Drug and Chemical Toxicology最新文献

{"title":"Renoprotective effect of roflumilast against amikacin- induced nephrotoxicity: upregulation of Nrf2 signaling, inhibition of cytokines, and renal apoptosis.","authors":"Mona A Abdel-Kareem, Medhat Taha, Magda E Ahmed, Reham Mohammed Atef, Sanad S El-Kholy, Noura H Zidane, Mohammed E Elmitwalli, Tourki A S Baokbah, Ibrahim El-Shenbaby, Kareem Gomaa Al Sayed Ali, Noha M Halloull, Omnia Hassan Megahed, Rehab Abd El Azeem Esa, Ahmed Nahed Zaky Mohamed, Emadeldeen Hussin","doi":"10.1080/01480545.2026.2657439","DOIUrl":"10.1080/01480545.2026.2657439","url":null,"abstract":"<p><p>ABSTARCTAmikacin (AK), a potent aminoglycoside antibiotic, is known to induce nephrotoxicity. This study evaluated the renoprotective effects of ROF, a selective PDE4 inhibitor, against AK-induced renal injury in Wistar rats. Forty male rats were divided into four groups (n = 10): Control (saline), ROF-only (1.5 mg/kg/day orally for 6 days), AK-only (single intraperitoneal injection of 1.2 g/kg on day 3), and AK+ROF (co-treatment). Renal function was assessed via serum creatinine and BUN. Oxidative stress was evaluated by measuring MDA and the antioxidants GSH, SOD, and CAT. The expression of key proteins in the Nrf2/HO-1, NF-κB, and apoptotic pathways was analyzed using ELISA and IHC. Kidney histopathology was examined using H&E, PAS, and Masson's trichrome staining. AK administration significantly elevated serum creatinine and BUN levels, increased lipid peroxidation, and suppressed antioxidant enzymes (SOD, CAT, and GSH). It also upregulated NF-κB along with TNF-α, IL-1β, and IL-6, and enhanced apoptotic markers (caspase-3, Bax) while reducing Bcl-2 expression. Histopathological analysis revealed severe tubular degeneration and inflammatory infiltration in the AK group. The most prominent finding was that ROF co-treatment robustly activated the Nrf2/HO-1 antioxidant pathway, leading to a comprehensive protective effect. ROF significantly ameliorated renal dysfunction, restored antioxidant enzyme activities, and reduced lipid peroxidation. It concurrently suppressed the NF-κB inflammatory cascade and modulated apoptotic signaling. These biochemical improvements were corroborated by marked histopathological recovery. In conclusion, ROF demonstrated potent renoprotection against AK-induced injury primarily through Nrf2/HO-1 pathway activation, which underpinned its synergistic antioxidant, anti-inflammatory, and anti-apoptotic actions, supporting its potential as a therapeutic strategy to mitigate aminoglycoside nephrotoxicity.</p>","PeriodicalId":11333,"journal":{"name":"Drug and Chemical Toxicology","volume":" ","pages":"1225-1235"},"PeriodicalIF":2.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phytochemical characterization and cytogenotoxic activity of leaves of <i>Centratherum punctatum</i> Cass.","authors":"Ana Karla Araújo Silva, Yasmin Lorene de Alvarenga Araujo, Helena Albuquerque Barbosa, Geicylanne da Silva Marques Belfort, Lívia Lorena Araújo Silva, Maria das Dores Alves Oliveira, Jurandy do Nascimento Silva, Nerilson Marques Lima, Joaquim Soares da Costa Júnior, Wildson Max Barbosa da Silva, Francielle Alline Martins, Francisco Artur E Silva Filho, Sâmya Danielle Lima de Freitas, Pedro Marcos de Almeida","doi":"10.1080/01480545.2025.2586137","DOIUrl":"10.1080/01480545.2025.2586137","url":null,"abstract":"<p><p><i>Centratherum punctatum</i> (Asteraceae), known as Brazilian bachelor's button, is used in folk medicine to treat liver problems, intestinal discomfort, and ulcers. The study aims to characterize the ethanolic extract (EE) of <i>C. punctatum</i> leaves, evaluate its antioxidant activity, and assess its cytogenotoxic and chemoprotective effects in <i>Allium cepa</i> and <i>Drosophila melanogaster</i> cells. The EE was characterized by qualitative phytochemical prospecting, TLC, ESI-IT/MSⁿ, HPLC-PDA, and isolation by column chromatography. Antioxidant activity (DPPH and ABTS) and total phenol content (TPC) were quantified. Cytogenotoxicity and the protective effect of EE were evaluated in the <i>A. cepa</i> and the somatic mutation and recombination test (SMART) bioassays at concentrations of 3.9; 15.6; 62.5 and 250 µg/mL. The phytochemical prospecting of EE revealed the presence of tannins, saponins, flavanones, alkaloids, terpenes, and flavonoids. ESI-IT/MSⁿ identified 15 compounds, HPLC-PDA also confirmed the same classes of metabolites, and the isolate was the triterpene acetyl aleuritolic acid. The result of DPPH, ABTS, and TPC was 142.10 ± 2.15 µg/mL; 623.94 ± 38.38 mM Trolox/g, and 77.78 ± 1.19 mg EAG/g, respectively. In <i>A. cepa</i> and SMART, none of the EE concentrations were cytogenotoxic. EE showed a protective effect (pre, simultaneous, and post-treatments) against methyl methanesulfonate damage at all concentrations in <i>A. cepa</i> and antigenotoxic activity (simultaneous) in SMART at 15.6; 62.5, and 250 µg/mL against doxorubicin damage. The findings of the present study demonstrate that <i>C. punctatum</i> is a promising source of compounds with antioxidant and chemoprotective properties.</p>","PeriodicalId":11333,"journal":{"name":"Drug and Chemical Toxicology","volume":" ","pages":"1197-1212"},"PeriodicalIF":2.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin attenuates valproic acid-induced developmental cardiotoxicity through activation of the AMPK/PGC-1α axis and restoration of mitochondrial and redox homeostasis in zebrafish embryos.","authors":"Ünsal Veli Üstündağ, Fümet Duygu Üstündağ, Neşe Ayşit","doi":"10.1080/01480545.2026.2684476","DOIUrl":"10.1080/01480545.2026.2684476","url":null,"abstract":"<p><p>Prenatal valproic acid (VPA) exposure is strongly linked to developmental cardiotoxicity, yet no targeted pharmacological countermeasure exists. Converging mechanistic evidence indicates that VPA cardiotoxicity centers on AMPK/PGC-1α suppression, positioning the AMPK activator metformin (MET) as a rational candidate for <i>in vivo</i> protection. We examined MET's protective effects against VPA-induced developmental cardiotoxicity in zebrafish embryos. Embryos were randomly allocated to four groups (Control, VPA 0.1 mM, MET 10 mM, VPA + MET) immediately after fertilization and chronically exposed until 96 hpf. Oxidative stress biomarkers (MDA, NO, SOD, GSH) and the expression of cardiac (<i>nkx2.5, vmhc, amhc</i>), AMPK (<i>prkaa2, acaca</i>), and mitochondrial/energy-related genes (<i>ppargc1a, cpt1b, pck1, atp5pb, mt-nd1</i>) were quantified. Compared with controls, VPA reduced <i>nkx2.5</i> (p < 0.01) and elevated <i>amhc</i> (p < 0.05), triggered pericardial edema (p < 0.0001), suppressed <i>prkaa2, ppargc1a</i>, and <i>atp5pb</i> (p < 0.05, p < 0.001, and p < 0.0001, respectively), upregulated <i>acaca</i> (p < 0.0001), increased MDA and NO (p < 0.0001), and lowered SOD and GSH (p < 0.0001 and p < 0.001, respectively). Relative to the VPA group, MET co-treatment restored <i>nkx2.5</i> expression (p < 0.001), attenuated pericardial edema (p < 0.0001), increased <i>prkaa2</i> (p < 0.05), <i>ppargc1a</i> (p < 0.01), and <i>atp5pb</i> (p < 0.0001), suppressed <i>acaca</i> (p < 0.0001), and normalized MDA (p < 0.05), NO (p < 0.0001), SOD, and GSH (both p < 0.0001). The restoration of <i>prkaa2/ppargc1a</i>, mitochondrial, and antioxidant capacity by MET suggests that the AMPK/PGC-1α axis may serve as a central target in VPA cardiotoxicity.</p>","PeriodicalId":11333,"journal":{"name":"Drug and Chemical Toxicology","volume":" ","pages":"1114-1124"},"PeriodicalIF":2.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quinestrol nanoparticle-based formulation for long-term oral contraception against the wild female rats, <i>Bandicota bengalensis</i>.","authors":"Dimple Mandla, Neena Singla, Anu Kalia, Varinder Uppal","doi":"10.1080/01480545.2025.2585142","DOIUrl":"10.1080/01480545.2025.2585142","url":null,"abstract":"<p><p>This study developed and evaluated a ready-to-use quinestrol nanoparticle-based bait for contraception in female <i>Bandicota bengalensis</i> (lesser bandicoot rat). <i>B. bengalensis</i> in three treatment groups: Control (plain bait), Q (bait with bulk quinestrol, 100 ppm), and QNP (bait with quinestrol nanoparticles, 10 ppm) were evaluated at 15, 45, and 75 days after a five-day treatment in a bi-choice setting. Results showed no significant difference between treated and plain bait consumptions, indicating good acceptability. Ovary weight decreased, and uterine weight increased significantly in the treated groups. Organ histology revealed significant contraceptive effects, including an increased number of atretic follicles, a reduced number of normal follicles in the ovaries, and increased uterine gland numbers and diameter. The 17β-hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase activities were significantly increased. Treated females produced 65-85% fewer pups when bred with untreated males. Quinestrol did not affect body weight, weight of vital organs, the activity of alkaline and acid phosphatases, and aspartate and alanine aminotransferases, indicating its safety. The effects of Q lasted up to 45 days, whereas the effects of QNP persisted for 75 days, despite using 10 times less active ingredient. This research represents a potential advancement in sustainable rodent pest management with extended efficacy and reduced dosage requirements.</p>","PeriodicalId":11333,"journal":{"name":"Drug and Chemical Toxicology","volume":" ","pages":"1154-1169"},"PeriodicalIF":2.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145539654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the SP1/ACSL4 axis attenuates ferroptosis in trastuzumab-induced cardiotoxicity.","authors":"Qiyuan Hu, Bincheng Zhong, Yajie Zheng, Henghua Zhou","doi":"10.1080/01480545.2025.2586862","DOIUrl":"10.1080/01480545.2025.2586862","url":null,"abstract":"<p><p>Trastuzumab, a mainstay in treating HER2-positive breast, gastric, and lung cancers, inhibits tumor growth by inducing cell cycle arrest, apoptosis, and anti-angiogenesis. However, its clinical use is limited by cardiotoxicity. This study demonstrates that trastuzumab-induced myocardial injury is mechanistically linked to ferroptosis. Trastuzumab dysregulates key ferroptosis-related proteins (increasing ACSL4 (Acyl-CoA Synthetase Long Chain Family Member 4) and decreasing SLC7A11 (Solute Carrier Family 7 Member 11) expression), elevating lipid peroxidation levels. Crucially, we screen out the transcription factor SP1 (Sp1 transcription factor) from the public database, regulator of ACSL4. Silencing SP1 significantly attenuates trastuzumab-triggered myocardial ferroptosis. Collectively, our findings establish ferroptosis as the primary pathway underlying trastuzumab-associated cardiotoxicity and propose SP1 inhibition as a promising therapeutic strategy to mitigate this adverse effect.</p>","PeriodicalId":11333,"journal":{"name":"Drug and Chemical Toxicology","volume":"49 5","pages":"1104-1113"},"PeriodicalIF":2.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative computational and experimental approach identifies PTGS2 as a candidate molecular target in aristolochic acid-induced kidney injury.","authors":"Heping Niu, Jiangwei Man, Ziyi Li, Xuezhen Ma, Zhendong Tian, Rongrong Deng, Shujun Shi, Xiaochun Zhou, Li Huang, Jianqin Wang","doi":"10.1080/01480545.2026.2704880","DOIUrl":"10.1080/01480545.2026.2704880","url":null,"abstract":"<p><p>Aristolochic acids (AAs) are a class of well-known nephrotoxic compounds; however, the molecular mechanisms underlying AA-induced kidney injury remain incompletely understood. This study aimed to identify potential molecular targets and explore the mechanisms involved in AA-induced kidney injury, with particular emphasis on prostaglandin-endoperoxide synthase 2 (PTGS2). An integrated computational and experimental approach was applied. Candidate targets associated with AA exposure and kidney injury were identified through database mining, followed by enrichment and network analyses to determine key regulatory genes. Molecular docking and molecular dynamics simulations were performed to evaluate AA-target interactions, and the association between PTGS2 and kidney injury was further assessed using two-sample Mendelian randomization based on genome-wide association study data. Experimental validation was conducted in an acute AAI-induced C57BL/6 mouse model through evaluation of renal function, histopathology, and PTGS2 expression. PTGS2 was identified as a central candidate gene associated with AA-induced kidney injury and exhibited stable binding with AA <i>in silico. In vivo</i>, AAI exposure caused renal dysfunction and histopathological alterations accompanied by reduced PTGS2 expression. These findings identified PTGS2 as a candidate molecular target involved in AA-induced kidney injury and provided a foundation for further mechanistic research.</p>","PeriodicalId":11333,"journal":{"name":"Drug and Chemical Toxicology","volume":" ","pages":"952-966"},"PeriodicalIF":2.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polystyrene microplastics induce liver toxicity and cytoskeleton alterations in female rats.","authors":"Kaouthar Kessabi, Sana Boughammoura, Latifa Knani, Asma Haddadi, Rania Mlouka, Mohamed Banni, Imed Messaoudi","doi":"10.1080/01480545.2026.2650389","DOIUrl":"10.1080/01480545.2026.2650389","url":null,"abstract":"<p><p>Microplastics (MPs) are emerging environmental pollutants that have received increasing attention in recent years. However, data on their potential risks to mammalian species remain limited. In this study, female rats were exposed via oral gavage to pristine (PPS) and fluorescent polystyrene (FPS) particles (5 μm diameter) over four estrous cycles. FPS-MPs were detected in hepatic tissue (133 ± 35 particles), confirming their translocation. Exposure to PPS-MPs increased superoxide dismutase (SOD) (2.58-fold) and catalase (CAT) activity (1.36-fold), while reducing protein sulfhydryl levels (PSH) (0.35-fold), indicating oxidative stress. Histological analysis and quantitative assessment revealed significant alterations, including significant decrease in glycogen content (2.4- fold). Immunofluorescence analysis showed a pronounced increase in α-tubulin and a decrease in DAAM-1 signals, a formin protein essential for actin filament assembly and cytoskeletal organization, suggesting impaired cytoskeletal dynamics. These observations were further supported by molecular analyses, which showed α-tubulin overexpression (3.35-fold) and reduced DAAM-1 expression (0.5-fold). Our findings indicate that exposure to environmentally relevant concentrations of MPs induces early hepatocellular alterations, suggesting that oxidative stress and cytoskeletal remodeling may be central mechanisms underlying MP-induced hepatotoxicity. These findings should be interpreted with caution, as the study used only female rats, a single dose, particle size, and polymer type, with a short exposure duration, and it should be noted that FPS-MPs were used only to track distribution, whereas toxicity assessments were performed with non-fluorescent particles.</p>","PeriodicalId":11333,"journal":{"name":"Drug and Chemical Toxicology","volume":" ","pages":"886-898"},"PeriodicalIF":2.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A single oral exposure to polyethylene terephthalate microplastics causes mild metabolic and gastrointestinal disruption: dose and sex determinants.","authors":"Ashley A Lewis, Adam Biales, Colette N Miller, Wendy Oshiro, Tracey Beasley, Mette C Schladweiler, Georges-Marie Momplaisir, Robert Flick, Mary J See, Weichun Huang, Wanda Williams, Makala L Moore, Gary Casuccio, Long Li, Michael Deible, Rachel D Grindstaff, Thomas W Jackson, Mehdi S Hazari, Kim Rogers, Kay Ho, Aimen K Farraj","doi":"10.1080/01480545.2026.2643619","DOIUrl":"10.1080/01480545.2026.2643619","url":null,"abstract":"<p><p>Polyethylene terephthalate (PET) microplastics, derived from consumer products such as plastic bottles and clothing, are pervasive in the environment with documented detection in human arteries and brains among other tissues, although their health impacts remain unclear. This study evaluated the biological effects of a single oral exposure to PET microplastics in female and male rats. Three-month-old Sprague-Dawley rats were exposed once via oral gavage to sterile water vehicle, or 5 mg/kg (low PET), or 50 mg/kg (high PET) of PET microplastics derived from cryomilling of plastic nurdles. Immediately after exposure, animals were monitored for ∼18 hours in an indirect calorimetry apparatus for changes in metabolic rate, respiratory exchange ratio, and differences between light and dark periods. At the end of the monitoring period, tissue samples were collected to measure systemic indicators of inflammation and injury, metabolic function, and changes in gene expression in the liver and gastrointestinal tissue. The findings indicate that males exposed to low PET, but not high PET, had significant decreases in metabolic rate, respiratory exchange ratio, and blood insulin. Low PET also caused significant changes in gene expression in the duodenum in males. However, males had dose-dependent increases in serum platelets. Females exposed to PET were limited to decreased metabolic rate with high PET, and dose-dependent increases in serum LDL. In summary, although there was variability across dose and sex, these findings suggest that exposure to PET has the potential to cause mild metabolic dysfunction and systemic and organ toxicity.</p>","PeriodicalId":11333,"journal":{"name":"Drug and Chemical Toxicology","volume":" ","pages":"868-885"},"PeriodicalIF":2.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147480156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In vivo</i> hepatic effects and post-exposure recovery following polyethylene terephthalate microplastic ingestion in Swiss Albino mice (<i>Mus musculus</i>).","authors":"Mayuri Manoj Verlekar, Ankit Anand Sinha, Avelyno H D'Costa","doi":"10.1080/01480545.2025.2609951","DOIUrl":"10.1080/01480545.2025.2609951","url":null,"abstract":"<p><p>The study focuses on the <i>in vivo</i> toxicity of two concentrations of Polyethylene Terephthalate (PET) microplastics (MPs) (average size 30.22 ± 10.21 µm; 1 mg/mL and 2 mg/mL in distilled water) in Swiss Albino mice after 14 days of exposure via their feeding bottles, followed by a depuration period of 7 days. After 14 days of exposure, PET-MPs induced significant effects on the activities of Alanine Aminotransferase (ALT), Catalase (CAT) and Superoxide Dismutase (SOD) in the liver (<i>p</i> < 0.001). Additionally, the levels of total carbohydrates, total proteins, Reduced Glutathione (GSH) and Thiobarbituric acid reactive substances (TBARS) were also significantly altered (<i>p</i> < 0.001; <i>p</i> < 0.01 for proteins). Upon completion of the depuration phase, parameters largely reverted to baseline although several remained statistically distinct from the control values, except for GSH and TBARS. Genotoxicity assessed by the comet assay was not observed with the concentrations used in the study.</p>","PeriodicalId":11333,"journal":{"name":"Drug and Chemical Toxicology","volume":" ","pages":"857-867"},"PeriodicalIF":2.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating computational chemistry, network pharmacology and in vitro experimental assays for deciphering the antitumor effects of naturally occurring sesquiterpene lactone-parthenolide in human oral carcinoma cells.","authors":"Fangyuan Wang, Qing Zhou, Qiuzi Wang","doi":"10.1080/01480545.2026.2633600","DOIUrl":"10.1080/01480545.2026.2633600","url":null,"abstract":"<p><p>This study evaluates the anticancer efficacy of Parthenolide against SCC-9 oral squamous cell carcinoma cells using an integrated in silico and in vitro strategy. Pharmacokinetic behavior and drug-likeness were predicted using SwissADME, while organ-specific and systemic toxicity were assessed via Protox-3.0. Parthenolide-associated targets and oral cancer-related genes were obtained from the Comparative Toxicogenomics Database and GeneCards, respectively. Common targets were identified using Jvenn and subjected to protein-protein interaction (PPI) analysis through STRING, with network visualization and hub gene identification performed in Cytoscape using the CytoHubba plugin. Functional enrichment analysis was conducted using ShinyGO, and gene expression patterns along with survival relevance were analyzed through GEPIA2. Molecular docking and normal mode analysis (NMA) were carried out using CB-Dock2, Discovery Studio, and iMODS. In vitro validation involved MTT assay, colony formation assay, Annexin V/PI flow cytometry, DAPI nuclear staining, and Western blot analysis in SCC-9 cells. Parthenolide demonstrated favorable drug-like characteristics, including high gastrointestinal absorption, blood-brain barrier permeability, and an absence of major predicted toxicities. A total of 42 shared targets were identified, primarily associated with apoptosis, IL-17 signaling, and TNF signaling pathways. PPI network analysis highlighted IL1B, TNF, and TP53 as key hub genes. Molecular docking revealed strong binding affinities of Parthenolide with TNF (-7.5 kcal/mol), TP53 (-6.2 kcal/mol), and IL1B (-6.0 kcal/mol), involving critical interactions such as hydrogen bonding. NMA results indicated that the Parthenolide-TP53 complex was the most stable, with an eigenvalue of 4.705 × 10^-4. Experimentally, Parthenolide significantly decreased SCC-9 cell viability and markedly suppressed colony formation at 120 µM. Annexin V/PI analysis confirmed apoptosis induction, with a substantial increase in apoptotic cell populations at higher concentrations. DAPI staining demonstrated pronounced nuclear fragmentation, while Western blotting revealed downregulation of IL1B and TNF alongside upregulation of TP53. Collectively, these findings indicate that Parthenolide exerts anticancer activity in oral squamous cell carcinoma by modulating inflammatory and apoptotic pathways, underscoring its potential as a promising candidate.</p>","PeriodicalId":11333,"journal":{"name":"Drug and Chemical Toxicology","volume":" ","pages":"714-732"},"PeriodicalIF":2.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147289784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}