Toxicological Research最新文献

{"title":"Methotrexate-induced hepatotoxicity-mechanism, clinical cases and treatment approaches.","authors":"Anand Kumar Shah, Souvik Banerjee, Shareen Singh, Vetriselvan Subramaniyan, Thakur Gurjeet Singh","doi":"10.1007/s43188-026-00345-z","DOIUrl":"10.1007/s43188-026-00345-z","url":null,"abstract":"<p><p>Methotrexate (MTX) is a class of antifolate chemotherapeutics and immunosuppressants that are effectively used in the treatment regimen of cancer and autoimmune diseases. In the current MASLD era, methotrexate-induced hepatotoxicity must be understood in the context of host metabolic dysfunction, obesity, diabetes, and alcohol use that amplify oxidative and inflammatory liver injury. But its administration is being restricted due to hepatic toxicity, which increases asymptomatic in transaminases and progresses to fibrosis. This review examines the complex mechanisms underlying MTX-induced liver damage, including oxidative stress, mitochondrial impairment, inflammatory signaling pathways such as NF-κB and JAK/STAT, and apoptosis. Factors such as total dosage, genetic variations such as MTHFR polymorphism, concurrently used hepatotoxicity medication, and existing metabolic conditions significantly influence liver injury. Diagnostic methods, including transient elastography and non-invasive fibrosis indicators, modify the liver monitoring. New non-invasive biomarkers and genetic tests open opportunities for early identification. Treatment with folinic acid, antioxidants (silymarin and Vitamin E), and glucarpidase shows potential to reduce hepatic toxicity. Furthermore, therapeutic drug monitoring and lifestyle changes may enhance the safety. A comprehensive understanding of MTX-induced liver toxicity is essential for tailoring individualized treatment plans. This review differentiates between low-dose methotrexate used in autoimmune diseases and high-dose methotrexate used in oncology, emphasizing mechanistic differences in hepatotoxicity pathways, integrating MASLD-related risk factors, and summarizing current non-invasive diagnostic strategies. Further studies are required to understand the molecular targets involved in methotrexate- induced hepatotoxicity, as well as to translate into therapeutic approaches.</p><p><strong>Graphical abstract: </strong>The above scientific illustration shows that, after intracellular polyglutamylation, Methotrexate induces oxidative stress in hepatocytes. This oxidative stress disrupts mitochondrial regulation and activates vital inflammatory signaling pathways, such as NF-κB and JAK/STAT. As a result, hepatic inflammation and apoptosis, along with the release of tumor necrosis factor-α, play a vital role in the progression of liver fibrosis. Potential therapeutic interventions, such as folinic acid and antioxidant therapy, have been identified as promising strategies to counteract MTX-induced hepatotoxicity (Created by BioRender.com).</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 4","pages":"395-426"},"PeriodicalIF":3.3,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13332104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The oncogenic signalosome: SQSTM1/p62 as a master integrator of signaling, metabolism, and autophagy in cancer.","authors":"Eun-Ji Choi, Sang-Min Jeon","doi":"10.1007/s43188-026-00349-9","DOIUrl":"10.1007/s43188-026-00349-9","url":null,"abstract":"<p><p>Sequestosome 1 (SQSTM1/p62), long established as a selective autophagy receptor and ubiquitin-binding scaffold, is now recognized as an emerging regulatory hub that integrates signaling, metabolism, and stress adaptation in cancer. Beyond its canonical role in proteostatic cargo degradation, recent advances have revealed that p62 orchestrates nutrient sensing, redox control, innate immune signaling, and metabolic reprogramming through highly dynamic, context-dependent mechanisms. A nascent paradigm emerging from recent studies is that p62 function is specified by a hierarchical post-translational modification (PTM) code, with phosphorylation acting as the primary regulatory layer. Site-specific phosphorylation events-together with modulatory PTMs such as S-acylation, arginine methylation, and O-GlcNAcylation-reshape p62 interaction networks, liquid-liquid phase separation (LLPS) behavior, and signaling output. Through these mechanisms, p62 operates as a sophisticated signal-metabolism interface that couples stress signaling pathways, including NFE2L2/NRF2, AMPK, mTORC1, and NF-κB to the systemic rewiring of glucose, lipid, amino acid, and nucleotide metabolism. Notably, a phosphorylation-dependent positive feedback loop between p62 and AMPK has emerged as a key driver of metabolic plasticity, enabling tumor cells to survive and proliferate under the stringent metabolic stress conditions of the tumor microenvironment. This review integrates recent mechanistic insights into the PTMs, phase behavior, and signaling hub functions of p62, highlighting how these principles manifest in distinct oncogenic contexts, such as lung, prostate, and brain tumors. We further discuss emerging therapeutic strategies that seek to modulate p62-centered assemblies rather than indiscriminately inhibit p62 function. Collectively, these findings position p62 as a phosphorylation-governed oncogenic nexus whose precise manipulation may enable new strategies for context-dependent precision oncology.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 3","pages":"325-343"},"PeriodicalIF":3.3,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13096288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disinfection's impact on the environment, molecular cross-resistance with antibiotics, and modern reduction approaches.","authors":"Mohammed F Hamdi","doi":"10.1007/s43188-026-00340-4","DOIUrl":"10.1007/s43188-026-00340-4","url":null,"abstract":"<p><p>Industrial disinfectant use has become concerning due to its antimicrobial resistance (AMR)- promoting properties, leading to antibiotic and disinfectant co-resistance. This research investigates the genetic processes by which disinfectants enhance bacterial resistance to antibiotics by analyzing multidrug efflux pumps and mobile genetic elements (MGEs). Bacterial cells that encounter disinfectants tend to increase their production of efflux pumps, which simultaneously protect them against disinfectants and various antibiotics. Multidrug resistance in Pseudomonas aeruginosa arises when the bacterium encounters chlorine disinfectants, which activate the MexEF-OprN efflux pump. Horizontal gene transfer (HGT) is an essential factor for the simultaneous selection of both antibiotic- and disinfectant-resistance genes. Scientific evidence demonstrates that chlorination, along with other disinfectants, increases horizontal gene transfer rates, thereby facilitating the exchange of antibiotic resistance genes among bacterial species. The uptake of foreign genetic material occurs through the combined effects of increased membrane permeability and oxidative stress, which promote the process. The development of resistance results from two main mechanisms: horizontal gene transfer and natural genetic adaptations. Bacteria are exposed to disinfectants, which can cause genetic mutations that activate resistance proteins and other defense systems. The resistance of <i>Pseudomonas aeruginosa</i> bacteria to antibiotics increases due to changes in the pmrB gene. Some experimental results indicate that contact with disinfectants may decrease bacterial antibiotic resistance by either slowing bacterial growth or altering the production of virulence factors. This paper highlights the need for stricter regulations on disinfectant use, given their potential to foster the development of multidrug resistance. Further research into the genetic mechanisms underlying disinfectant-induced resistance is essential to understand better and mitigate its impact on public health.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-026-00340-4.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 3","pages":"289-306"},"PeriodicalIF":3.3,"publicationDate":"2026-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13096454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147781062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In silico</i> cardiac safety assessment using a multi-biomarker approach based on an electrophysiological model of hiPSC-derived cardiomyocytes.","authors":"Ari Kurniawan Saputra, Ali Ikhsanul Qauli, Aroli Marcellinus, Ki Moo Lim","doi":"10.1007/s43188-026-00341-3","DOIUrl":"10.1007/s43188-026-00341-3","url":null,"abstract":"<p><p>Torsade de Pointes (TdP) is a potentially fatal ventricular arrhythmia associated with drug-induced disturbances of cardiac repolarization. Because QT interval prolongation alone provides limited mechanistic specificity, the Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm promotes integrated evaluation using ion-channel pharmacology, <i>in silico</i> electrophysiology, and human stem-cell-based evidence. In this study, we benchmarked the Paci2020 human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) <i>in silico</i> model for CiPA-aligned TdP risk prediction using an interpretable ordinal logistic regression (OLR) framework. Ten mechanistically grounded biomarkers spanning ionic charge balance, action-potential morphology, and calcium handling dynamics were extracted from simulations of 28 CiPA reference drugs across clinically relevant exposures (up to fourfold free peak plasma concentration, Cmax) and evaluated using CiPA-recommended diagnostic metrics under repeated resampling. Single-biomarker models-including qNet and APD90 (a net ionic charge metric and action potential duration at 90% repolarization)-exhibited strong discrimination in some comparisons but did not consistently meet CiPA confidence requirements for reliably excluding high-risk compounds, which motivated the integration of multiple biomarkers. Exhaustive screening of all non-empty biomarker subsets (1023 combinations) identified a parsimonious four-biomarker signature (qNet, Ca_resting, dVm/dtmax, Cycle_length) that satisfied all CiPA acceptance criteria on the independent test set, outperforming the Tomek-ORd benchmark and approaching the performance of the CiPAORdv1.0 adult-ventricular model. Collectively, these findings demonstrate that, despite the immature electrophysiology of hiPSC-CMs, CiPA-grade TdP risk prediction can be achieved through systematic, mechanistically interpretable multi-biomarker integration, supporting the role of hiPSC-CM <i>in silico</i> models as complementary tools for early-stage cardiotoxicity screening.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-026-00341-3.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 4","pages":"517-534"},"PeriodicalIF":3.3,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13332093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of a B cell acute lymphoblastic leukemia xenograft rat model for integrated efficacy, pharmacokinetics and safety of CD19 CAR-T.","authors":"Joo-Il Kim, Mi-Young Park, Euna Kwon, Tomoji Mashimo, Hyoung Jin Kang, Byeong-Cheol Kang","doi":"10.1007/s43188-026-00343-1","DOIUrl":"10.1007/s43188-026-00343-1","url":null,"abstract":"<p><p>In preclinical studies of B cell acute lymphoblastic leukemia (B-ALL), mouse models have limitations related to their small body size, which restricts serial sampling required for integrated assessment of efficacy, safety, and pharmacokinetics (PK) assessments. To overcome these limitations, we developed a B-ALL xenograft rat model as an integrated platform for the preclinical evaluation of cell therapies and validated this platform by testing its ability to simultaneously assess efficacy, PK, and safety using a CD19 CAR-T standard. The B-ALL rat model was established using NALM-6 (human B-ALL cell line) cells, followed by intravenous injection of CD19 CAR-T three days later at doses of 1.0 (low) and 2.0 × 10⁸ cells/kg (high). B-ALL xenograft rat model successfully differentiated dose-dependent responses, demonstrating significant tumor regression without adverse effects in high-dose group, whereas low-dose group showed no efficacy. Kinetic analysis revealed peak expansion of CAR-T cells in high-dose group 3 weeks after injection, while low-dose group displayed no significant expansion. Crucially, this study demonstrates the utility of the model as an integrated PK-Efficacy evaluation platform with exploratory safety monitoring. We identified 2.0 × 10⁸ cells/kg as an effective therapeutic dose with a favorable safety profile, showing complete remission without evident toxicity under the tested conditions. This study is the first to validate a B-ALL xenograft rat model capable of simultaneously analyzing efficacy, safety, and biodistribution. By utilizing rats, a species widely accepted in toxicology, this disease-relevant model provides a robust platform to support the preclinical assessment of next-generation cell-based therapies.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-026-00343-1.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 4","pages":"535-546"},"PeriodicalIF":3.3,"publicationDate":"2026-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13332086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Punicalagin mitigates benzo[α]pyrene induced epithelial-mesenchymal transition and migration in triple‑negative breast cancer cells.","authors":"Zeeshan Ahmad Bhutta, Cho-Won Kim, Kyung-Chul Choi","doi":"10.1007/s43188-026-00338-y","DOIUrl":"10.1007/s43188-026-00338-y","url":null,"abstract":"<p><p>Breast cancer is one of the most prevalent cancers among women, often attributed to genetic mutations, hormonal imbalances, and lifestyle factors. The compound benzo[α]pyrene (B[α]P) is commonly found in emissions and fumes from industrial processes and cigarette smoke. Punicalagin (PCG), a polyphenolic compound in pomegranates, is reported to have antioxidant, anti-inflammatory, anti-cancer, and antiviral activities. In this study, we aimed to determine whether B[α]P induced toxicity in breast cancer cells and to assess the role of PCG in mitigating this toxicity. The water-soluble tetrazolium salt (WST) assay showed that exposure of MDA-MB-231 and MCF-7 cells to B[α]P at 1-32 µM decreased their viability. B[α]P also resulted in the decrease of the mitochondrial membrane potential in both cell lines. The change in mitochondrial reactive oxygen species levels was confirmed using MitoSOX™ staining of MDA-MB-231 and MCF-7 cells, and the level of red fluorescence increased upon exposure to B[α]P compared to the control group. In the scratch wound healing and transwell migration assays, B[α]P induced migration of MDA-MB-231 cells, which was mitigated by PCG. Furthermore, there was an increase in the N-cadherin expression and a decrease in the E-cadherin expression on exposure to B[α]P. However, PCG reversed this trend. Our findings suggest that PCG mitigates B[α]P-induced mitochondrial dysfunction, oxidative stress, and epithelial-mesenchymal transition, thereby reversing B[α]P's pro-tumorigenic effects in breast cancer cells.</p><p><strong>Graphical abstract: </strong></p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 4","pages":"501-515"},"PeriodicalIF":3.3,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13332091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Esculetin alleviates IgA nephropathy in rats by improving intestinal mucosal function through the IL-17/NF-κB signaling.","authors":"Fan Ye, Jian Liu","doi":"10.1007/s43188-026-00337-z","DOIUrl":"10.1007/s43188-026-00337-z","url":null,"abstract":"<p><p>Based on the \"gut-kidney axis\" theory, the disruption of the intestinal barrier function has been identified as a contributor to the occurrence and development of IgA nephropathy (IgAN). Esculetin, as a bioactive compound isolated from the medicinal herb <i>Cortex Fraxin</i>, has been demonstrated to exert protective effects against kidney and intestinal injury. Our study aimed to evaluate the effects of esculetin on IgAN progression and the associated mechanism. Sprague-Dawley rats were treated with bovine serum albumin (BSA), lipopolysaccharide (LPS), and carbon tetrachloride (CCL4) to establish the IgAN animal models, during which period the rats were orally administrated with esculetin (100 mg/kg) once a day for 12 weeks. After collecting 24-h urine samples to detect proteinuria levels, the rats were sacrificed and blood samples were harvested to examine serum blood urea nitrogen (BUN), serum creatinine (SCr), and serum IgA, IL-17, and pro-inflammatory cytokine levels. Kidney and intestinal tissues were subjected to hematoxylin-eosin (HE), periodic acid-Schiff (PAS), and alcian blue-periodic acid-Schiff (AB/PAS) staining, immunofluorescent and immunohistochemical staining, RT-qPCR, and western blotting to determine histopathological changes, IgA glomerular deposition, and the expression of tight junction proteins, IL-17, and NF-κB pathway-related molecules. Esculetin administration attenuated 24-h proteinuria, BUN, and SCr levels, alleviated renal pathological injury, inhibited IgA glomerular deposition, and decreased serum IgA and pro-inflammatory cytokines levels in IgAN rats. Furthermore, esculetin mitigated pathological injury, increased the number of mucin-producing goblet cells, and enhanced tight junction protein expression in the intestinal tissues of IgAN rats. Esculetin downregulated serum, renal, and intestinal levels of IL-17 as well as renal and intestinal levels of p-NF-κB p65 and p-IκBα in IgAN rats. Esculetin exerts both renal protection and intestinal mucosal barrier protection effect in IgAN rat models by inactivating the IL-17/NF-κB signaling.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 4","pages":"489-500"},"PeriodicalIF":3.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13332095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-dependent neurotoxicity of environmental toxicants: a narrative review.","authors":"Yunkyung Eom, Jaebeom Cho, Ki-Woon Kang, Sung Hoon Lee","doi":"10.1007/s43188-026-00339-x","DOIUrl":"10.1007/s43188-026-00339-x","url":null,"abstract":"<p><p>Environmental pollutants, whether naturally occurring or manufactured for commercial use, are pervasive in modern ecosystems. Endocrine disruptors, particulate matter, and micro- and nanoplastics are especially concerning because of their ubiquity, persistence, resistance to degradation, and bioaccumulation. Their global dispersal enables widespread human exposure and poses systemic health risks. The brain, with limited antioxidant capacity and a lipid-rich composition, is highly vulnerable to pollutant-induced injury. It exhibits sex-dependent differences in neurotransmission, neuroanatomy, glial populations, and neuroinflammatory responses, which can shape susceptibility to environmental insults. Yet the direct effects of environmental toxicants on the brain remain incompletely defined, partly because many toxicology studies have used only male animals, lacked sex-stratified analyses, or omitted sex altogether. Converging evidence from epidemiological, animal, and cellular studies links pollutant exposure to sex-dependent neurotoxic outcomes spanning neurodevelopmental and neurodegenerative disorders and functional impairments, reflecting intrinsic differences between male and female brains. This review synthesizes current knowledge on sources and exposure routes of key pollutants-endocrine disruptors, particulate matter, and micro- and nanoplastics-along with their sex-dependent neurotoxic effects and underlying mechanisms. Recognizing sex-dependent vulnerabilities is essential to inform public health policies, targeted interventions, and regulatory strategies to prevent pollutant-associated brain diseases.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 2","pages":"127-147"},"PeriodicalIF":3.3,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147327104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cigarette smoke exposure worsens the severity of alcoholic liver disease by increasing CYP pathway signaling in mice.","authors":"Hyuneui Jeong, Jong-Won Kim, Daram Yang, Min-Seok Kim, Kyuhong Lee, Bumseok Kim","doi":"10.1007/s43188-025-00336-6","DOIUrl":"10.1007/s43188-025-00336-6","url":null,"abstract":"<p><p>Cigarette smoke (CS) is a major risk factor for both acute and chronic diseases, predominantly impacting the lungs and cardiovascular system. Increasing evidence indicates that CS also has substantial but underappreciated effects on liver health, including accelerating the progression of alcoholic liver disease (ALD). Because smoking and alcohol consumption often co-occur in clinical populations, understanding their combined effects is important for translational research. This study aimed to elucidate the mechanisms by which CS intensifies ALD through a comprehensive assessment of histopathological changes, biochemical indices, and molecular alterations in the liver. Six-week-old male C57BL/6 mice were initially exposed to three concentrations of CS (150, 300, and 600 μg/L) or filtered air for 2 h per day, 5 days each week, and then administered ethanol to induce ALD. Exposure to CS markedly worsened alcohol-induced liver injury, as evidenced by higher serum alanine aminotransferase and aspartate transaminase activities, increased hepatic lipid accumulation, enhanced oxidative stress, and elevated inflammation. Mice subjected to both CS and ethanol displayed more pronounced hepatic injury than those exposed to either stimulus alone, suggesting an additive deleterious effect that accelerates ALD progression. Importantly, CS strongly induced hepatic cytochrome P450 enzymes, particularly CYP1A2 and CYP2E1, thereby enhancing ethanol metabolism and worsening ALD progression. This mechanistic effect provides an insight that contributes a notable element of novelty to the study. Confirmatory results were observed in ex vivo studies, where primary hepatocytes treated with various concentrations of CS extract and 100 mM ethanol showed comparable injury patterns and CYP induction. Overall, these results indicate that CS exposure exacerbates ALD development, partially through the modulation of hepatic cytochrome P450 enzyme activity.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-025-00336-6.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 4","pages":"473-487"},"PeriodicalIF":3.3,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13332106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory reprogramming of alveolar macrophages by the bacterial peptide iE-DAP via PEPT2 transport.","authors":"Masashi Kawami, Yutaka Takeuchi, Kosuke Fuji, Ryoko Yumoto, Mikihisa Takano, Yasuo Uchida","doi":"10.1007/s43188-025-00335-7","DOIUrl":"10.1007/s43188-025-00335-7","url":null,"abstract":"<p><p>Alveolar macrophages serve as key sentinels of pulmonary immunity, yet the mechanisms by which they recognize and respond to bacterial-derived peptides remain poorly understood. Here, we demonstrate for the first time that the peptide transporter PEPT2 is functionally expressed in NR8383 cells, a rat alveolar macrophage-derived cell line, and mediates the uptake of the bacterial-derived dipeptide iE-DAP, triggering pro-inflammatory responses. iE-DAP treatment significantly increased TNF-α and IL-6 expression in a PEPT2-dependent manner. Using SWATH-based quantitative proteomics, we identified 1,198 upregulated and 1404 downregulated proteins following iE-DAP exposure, among which proteasome components and NF-κB subunits were markedly induced, while lysosome-related proteins were downregulated. Inhibitor studies confirmed that iE-DAP activates the MAPK/NF-κB pathway, with a unique involvement of the JNK cascade in macrophages. Notably, the upregulation of cathepsin B (CTSB) and its potential role in inflammasome activation via NLRP3 resemble key elements of pyroptotic cell death, suggesting a link between lysosomal dysfunction and exaggerated inflammatory signaling. These findings indicate that PEPT2 facilitates the uptake of iE-DAP in alveolar macrophages, leading to enhanced proteasome activity, lysosomal impairment, and M1 polarization, ultimately amplifying inflammatory signaling. Our study uncovers a novel innate mechanism by which bacterial peptides can induce alveolar macrophage activation and suggests that dysregulated PEPT2-NOD1-proteasome signaling may contribute to the pathogenesis of pulmonary inflammatory disorders. These insights provide a foundation for targeting peptide transporters in the regulation of macrophage-driven lung inflammation.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at 10.1007/s43188-025-00335-7.</p>","PeriodicalId":23181,"journal":{"name":"Toxicological Research","volume":"42 4","pages":"461-472"},"PeriodicalIF":3.3,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13332088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}