (BET) proteins, epigenetic readers, act as putative regulators of the KEAP1-NRF2 pathway, but their role in acute drug-induced liver injury (DILI) remains unclear. In this study, we employed complementary <em>in vitro</em> and <em>in vivo</em> approaches utilizing pharmacological inhibition and gene knockdown techniques to examine the role of BET proteins in APAP-induced toxicity. Our findings indicate that APAP treatment significantly alters the gene and protein expression of BET proteins in both mouse liver and the HC-04 cell line. Cytotoxicity analysis using lactate dehydrogenase (LDH) leakage assay revealed that treatment with the small molecule BET inhibitor JQ1 did not alter APAP-induced cytotoxicity. However, siRNA-mediated knockdown of the BET genes <em>Brd3</em> and <em>Brd4</em>, but not <em>Brd2</em>, reduced APAP-induced cytotoxicity in HC-04 cells. In hepatic gene expression analysis experiments, JQ1 pretreatment in mice activated the <em>Nrf2</em> pathway and altered antioxidant genes such as <em>Gclc</em>, <em>Gclm</em>, <em>Ho-1</em>, and <em>Txnrd1</em>, suggesting an enhancement of cellular defenses against APAP-induced oxidative stress at 12 h timepoint. However, by 24 h, histopathological findings revealed significant liver necrosis and inflammation in the JQ1-APAP treated group, indicating that while BET inhibition may confer early protection, it may not fully prevent long-term liver injury.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"413 ","pages":"Article 111491"},"PeriodicalIF":4.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744679","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}