Toxicology and applied pharmacology最新文献

{"title":"Angelicin attenuates sepsis-associated splenic injury by targeting NF-κB/JAK2/STAT3 and PI3K/Akt pathways to inhibit inflammation and apoptosis","authors":"Enzhuang Pan ,&nbsp;Huilin Sun ,&nbsp;Zhihao Ma ,&nbsp;Shasha Zhang ,&nbsp;Yedan Liu ,&nbsp;Zihan Xu ,&nbsp;Yusa Li ,&nbsp;Xiaomin Jin ,&nbsp;Heng Wang ,&nbsp;Jingquan Dong","doi":"10.1016/j.taap.2026.117737","DOIUrl":"10.1016/j.taap.2026.117737","url":null,"abstract":"<div><div>Sepsis represents a clinical syndrome characterized by maladaptive host immune dysregulation in response to infection, leading to potentially fatal multiorgan dysfunction. As the largest secondary lymphoid organ in mammals, spleen tissue plays a fundamental role in immune defense. Angelicin (ANG), the main active ingredient in the traditional Chinese medicine <em>Psoralea corylifolia</em> Linn., possesses biological activities such as anti-inflammation and anti-apoptosis. This study established a mouse sepsis-associated splenic injury model using cecal ligation and puncture (CLP) to systematically analyze the protective effects of ANG and its underlying mechanisms. Additionally, the J774A.1 cell model stimulated with lipopolysaccharide (LPS) was used to further validate the pathway regulation phenomena observed <em>in vivo</em>. The results showed that ANG treatment significantly attenuated sepsis-associated splenic injury in mice. qPCR results showed that ANG downregulated pro-inflammatory and upregulated anti-inflammatory cytokine transcripts. TUNEL results showed that ANG treatment inhibited the ratio of TUNEL-positive cells. Further studies demonstrated that ANG suppressed inflammatory responses by inhibiting the NF-κB and JAK2/STAT3 pathways, and alleviate apoptosis by activating the PI3K/Akt pathway. Notably, the suppressive effect of ANG on JAK2/STAT3 pathway was dependent on the inhibition of the NF-κB pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117737"},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079668","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":"Sustained cadmium exposure and hyperglycemia additively drives mitochondrial dysfunction in hepatic cells: Implications for MASLD etiopathogenesis","authors":"Rahul Kumar ,&nbsp;Ashwin Chinala ,&nbsp;Sharina Palencia Desai ,&nbsp;Li Chen ,&nbsp;Marcus A. Garcia ,&nbsp;Sarah J. Blossom ,&nbsp;Matthew J. Campen ,&nbsp;Rama R. Gullapalli","doi":"10.1016/j.taap.2026.117729","DOIUrl":"10.1016/j.taap.2026.117729","url":null,"abstract":"<div><div>Effects of chronic heavy metal stress on hepatocellular pathophysiology remains ill-understood. Human livers are a long-term accumulative site for many toxic heavy metals (e.g., cadmium and arsenic) whose health effects are unknown. In the current study, we studied the effects of chronic, low-dose exposures of cadmium (CLEC) modulated by normoglycemic (5.6 mM) and diabetes relevant hyperglycemic (15 mM) exposures, focusing on hepatocellular mitochondrial function. Hepatocellular cell lines were exposed to CLEC and glucose for 24 weeks, mimicking a chronic heavy metal exposure paradigm of normal and type II diabetic individuals. CLEC exposures significantly affect the long-term health of mitochondria, including decreased mitochondrial mass, increased superoxide production, and loss of mitochondrial membrane potential (MMP) in a CLEC and glucose-dependent manner. Furthermore, CLEC induced significant chronic oxidative stress revealed by the Seahorse MitoStress assay. In particular, CLEC cells show altered levels of basal and non-mitochondrial respiration, causing dysregulation in mitochondrial oxygen consumption rates (OCRs) of the cells. Lastly, we identify significant impacts of CLEC and glucose exposures on mitochondrial dynamics (fission/fusion), which show enhanced mitochondrial fragmentation and turnover rates. We also identified novel cell compensatory mechanisms that may mask the true extent of chronic Cd exposure induced damage in liver cells. New approach methodologies (NAMs) such as the current toxicology study, establish the insidious, long-term damaging effects of chronic heavy metal pollutant exposures on human hepatocellular function.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117729"},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041329","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":"2026-03-01","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":"Paclitaxel impairs mitochondrial dynamics in human sensory-like neuron cells","authors":"Mariana Caprio Schiess ,&nbsp;Gessica Sabrina de Assis Silva ,&nbsp;Natália Gabriele Hösch ,&nbsp;Vitória Carvalho Troitiño ,&nbsp;Marcelo Medina de Souza ,&nbsp;Carlos DeOcesano-Pereira ,&nbsp;Talita Glaser ,&nbsp;Henning Ulrich ,&nbsp;Ana Marisa Chudzinski-Tavassi ,&nbsp;Michelle Cristiane Bufalo ,&nbsp;Vanessa Olzon Zambelli","doi":"10.1016/j.taap.2026.117715","DOIUrl":"10.1016/j.taap.2026.117715","url":null,"abstract":"<div><div>Taxanes are considered first-line chemotherapeutic agents to treat solid cancer. Paclitaxel (PTX) is a commonly used taxane and although effective, it induces peripheral chronic neuropathy in around 60–70% of patients. Studies have demonstrated a correlation between impairment in bioenergetic metabolism and the development of neuropathies. However, the correlation between mitochondrial fusion-fission processes in sensory neurons and the development of neurodegeneration and pain remains poorly understood. Considering that neurons have a high metabolic demand and numerous mitochondria, and that chemotherapy-induced neuropathy is often accompanied by mitochondrial dysfunction, we investigated the role of mitochondrial plasticity in sensory-like neuron cells incubated with paclitaxel. Our findings indicate that neurotoxic concentrations of paclitaxel induce mitochondrial fragmentation by downregulating fusion proteins, such as mitofusin-1 and − 2 (MFN1 and MFN2), and upregulating fission proteins, such as dynamin-related protein 1 (Drp1). Also, paclitaxel increases superoxide release, impairs neuritogenesis, and activates pro-nociceptive signaling, measured by activating transcription factor 3 (ATF-3) expression, substance P release, and prostaglandin E2 (PGE2) - induced calcium influx. Of note, blocking excessive fission with P110, a pharmacological inhibitor of Drp1, PTX-induced cytotoxicity was prevented in sensory neuron-like cells. Together, our data suggest that impairment in mitochondrial dynamics of sensory neurons contributes to paclitaxel neurotoxicity and, consequently, to nociception. Therefore, preventing mitochondrial fission may be a strategy to prevent PTX-induced neurotoxicity, opening a new perspective to understanding the mechanisms involved in the development of PTX-induced neuropathy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117715"},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145982105","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":"Pharmacological inhibition of USP7 attenuates deltamethrin-induced neuronal ferroptosis via GPX4 stabilization","authors":"Minjia Wu ,&nbsp;Yang Chen ,&nbsp;Peixuan Ma ,&nbsp;Wen Pan ,&nbsp;Yaqin Deng ,&nbsp;Lexing Wei ,&nbsp;Guodong Lu ,&nbsp;Michael Aschner ,&nbsp;Yueming Jiang ,&nbsp;Jing Zhou ,&nbsp;Xiaowei Huang","doi":"10.1016/j.taap.2026.117716","DOIUrl":"10.1016/j.taap.2026.117716","url":null,"abstract":"<div><div>Recent studies suggest a significant association between deltamethrin (DM) exposure and an elevated risk of neurodegenerative diseases, yet the underlying molecular mechanisms remain poorly understood. The role of Ubiquitin-specific protease 7 (USP7), a key deubiquitinating enzyme regulating protein homeostasis, in DM-induced neurotoxicity is particularly elusive. Here, we combined <em>in vitro</em> HT22 mouse hippocampal neuronal cells and <em>in vivo</em> male C57BL/6 J mice, which received daily oral gavage of DM at 4.5, 9.0, and 18.0 mg/kg for 30 consecutive days, to investigate the molecular mechanisms underlying DM-induced neurotoxicity. DM exposure significantly induced ferroptosis which was characterized by lipid peroxidation, disruption of iron homeostasis, mitochondrial damage and GPX4 degradation in HT22 cells and in the hippocampus, and was accompanied by impaired spatial learning and memory and neuronal hyperexcitability in mice. Consistently, DM decreased GSH and SOD levels, increased MDA and Fe²⁺, and reduced GPX4, supporting ferroptosis-associated oxidative injury in both models. Mechanistically, DM treatment markedly increased USP7 expression and enhanced GPX4 ubiquitination, thereby promoting its degradation. Increased USP7 levels subsequently induced the ubiquitination of GPX4. Critically, inhibition of USP7 reversed DM-induced GPX4 degradation, lipid peroxidation, iron dysregulation, and mitochondrial damage, thereby stabilizing GPX4 and mitigating neuronal ferroptosis. In conclusion, our findings identify that the upregulation of USP7 is a key mechanism in DM-induced neurotoxicity. USP7 promotes GPX4 degradation <em>via</em> ubiquitination, and inhibition of USP7 preserves GPX4 stability, thereby protecting neurons from ferroptosis and highlighting USP7 as a promising therapeutic target for preventing and treating DM-induced neurotoxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117716"},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990801","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 “Toxicokinetics and in vivo genotoxicity after single dose oral gavage and intravenous administration of N-Nitrosonornicotine in Sprague Dawley rats” [Toxicology and Applied Pharmacology 505 (2025), 117572]","authors":"Mamata De,&nbsp;Ashley Fields,&nbsp;Guy Lagaud","doi":"10.1016/j.taap.2025.117689","DOIUrl":"10.1016/j.taap.2025.117689","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117689"},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757836","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":"Cardamonin attenuates osteoporosis progression and promotes osteogenic differentiation of bone mesenchymal stem cells by upregulating TCF4 expression","authors":"Haizhong Sun ,&nbsp;Runwu Hu ,&nbsp;Jianlong Wu","doi":"10.1016/j.taap.2026.117731","DOIUrl":"10.1016/j.taap.2026.117731","url":null,"abstract":"<div><h3>Background</h3><div>Osteoporosis is a common skeletal metabolic disorder. Cardamonin (CAR) is a natural chalcone compound with multiple activities. However, the role and mechanism of CAR in osteoporosis progression remain largely unknown.</div></div><div><h3>Methods</h3><div>Mice underwent ovariectomy (OVX) to establish a model of osteoporosis, and bone loss was analyzed. Osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) was induced by culturing in osteoblast medium, and evaluated by determining ALP, OCN, RUNX2, and OSX levels using qRT-PCR and western blotting. Bioinformatics analysis was conducted using the SEA server, DisGeNet database, and GSE35959 GEO dataset. TCF4 protein expression was examined using western blotting.</div></div><div><h3>Results</h3><div>CAR mitigated OVX-induced bone loss in mice and promoted osteogenic differentiation of hBMSCs by increasing the expression levels of ALP, OCN, RUNX2, and OSX. TCF4 expression was reduced in osteoporosis, and CAR upregulated TCF4 level. TCF4 overexpression promoted osteogenic differentiation of hBMSCs, while its silencing weakened the promoting effect of CAR on osteogenic differentiation.</div></div><div><h3>Conclusion</h3><div>CAR attenuates bone loss in an OVX-induced mouse model of osteoporosis and promotes osteogenic differentiation of hBMSCs via increasing TCF4 expression, indicating the therapeutic potential of CAR in osteoporosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117731"},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047156","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":"Genipin ameliorates cholestatic liver injury in Mdr2−/− mice: the role of gut microbiota modulation by its dialdehyde intermediates","authors":"Junli Jin ,&nbsp;Lulu Zhu ,&nbsp;Chengjiang He,&nbsp;Haiping Deng,&nbsp;Ni Li,&nbsp;Hong Pan,&nbsp;Fuguo Shi","doi":"10.1016/j.taap.2026.117717","DOIUrl":"10.1016/j.taap.2026.117717","url":null,"abstract":"<div><div>Cholestasis causes severe hepatobiliary diseases with poor prognosis and limited therapeutic drugs. Under cholestatic conditions, impairment of the bile acid (BA)-metabolizing function of gut microbiota, along with abnormal BA profiles, exacerbates disease progression. Interventions targeting the composition and function of gut microbiota represent promising strategies for alleviating cholestatic liver injury. Genipin (GP) is the aglycone of geniposide, the primary bioactive compound in the choleretic herbal medicine <em>Gardenia jasminoides</em> Ellis. The hemiacetal group in GP can generate reactive dialdehyde intermediates that covalently modify intestinal proteins. This study investigates the protective effect of GP against cholestatic liver injury in <em>Mdr2</em>^{<em>−/−</em>} mice and explores the role of these dialdehyde intermediates in this process. Methylated GP (MGP) was synthesized by methylating the hemiacetal hydroxyl group of GP. The mice received intragastric gavage of GP or MGP at 100 mg/kg for 14 days. GP exhibited significant ameliorative effects on cholestatic liver injury in <em>Mdr2</em>^{<em>−/−</em>} mice. GP treatment generated dialdehyde intermediates that covalently modified intestinal proteins and restored the gut microbiota composition along with bile salt hydrolase and 7α-dehydroxylase activities, leading to increased levels of intestinal unconjugated BAs and decreased levels of conjugated BAs. These changes activated intestinal farnesoid X receptor (FXR)-FGF15-hepatic CYP7A1 pathway. The ameliorative effect of GP on cholestasis was abolished by co-administration of a specific intestinal FXR inhibitor. In contrast, MGP did not exhibit these beneficial effects. In conclusion, the gut microbiota modulation by dialdehyde intermediates generated from GP contributes to its amelioration of cholestatic liver injury in <em>Mdr2</em>^{<em>−/−</em>} mice.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117717"},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998793","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":"Potassium channel tetramerization domain-containing 10 exerts a tumor suppressive function in breast cancer by destabilizing SLC7A11 to induce ferroptosis","authors":"Xin He,&nbsp;Ying Wang,&nbsp;Dan Wang,&nbsp;Lirong Wang,&nbsp;Shanshan Yu,&nbsp;Jue Jiang,&nbsp;Qi Zhou","doi":"10.1016/j.taap.2026.117732","DOIUrl":"10.1016/j.taap.2026.117732","url":null,"abstract":"<div><div>Potassium channel tetramerization domain-containing 10 (KCTD10) plays a crucial role in the progression of various tumors. However, comprehensive studies on the involvement of KCTD10 in breast cancer are still lacking. This research aims to elucidate the potential roles and mechanisms of KCTD10 in breast cancer. Reduced KCTD10 expression was observed in breast cancer and was associated with poorer overall survival. Upregulation of KCTD10 resulted in a significant decline in cell growth and proliferation. Notably, KCTD10 overexpression induced ferroptosis, as evidenced by increased cell death, elevated ferrous ion levels, and enhanced lipid peroxidation. The anti-tumor effects mediated by KCTD10 elevation were significantly counteracted by ferroptosis inhibitors, while KCTD10 knockdown resulted in increased resistance to this form of cell death. KCTD10 overexpression reduced the protein levels of SLC7A11, a process reversible by proteasome inhibitors. In KCTD10 knockdown cells, the degradation rate of SLC7A11 protein was significantly decreased. Notably, restoring SLC7A11 expression in KCTD10-overexpressing cells significantly counteracted the tumor-suppressive effects of KCTD10. Tumor-bearing mouse models demonstrated that KCTD10-overexpressing cells exhibited significantly reduced tumor formation capabilities, accompanied by increased ferroptosis levels in tumor tissues. Collectively, KCTD10 exerts a vital anti-cancer role in breast cancer by promoting the ubiquitin-proteasome degradation of SLC7A11, which reduces GSH synthesis, limits the inhibition of lipid peroxidation, and ultimately triggers ferroptosis. By providing new insights into the molecular mechanisms underlying breast cancer pathogenesis, this research identifies KCTD10 as a valuable therapeutic target and suggests that gene therapies aimed at restoring its expression may offer promising avenues for breast cancer treatment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"508 ","pages":"Article 117732"},"PeriodicalIF":3.4,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044048","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":"Duloxetine-induced inhibition of voltage-gated K+ 3.1 (Kv3.1) channels and underlying electrophysiological mechanisms","authors":"Jin Ryeol An ,&nbsp;Junsu Jeong ,&nbsp;Hye Ryung Kim ,&nbsp;Sooa Lee ,&nbsp;Armin Sultana ,&nbsp;Raju Das ,&nbsp;Joohan Woo ,&nbsp;Seong Woo Choi ,&nbsp;Young Min Bae ,&nbsp;Yeji Lim ,&nbsp;Hongzoo Park ,&nbsp;Mi Seon Seo ,&nbsp;Won Sun Park","doi":"10.1016/j.taap.2025.117685","DOIUrl":"10.1016/j.taap.2025.117685","url":null,"abstract":"<div><div>Duloxetine is a serotonin-norepinephrine reuptake inhibitor that has been widely used to treat major depression; however, it has also been associated with severe neuropsychiatric side effects, including hallucinations, confusion, and suicide attempts. Nevertheless, the electrophysiological mechanisms underlying these adverse effects remain poorly understood. In this study, we investigated the effect of duloxetine on cloned neuronal rat voltage-gated K⁺ (Kv) channel subunit Kv3.1, stably expressed in Chinese hamster ovary (CHO) cells. Duloxetine inhibited the Kv3.1 current in a concentration-dependent manner with a half-maximal inhibitory concentration (IC₅₀) of 2.04 ± 0.27 μM (approximately 5-fold higher than the peak therapeutic plasma concentration of 0.4 μM) and a Hill coefficient of 0.94 ± 0.08. This inhibitory effect was associated with accelerated current inactivation. The association and dissociation rate constants for duloxetine were 43.43 ± 4.57 μM⁻¹·s⁻¹ and 122.12 ± 68.2 s⁻¹, respectively. In addition, duloxetine shifted the voltage dependence of Kv3.1 steady-state inactivation toward a more negative direction and led to use-dependent inhibition upon repetitive stimulation (1 and 2 Hz). Duloxetine also slowed recovery from inactivation. Docking analysis predicted that duloxetine binds to the central pore and interface between the voltage-sensing and pore domains on Kv3.1 channel, supporting the inhibitory mechanisms of duloxetine. Furthermore, duloxetine inhibited Kv3.1-mediated currents in SH-SY5Y human neuroblastoma cells. Taken together, our results indicate that duloxetine inhibits Kv3.1 expressed in CHO cells in concentration-, time-, and use (open and inactivated states)-dependent manners, independently of its anti-depressive effects.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117685"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726257","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}