Toxicology and applied pharmacology最新文献

{"title":"Gastrodin alleviates alcohol-induced developmental and neurotoxic effects in zebrafish larvae by suppressing ferroptosis via regulating the Nrf2/GPX4 signaling pathway","authors":"Ruijing Li ,&nbsp;Weili Yang ,&nbsp;Lijuan Zheng ,&nbsp;Xingxue Yan ,&nbsp;Cuihua Liu ,&nbsp;Yaodong Zhang ,&nbsp;Jitong Li","doi":"10.1016/j.taap.2025.117684","DOIUrl":"10.1016/j.taap.2025.117684","url":null,"abstract":"<div><div>Prenatal alcohol exposure is a leading cause of developmental abnormalities and neurobehavioral deficits, collectively known as fetal alcohol spectrum disorder (FASD). The underlying molecular mechanisms, however, are not fully elucidated, hindering the development of effective therapeutic strategies. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key pathological process in various diseases. Gastrodin (GAS), the primary bioactive component of <em>Gastrodia elata</em>, has demonstrated potent antioxidant and neuroprotective properties. This study aimed to investigate the protective effects of GAS against alcohol-induced developmental and neurotoxic damage and to elucidate the underlying molecular mechanisms. Using a zebrafish larval model, we found that exposure to 200 mM alcohol from 2 to 24 hours post-fertilization (hpf) induced significant developmental toxicity, including a decreased hatching rate, body length and eye diameter, and increased morphological malformations in larvae. Alcohol-exposed larvae also exhibited severe neurobehavioral deficits, characterized by a reduction in movement distance and average velocity in dark conditions. Mechanistically, alcohol exposure triggered ferroptosis, evidenced by an increase in intracellular Fe²⁺, malondialdehyde (MDA), and reactive oxygen species (ROS) levels, alongside a decrease in the levels of glutathione (GSH) and reduced glutathione peroxidase 4 (GPX4) and the nuclear factor erythroid 2-related factor 2 (Nrf2) activities. Co-treatment with GAS (200 mg/L) significantly ameliorated these alcohol-induced developmental and neurobehavioral defects. GAS administration effectively suppressed the hallmarks of ferroptosis by restoring the ROS level and altering the expression of genes related to oxidative stress. In addition, GAS suppressed alcohol-induced cell apoptosis, downregulated <em>caspase3b</em>, <em>bax</em>, <em>caspase8</em>, and upregulated <em>bcl2</em> in mRNA levels. Molecular analysis revealed that GAS exerts its anti-ferroptotic effect by activating Nrf2/GPX4 signaling pathway, which was suppressed by alcohol. Our findings indicate that ferroptosis plays a key role in alcohol-induced developmental neurotoxicity, and GAS provides protection by activating the Nrf2/GPX4 axis. This suggests that GAS could be a potential therapeutic option for reducing the negative effects of prenatal alcohol exposure.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117684"},"PeriodicalIF":3.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to a PFAS mixture alters cholesterol lipoprotein subfractions and induces a foam cell-like aortic macrophage expression profile in hyperlipidemic LDLr−/− mice","authors":"Katherine Roth ,&nbsp;Zhao Yang ,&nbsp;Manisha Agarwal ,&nbsp;Katherine Gurdziel ,&nbsp;Michael C. Petriello","doi":"10.1016/j.taap.2025.117683","DOIUrl":"10.1016/j.taap.2025.117683","url":null,"abstract":"<div><div><em>Per</em>- and polyfluoroalkyl substances (PFAS) have been associated with elevated cholesterol, a clinically-relevant risk factor for atherosclerosis. Macrophages are key mediators of atherosclerosis progression through their polarization to various subsets including inflammatory macrophages and foam cells. However, studies examining impacts of PFAS on macrophages in the context of atherosclerosis are lacking. Here, we investigate the impact of PFAS mixtures on cholesterol subfractions and transcriptional profiling of aortic macrophages during early atherosclerosis. Male low density lipoprotein receptor (Ldlr) deficient mice were fed an atherogenic diet and exposed via their drinking water to a mixture of 5 PFAS (i.e., PFOA, PFOS, PFNA, PFHxS, and GenX), each at a concentration of 2 mg/L, for 7 weeks. Circulating cholesterol subfractions and subclasses were analyzed, and aortic macrophages were isolated using immuno-magnetic beads for RNA-sequencing. Total circulating cholesterol was significantly elevated by 10 % following PFAS exposure which was predominately due to a 25 % increase in intermediate-density lipoprotein (IDL). The densest subfraction of low-density lipoprotein, LDL7, also increased by 206 %. RNA sequencing of aortic macrophages revealed PFAS downregulated 389 and upregulated 593 genes; many related to lipid metabolism and foam cell development. Specifically, expression of inflammatory mediators chemokine (C-X-C motif) ligand 2 (<em>Cxcl2</em>) and chemokine (C-X-C motif) ligand 17 (<em>Cxcl17</em>) were significantly increased due to PFAS (2.4 log2 fold change and 10.4 log2 FC respectively) and levels of lipid metabolism and transport genes fatty acid binding protein 4 (<em>Fabp4</em>) and fatty acid synthase (<em>Fasn</em>) were similarly increased (3 log2 FC and 5.2 log2 FC respectively). This work provides additional mechanistic information related to PFAS-mediated acceleration of atherosclerosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117683"},"PeriodicalIF":3.4,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Arsenic exposure affects Pdgfrα stromal cells in the ileum of the small intestine” [Toxicology and Applied Pharmacology Volume 505, December 2025, 117582]","authors":"Scott W. Ventrello,&nbsp;Kayla A. Lea,&nbsp;Lisa J. Bain","doi":"10.1016/j.taap.2025.117677","DOIUrl":"10.1016/j.taap.2025.117677","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117677"},"PeriodicalIF":3.4,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145709327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ghrelin-disrupting activity of arsenic and its relation to cardiometabolic diseases","authors":"Kamrun Nahar Rossi ,&nbsp;Faysal Abedin ,&nbsp;Nayan Chandra Mohanto ,&nbsp;Biplob Ahmed ,&nbsp;Sobuj Mia ,&nbsp;Nesar Uddin ,&nbsp;Rajoana Karim Rimi ,&nbsp;Osman Goni ,&nbsp;Sharon Jahan Sarder ,&nbsp;Sajib Hossain ,&nbsp;Mainul Islam ,&nbsp;Ahsanul Mahbub Jubayar ,&nbsp;Md Shofikul Islam ,&nbsp;Shakhawoat Hossain ,&nbsp;Md Ashraful Hoque ,&nbsp;Daigo Sumi ,&nbsp;Zahangir Alam Saud ,&nbsp;Seiichiro Himeno ,&nbsp;Khaled Hossain","doi":"10.1016/j.taap.2025.117676","DOIUrl":"10.1016/j.taap.2025.117676","url":null,"abstract":"<div><div>Arsenic (As) exposure is linked to a special type of obesity without increasing body mass index. This obesity is accompanied by the reduction of skeletal muscle mass and elevation of insulin resistance (IR). Obesity and IR are the key risk factors for cardiometabolic diseases (CMDs). Ghrelin, a small peptide hormone, is linked to CMDs through multiple mechanisms. However, the ghrelin-disrupting activity of As and its implication in the promotion of CMDs has not yet been documented. Therefore, this study was designed to explore the association of As exposure with serum ghrelin levels and its relation to the risk of CMDs, particularly obesity, skeletal muscle mass reduction, and IR in the participants (<em>n</em>=421) selected from low- and high-As exposure rural areas in Bangladesh. The participants in high-exposure areas had a significantly lower median interquartile range of serum ghrelin levels than those in low-exposure area. Serum ghrelin levels of the participants were decreased with increasing concentrations of As in drinking water, hair, and nails. Ghrelin levels were inversely linked to obesity measures related to As exposure, including waist circumference, triceps skinfold thickness, and serum leptin levels. Decreased ghrelin levels were associated with the reduction of muscle mass measures, serum creatinine levels, and lean body mass. Ghrelin levels were decreased with increasing levels of insulin and IR as assessed by HOMA-IR. Furthermore, As-related HOMA-IR was significantly mediated by lowering the ghrelin levels. These findings collectively indicated that the ghrelin-disrupting activity of As might be involved in the pathophysiology of As-promoted CMDs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117676"},"PeriodicalIF":3.4,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Elucidating the distinctive regulatory effects and mechanisms of active compounds in Salvia miltiorrhiza Bunge via network pharmacology: Unveiling their roles in the modulation of platelet activation and thrombus formation” [Toxicology and Applied Pharmacology volume 484, March 2024, 116871]","authors":"Ying Zhang ,&nbsp;Guang Xin ,&nbsp;Qilong Zhou ,&nbsp;Xiuxian Yu,&nbsp;Lijuan Feng,&nbsp;Ao Wen,&nbsp;Kun Zhang,&nbsp;Tingyu Wen,&nbsp;Xiaoli Zhou,&nbsp;Qiuling Wu,&nbsp;Hongchen He,&nbsp;Wen Huang","doi":"10.1016/j.taap.2025.117668","DOIUrl":"10.1016/j.taap.2025.117668","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117668"},"PeriodicalIF":3.4,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Silico, in vitro, and in vivo studies of a 2-substituted quinazolin-4(3H)-one in T-cell acute lymphoblastic leukemia","authors":"Giorgio Antoniolli ,&nbsp;Gilberto Carlos Franchi Junior ,&nbsp;Keli Lima ,&nbsp;Rayssa de Mello Lopes ,&nbsp;Euzebio Guimarães Barbosa ,&nbsp;João Agostinho Machado-Neto ,&nbsp;Carmen Silvia Passos Lima ,&nbsp;Tiago Rodrigues ,&nbsp;Fernando Coelho","doi":"10.1016/j.taap.2025.117667","DOIUrl":"10.1016/j.taap.2025.117667","url":null,"abstract":"<div><div>This study reports the synthesis, physicochemical characterization, and preliminary pharmacological evaluation of a novel 2-substituted quinazolin-4(3<em>H</em>)-one, Qona11. The compound was synthesized from 2-aminobenzamide and 1<em>H</em>-benzo[<em>d</em>]imidazole-2-carbaldehyde in dimethyl sulfoxide with a 55 % yield, in a catalyst-free, atom-efficient process that adheres to Green Chemistry principles. Structural confirmation was achieved through IR (1667 cm⁻¹, carbonyl), ¹H NMR (13.50 and 12.50 ppm, NH protons), and ¹³C NMR (161.17 ppm, carbonyl carbon). <em>In silico</em> analysis suggested Qona11 possesses favorable oral bioavailability, high intestinal absorption, limited CYP450 inhibition, and predicted blood-brain barrier permeability. Toxicity predictions highlighted potential hepatotoxicity, neurotoxicity, and respiratory toxicity, while no significant risks for cardiotoxicity, carcinogenicity, immunotoxicity, or cytotoxicity were found. Comparative analysis with idelalisib revealed similar toxicity profiles to Qona11, distinct from vincristine. Biological evaluation in acute leukemia models demonstrated concentration- and time-dependent cytotoxicity, with Jurkat T-ALL cells being more sensitive (IC₅₀ 2.3 μM) than NB4 APL cells (IC₅₀ 12.7 μM). Flow cytometry confirmed apoptosis induction in Jurkat cells <em>via</em> mitochondrial permeabilization and caspase 3 activation. <em>In vivo</em> studies in NOD/SCID mice bearing Jurkat xenografts showed that Qona11 (100 mg.kg⁻¹) was well tolerated with no systemic toxicity, although it did not inhibit leukemia cell proliferation in immune-independent models. Overall, Qona11 exhibits promising anticancer activity and low systemic toxicity, warranting further preclinical investigation in solid tumor models and combination therapies.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117667"},"PeriodicalIF":3.4,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal ozone exposure and differential cardiometabolic outcomes in aging male and female offspring","authors":"Brendan Yoo ,&nbsp;Janice A. Dye ,&nbsp;Mehdi S. Hazari ,&nbsp;Aimen K. Farraj ,&nbsp;Erica J. Stewart ,&nbsp;Leslie C. Thompson ,&nbsp;Helen H. Nguyen ,&nbsp;Samantha J. Snow ,&nbsp;Michelle Fiamingo ,&nbsp;Anna A. Fisher ,&nbsp;Katherine L. O'Shaughnessy ,&nbsp;Colette N. Miller","doi":"10.1016/j.taap.2025.117669","DOIUrl":"10.1016/j.taap.2025.117669","url":null,"abstract":"<div><div>Fetal development is a vulnerable life stage for exposure to environmental stressors. Gestational exposure to ozone (O₃) has been shown to compromise fetal growth, predisposing offspring to increased risk of pulmonary and metabolic dysfunction later in life. However, the cardiovascular consequences of maternal O₃ exposure on offspring health remain uncharacterized. Herein, pregnant Long-Evans rats were exposed to 0.8 ppm O₃ for 4 h each day on gestation day (GD) 5 and 6. Following weaning, male and female offspring were monitored for cardiometabolic health for up to ∼5 months of age. Although there were little-to-no changes in most metabolic endpoints (<em>e.g.</em>, growth, food intake, body composition, or glucose tolerance), offspring from O₃ exposed dams had an altered respiratory exchange ratio at ∼4 months old that differed by sex. Furthermore, female offspring had adipocyte hyperplasia in the retroperitoneal depot, effects that were not evident in male offspring. Males from O₃-exposed dams had altered cardiac structure and function, including left ventricular wall thickening and increased ejection fraction and fractional shortening. Females from O₃-exposed dams, on the other hand, had decreased myocardial performance attributed to shortened aortic ejection. RNAseq on hearts from GD 21 fetuses revealed sexually dimorphic effects of maternal O₃ exposure on cardiac gene expression, consistent with altered structure and function that was present in adulthood. Collectively, these findings demonstrate that peri-implantation O₃ exposure increases the risk of multiple adverse effects, including cardiac dysfunction, in adulthood.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117669"},"PeriodicalIF":3.4,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DEHP induces hepatic fibrosis through STAT3-SLC7A11-ROS axis","authors":"Siqin Liang ,&nbsp;Zhiliang Xu ,&nbsp;Xiaoxiang You ,&nbsp;Tinghao Yuan ,&nbsp;Jun He ,&nbsp;Lei Mao ,&nbsp;Anan Jin ,&nbsp;Xinwen Zhou ,&nbsp;Bo Yi ,&nbsp;Ming Li ,&nbsp;Qiang Tu ,&nbsp;Bin Xu","doi":"10.1016/j.taap.2025.117665","DOIUrl":"10.1016/j.taap.2025.117665","url":null,"abstract":"<div><div>Di-(2-ethylhexyl) phthalate (DEHP) is a pervasive environmental contaminant commonly found in daily life, and numerous studies have linked it to the progression of liver diseases and organ fibrosis. However, the precise molecular mechanisms by which DEHP induces liver fibrosis remain incompletely understood. This study aimed to investigate the effects of DEHP on liver fibrosis and its underlying mechanisms. We observed that 100 μM DEHP and 6 days of exposure significantly induced activated human hepatic stellate cells (HSCs) and upregulated the fibrosis marker α-smooth muscle actin (α-SMA). By integrating DEHP and liver fibrosis-related target information from various databases, followed by an assessment of the protein-protein interactome (PPI) network and corresponding functional pathway mapping, we predicted that DEHP-induced liver fibrosis is closely associated with the accumulation of reactive oxygen species (ROS). Molecular docking experiments revealed that DEHP spontaneously binds to STAT3, with GLU-638 identified as a critical amino acid residue for this interaction. Further functional experiments confirmed that DEHP promotes ROS accumulation by downregulating SLC7A11 expression, a process mediated by STAT3. In summary, DEHP facilitates intracellular ROS accumulation by mediating the STAT3-SLC7A11-ROS signaling axis, thereby triggering the formation of liver fibrosis. This research provides novel molecular targets and therapeutic strategies for the future prevention and treatment of liver fibrosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117665"},"PeriodicalIF":3.4,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ditrioxzin synergizes with 2-deoxy-d-glucose to induce redox-dependent metabolic crisis in gastric cancer through dual targeting of peroxiredoxin 3 and glycolysis","authors":"Nan Su ,&nbsp;Lulu Pan ,&nbsp;Xiaojing Shi ,&nbsp;Ying Liu ,&nbsp;Xiaxia Fan ,&nbsp;Shilin Liu ,&nbsp;Yong-Cheng Ma","doi":"10.1016/j.taap.2025.117666","DOIUrl":"10.1016/j.taap.2025.117666","url":null,"abstract":"<div><div>Emerging evidence demonstrates that dual inhibition of glycolysis and mitochondrial function represents a potent anticancer strategy. Here, we report that Ditrioxzin (DTO), a synthetic <em>ent-</em>kaurane diterpenoid analog, selectively disrupts mitochondrial redox homeostasis by targeting peroxiredoxin 3 (Prx3) to induce hydrogen peroxide (H₂O₂) accumulation, thereby depolarizing mitochondrial membrane potential (MMP) and impairing oxidative phosphorylation (OXPHOS) in gastric cancer cells. DTO synergized with the glycolytic inhibitor 2-deoxy-<span>d</span>-glucose (2-DG) to deplete ATP through dual metabolic blockade. In vitro studies revealed that DTO exerted selective cytotoxicity against gastric cancer cells (IC₅₀ 3.82–6.10 μM) but spared normal gastric epithelial cells (GES-1). Mechanistically, DTO directly bound Prx3, elevating H₂O₂ levels (&gt;3-fold at 8 μM), oxidizing mitochondrial peroxiredoxins, and triggering redox-dependent mitochondrial dysfunction. Combined DTO/2-DG treatment promoted ATP depletion and apoptosis (69.6 % vs 24.1 % DTO alone) via ROS-dependent pathways, an effect abrogated by <em>N</em>-acetylcysteine. In vivo, DTO (10 mg/kg) and 2-DG (500 mg/kg) synergistically suppressed tumor growth (66 %, <em>P</em> &lt; 0.001) in xenograft models without body weight loss or histopathological changes in kidney/heart. Our findings establish DTO as a novel Prx3-targeted agent that synergizes with 2-DG to induce metabolic crisis, providing a high-safety-profile therapeutic strategy for gastric cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117666"},"PeriodicalIF":3.4,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145683525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zingiberensis new saponin reverses sorafenib resistance by targeting lncRNA TCONS-00026762/AKR1C1 and modulating autophagy and ferroptosis in hepatocellular carcinoma","authors":"Liang Luo ,&nbsp;Pingsheng Zhou ,&nbsp;Keqing He","doi":"10.1016/j.taap.2025.117664","DOIUrl":"10.1016/j.taap.2025.117664","url":null,"abstract":"<div><h3>Introduction</h3><div>Zingiberensis new saponin (ZnS) extracted from Dioscorea zingiberensis has antitumor activity. Our previous study found that Zns could exert anti- hepatocellular carcinoma (HCC) effects by regulating lncRNA TCONS-00026762. In addition, lncRNA TCONS-00026762 may act synergistically with AKR1C1. However, the relationship between them and their specific molecular mechanism underlying the anti-HCC effects of Zns has not been elucidated. This study aimed to investigate the role of TCONS-00026762/ AKR1C1 axis and ZnS in HCC cells from the perspective of autophagy, ferroptosis, and sorafenib resistance.</div></div><div><h3>Methods</h3><div>Bioinformatics analysis was used to assess the prognostic significance and expression level of AKR1C1 in TCGA liver cancer data. In vitro experiments, the effect of TCONS-00026762 knockdown or Zns on AKR1C1 expression, autophagy, and ferroptosis in HCC cells (Huh7) was investigated. Their function was further confirmed by rescue experiments. In addition, a sorafenib-resistant cell line (Huh7-SR) was constructed to explore the regulatory effects of TCONS-0026762 or Zns on cell viability.</div></div><div><h3>Results</h3><div>AKR1C1 was overexpressed in HCC and association with prognosis. It was involved in autophagy and ferroptosis related pathways. TCONS-00026762 knockdown inhibited AKR1C1 expression. TCONS-00026762 knockdown and Zns treatment suppressed the levels of autophagy marker (LC3) and ferroptosis markers (GPX4, SLC7A11) in Huh7 cell, as well as decreased the proliferation and invasion capacities of Huh7-SR cells after sorafenib treatment. Notably, these effects were eliminated by AKR1C1 overexpression or TCONS-00026762 overexpression.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that ZnS inhibits autophagy, promotes ferroptosis, and enhances sensitivity to sorafenib in HCC cells through the TCONS-00026762/AKR1C1 axis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117664"},"PeriodicalIF":3.4,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}