Toxicology and applied pharmacology最新文献_第3页

Potassium channel tetramerization domain-containing 10 exerts a tumor suppressive function in breast cancer by destabilizing SLC7A11 to induce ferroptosis 含钾通道四聚结构域10通过破坏SLC7A11的稳定性诱导铁下垂，在乳腺癌中发挥肿瘤抑制作用。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-22 DOI: 10.1016/j.taap.2026.117732

Xin He, Ying Wang, Dan Wang, Lirong Wang, Shanshan Yu, Jue Jiang, Qi Zhou

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.

含钾通道四聚域10 （KCTD10）在多种肿瘤的发展中起着至关重要的作用。然而，关于KCTD10在乳腺癌中的作用，目前还缺乏全面的研究。本研究旨在阐明KCTD10在乳腺癌中的潜在作用和机制。在乳腺癌中观察到KCTD10表达降低，并与较差的总生存率相关。KCTD10的上调导致细胞生长和增殖显著下降。值得注意的是，KCTD10过表达诱导铁下垂，这可以通过细胞死亡增加、亚铁离子水平升高和脂质过氧化增强来证明。KCTD10升高介导的抗肿瘤作用被铁下垂抑制剂显著抵消，而KCTD10敲低导致对这种形式的细胞死亡的抵抗力增加。KCTD10过表达降低了SLC7A11的蛋白水平，这一过程可通过蛋白酶体抑制剂逆转。在KCTD10敲低的细胞中，SLC7A11蛋白的降解率显著降低。值得注意的是，在KCTD10过表达的细胞中恢复SLC7A11的表达显著抵消了KCTD10的肿瘤抑制作用。荷瘤小鼠模型显示，kctd10过表达细胞的肿瘤形成能力显著降低，同时肿瘤组织中铁下垂水平升高。总的来说，KCTD10通过促进SLC7A11的泛素蛋白酶体降解，减少GSH的合成，限制脂质过氧化的抑制，最终引发铁凋亡，在乳腺癌中发挥重要的抗癌作用。通过对乳腺癌发病机制的分子机制提供新的见解，本研究确定了KCTD10是一个有价值的治疗靶点，并表明旨在恢复其表达的基因治疗可能为乳腺癌治疗提供有希望的途径。

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引用次数: 0

Sustained cadmium exposure and hyperglycemia additively drives mitochondrial dysfunction in hepatic cells: Implications for MASLD etiopathogenesis 持续镉暴露和高血糖叠加驱动肝细胞线粒体功能障碍：对MASLD发病机制的影响。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-21 DOI: 10.1016/j.taap.2026.117729

Rahul Kumar , Ashwin Chinala , Sharina Palencia Desai , Li Chen , Marcus A. Garcia , Sarah J. Blossom , Matthew J. Campen , Rama R. Gullapalli

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.

慢性重金属应激对肝细胞病理生理的影响尚不清楚。人类肝脏是许多有毒重金属（如镉和砷）的长期累积场所，其健康影响尚不清楚。在目前的研究中，我们研究了慢性低剂量镉暴露（CLEC）在正常血糖（5.6 mM）和糖尿病相关高血糖（15 mM）暴露下的影响，重点关注肝细胞线粒体功能。肝细胞系暴露于CLEC和葡萄糖中24 周，模拟正常和II型糖尿病患者的慢性重金属暴露模式。CLEC暴露显著影响线粒体的长期健康，包括线粒体质量下降、超氧化物产生增加以及线粒体膜电位（MMP）的丧失，这是CLEC和葡萄糖依赖的方式。此外，通过海马有丝分裂应激实验显示，CLEC诱导了显著的慢性氧化应激。特别是，CLEC细胞显示出基础和非线粒体呼吸水平的改变，导致细胞的线粒体耗氧量（ocr）失调。最后，我们确定了CLEC和葡萄糖暴露对线粒体动力学（裂变/融合）的显著影响，这表明线粒体碎片化和周转率增强。我们还发现了新的细胞代偿机制，可能掩盖了慢性Cd暴露引起肝细胞损伤的真实程度。新的方法方法（NAMs），如目前的毒理学研究，确立了慢性重金属污染物暴露对人肝细胞功能的潜在的、长期的破坏性影响。

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引用次数: 0

EP300 promotes cervical cancer progression through a Wnt/β-catenin–dependent HIF-1α signaling axis EP300通过Wnt/β-catenin依赖性HIF-1α信号轴促进宫颈癌进展。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-19 DOI: 10.1016/j.taap.2026.117718

Yue Zhang , Yongxin Zhang , Ke Wang

This study aimed to investigate the role of EP300 in cervical cancer progression, focusing on its functional effects related to pyroptosis under Wnt/β-catenin–dependent conditions. In SiHa and HeLa cells, EP300 was silenced using lentiviral-mediated knockdown under hypoxic conditions, and subsequent changes in cell proliferation, inflammatory cytokine secretion, and pyroptosis-related protein expression were evaluated. A subcutaneous HeLa xenograft model was established to examine the in vivo effects. Hypoxia-inducible factor 1-alpha (HIF-1α) expression was also analyzed. The results showed that hypoxia significantly increased the expression levels of EP300, β-catenin, and HIF-1α. EP300 knockdown was associated with decreased Wnt/β-catenin signaling and, under Wnt/β-catenin–dependent conditions, resulted in reduced HIF-1α expression and enhanced pyroptosis-related phenotypes. Activation of Wnt/β-catenin signaling by HLY78 partially reversed these alterations. In vivo, silencing EP300 suppressed tumor growth, decreased Ki67 expression, and increased pyroptosis markers, while activation of the Wnt/β-catenin pathway partially restored proliferation and reduced pyroptosis. Taken together, loss of EP300 function impedes cervical cancer progression by affecting the Wnt/β-catenin signaling axis and inducing concomitant changes in HIF-1α expression. This study provides functional evidence supporting the role of EP300 in the progression of cervical cancer under hypoxic conditions.

本研究旨在探讨EP300在宫颈癌进展中的作用，重点研究其在Wnt/β-catenin依赖条件下与焦亡相关的功能作用。在SiHa和HeLa细胞中，在缺氧条件下，通过慢病毒介导的敲低来沉默EP300，并评估随后细胞增殖、炎症细胞因子分泌和焦热相关蛋白表达的变化。建立皮下HeLa异种移植模型，观察其在体内的作用。分析缺氧诱导因子1- α (HIF-1α)的表达。结果显示，低氧显著提高了EP300、β-catenin和HIF-1α的表达水平。EP300敲低与Wnt/β-catenin信号传导减少相关，并且在Wnt/β-catenin依赖条件下，导致HIF-1α表达降低和焦热相关表型增强。HLY78激活Wnt/β-catenin信号部分逆转了这些改变。在体内，沉默EP300抑制肿瘤生长，降低Ki67表达，增加焦亡标志物，而激活Wnt/β-catenin途径部分恢复增殖，减少焦亡。综上所述，EP300功能的丧失通过影响Wnt/β-catenin信号轴和诱导HIF-1α表达的伴随变化来阻碍宫颈癌的进展。本研究提供了功能证据，支持EP300在缺氧条件下宫颈癌进展中的作用。

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引用次数: 0

Nuclear protein 1 defends against acute pancreatitis by mitigating pancreatic acinar cell ferroptosis through the maintenance of cellular iron homeostasis 核蛋白1通过维持细胞铁稳态来减轻胰腺腺泡细胞铁下垂，从而防御急性胰腺炎。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-17 DOI: 10.1016/j.taap.2026.117720

Xiangtian Zeng , Wenhui Chen , Qixin Dai , Yong He , Xinsong Fu , Jiaxin Liu , Dingwen Zhong , Yonghui Liao

Acute pancreatitis (AP) is a severe inflammatory condition marked by pancreatic acinar cell death, with ferroptosis emerging as a critical factor in its pathogenesis. The nuclear protein 1 (Nupr1) has been identified as a key regulator of ferroptosis; however, its role in modulating pancreatic acinar cell ferroptosis and its involvement in AP remain unexplored. The objective of this research was to examine whether Nupr1 regulates ferroptosis in pancreatic acinar cells and influences the progression of AP, while elucidating the underlying molecular mechanisms. Nupr1 was significantly upregulated in caerulein-induced AP models. Nupr1 knockdown pancreatic acinar cells exhibited heightened susceptibility to caerulein-induced damage and inflammatory responses, accompanied by elevated levels of ferroptosis. Conversely, overexpression of Nupr1 conferred resistance against caerulein-induced injury, inflammation, and ferroptosis. Inhibition of ferroptosis reversed the sensitivity of Nupr1 knockdown cells to caerulein-induced damage. Further investigations revealed that Nupr1 regulates the expression of lipocalin 2 (Lcn2), thereby maintaining intracellular iron homeostasis. Silencing Lcn2 negated the protective effects of Nupr1 overexpression in pancreatic acinar cells against ferroptosis. In animal models, Nupr1 overexpression significantly attenuated the progression of AP and reduced ferroptotic levels in pancreatic tissues. Collectively, our findings demonstrate that Nupr1 inhibits pancreatic acinar cell ferroptosis by regulating Lcn2-mediated iron homeostasis, thereby mitigating the progression of AP. This research reveals a previously unidentified regulatory mechanism governing acinar cell death in AP and suggests a possible therapeutic target for managing this condition.

急性胰腺炎（AP）是一种以胰腺腺泡细胞死亡为特征的严重炎症，铁下垂是其发病机制的关键因素。核蛋白1 （Nupr1）已被确定为铁下垂的关键调节因子；然而，其在调节胰腺腺泡细胞铁下垂中的作用及其在AP中的作用仍未被探索。本研究的目的是研究Nupr1是否调节胰腺腺泡细胞的铁下垂并影响AP的进展，同时阐明其潜在的分子机制。Nupr1在细小蛋白诱导的AP模型中显著上调。Nupr1敲低的胰腺腺泡细胞对小蛋白诱导的损伤和炎症反应表现出更高的易感性，并伴有铁下垂水平升高。相反，过表达Nupr1可以抵抗小蛋白诱导的损伤、炎症和铁下垂。抑制铁凋亡逆转了Nupr1敲低细胞对小蛋白诱导损伤的敏感性。进一步的研究表明，Nupr1调节脂钙蛋白2 （lipocalin 2, Lcn2）的表达，从而维持细胞内铁稳态。沉默Lcn2可否定Nupr1过表达在胰腺腺泡细胞中对铁凋亡的保护作用。在动物模型中，Nupr1过表达显著减缓了AP的进展，降低了胰腺组织中的铁下垂水平。总的来说，我们的研究结果表明，Nupr1通过调节lcn2介导的铁稳态来抑制胰腺腺泡细胞铁凋亡，从而减缓AP的进展。这项研究揭示了一种以前未被发现的控制AP中腺泡细胞死亡的调节机制，并提出了一种可能的治疗靶点。

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引用次数: 0

Genipin ameliorates cholestatic liver injury in Mdr2−/− mice: the role of gut microbiota modulation by its dialdehyde intermediates Genipin改善Mdr2-/-小鼠的胆汁淤积性肝损伤：其双醛中间体调节肠道微生物群的作用

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-16 DOI: 10.1016/j.taap.2026.117717

Junli Jin , Lulu Zhu , Chengjiang He, Haiping Deng, Ni Li, Hong Pan, Fuguo Shi

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 Gardenia jasminoides 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 Mdr2^−/− 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 Mdr2^−/− 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 Mdr2^−/− mice.

胆汁淤积导致严重的肝胆疾病，预后差，治疗药物有限。在胆汁淤积的情况下，肠道微生物群胆汁酸（BA）代谢功能的损害，以及BA谱的异常，加剧了疾病的进展。针对肠道微生物群的组成和功能的干预措施是缓解胆汁淤积性肝损伤的有希望的策略。Genipin （GP）是胆甾类中药栀子中的主要生物活性化合物genipo苷的苷元。GP中的半缩醛可以产生活性双醛中间体，共价修饰肠道蛋白。本研究探讨了GP对Mdr2-/-小鼠胆汁淤积性肝损伤的保护作用，并探讨了这些双醛中间体在这一过程中的作用。甲基化GP （MGP）是通过甲基化GP的半缩醛羟基合成的。小鼠分别灌胃100 mg/kg的GP或MGP，持续14 天。GP对Mdr2-/-小鼠胆汁淤积性肝损伤有明显的改善作用。GP处理产生的双醛中间体共价修饰肠道蛋白，恢复肠道微生物群组成，同时提高胆盐水解酶和7α-去羟化酶活性，导致肠道未偶联BAs水平升高，偶联BAs水平降低。这些变化激活了肠法内甾体X受体(FXR)- fgf15 -肝脏CYP7A1通路。GP对胆汁淤积的改善作用被一种特定的肠道FXR抑制剂联合使用所消除。相比之下，MGP没有表现出这些有益的效果。综上所述，GP产生的双醛中间体调节肠道微生物群有助于改善Mdr2-/-小鼠的胆汁淤积性肝损伤。

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引用次数: 0

Pharmacological inhibition of USP7 attenuates deltamethrin-induced neuronal ferroptosis via GPX4 stabilization 药理抑制USP7通过GPX4稳定减轻溴氰菊酯诱导的神经元铁下垂。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-13 DOI: 10.1016/j.taap.2026.117716

Minjia Wu , Yang Chen , Peixuan Ma , Wen Pan , Yaqin Deng , Lexing Wei , Guodong Lu , Michael Aschner , Yueming Jiang , Jing Zhou , Xiaowei Huang

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 in vitro HT22 mouse hippocampal neuronal cells and in vivo 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 via 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.

最近的研究表明，溴氰菊酯（DM）暴露与神经退行性疾病风险升高之间存在显著关联，但其潜在的分子机制尚不清楚。泛素特异性蛋白酶7 （USP7）是一种调节蛋白质稳态的关键去泛素化酶，在dm诱导的神经毒性中的作用尤其难以捉摸。本研究将体外HT22小鼠海马神经元细胞与体内雄性C57BL/6 J小鼠相结合，连续30天每天口服4.5、9.0和18.0 mg/kg的DM，研究DM诱导神经毒性的分子机制。DM暴露显著诱导小鼠铁下沉，表现为HT22细胞和海马的脂质过氧化、铁稳态破坏、线粒体损伤和GPX4降解，并伴有空间学习记忆和神经元高兴奋性受损。DM降低GSH和SOD水平，增加MDA和Fe2+，降低GPX4，支持两种模型中与铁中毒相关的氧化损伤。机制上，DM处理显著增加USP7表达，增强GPX4泛素化，从而促进其降解。增加的USP7水平随后诱导GPX4泛素化。关键的是，抑制USP7逆转dm诱导的GPX4降解、脂质过氧化、铁失调和线粒体损伤，从而稳定GPX4并减轻神经元铁下垂。总之，我们的研究结果表明，USP7的上调是dm诱导的神经毒性的关键机制。USP7通过泛素化促进GPX4降解，抑制USP7可保持GPX4的稳定性，从而保护神经元免于铁凋亡，并突出显示USP7是预防和治疗dm诱导的神经毒性的有希望的治疗靶点。

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引用次数: 0

GKB7I-53: A novel anti-metastatic agent for colorectal cancer GKB7I-53：一种新型结直肠癌抗转移药物

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-12 DOI: 10.1016/j.taap.2026.117712

Min Hee Yang , Ducdat Le , Thinhulinh Dang , Vinhquang Truong , In Jin Ha , Mina Lee , Kwang Seok Ahn

Metastasis driven by epithelial-mesenchymal transition (EMT) remains a critical challenge in colorectal cancer treatment. This study investigated GKB7I-53, a saponin compound isolated through feature-based molecular networking, as a potential therapeutic agent targeting EMT pathways. GKB7I-53 demonstrated minimal cytotoxicity (>90% cell viability at 50 μM) while effectively inhibiting metastatic processes. The compound downregulated mesenchymal markers (CXCR4, CXCR7) and upregulated epithelial markers (E-cadherin, occludin), suppressing EMT progression. In CXCL12-stimulated cells, GKB7I-53 significantly reduced cell migration and invasion while decreasing MMP-2/9 activity, key enzymes facilitating metastatic spread. Mechanistically, GKB7I-53 suppressed MnSOD-induced STAT3 activation, thereby blocking the JAK/STAT3 signaling pathway crucial for metastasis. Molecular docking studies confirmed strong binding affinity to target proteins involved in EMT and cancer progression. These findings suggest that GKB7I-53 may serve as a potential lead compound with anti-metastatic properties in colorectal cancer. Rather than inducing general cytotoxicity, GKB7I-53 selectively modulates EMT-related pathways, indicating a mechanistic basis for its anti-metastatic effects. However, further in vivo validation and preclinical studies are required to determine its therapeutic relevance.

上皮-间质转化（EMT）驱动的转移仍然是结直肠癌治疗的一个关键挑战。GKB7I-53是一种通过基于特征的分子网络分离的皂苷化合物，该化合物有望作为一种靶向EMT通路的潜在治疗剂。GKB7I-53表现出最小的细胞毒性（50 μM时细胞存活率为90%），同时有效抑制转移过程。该化合物下调间充质标志物（CXCR4, CXCR7）和上调上皮标志物（E-cadherin, occludin），抑制EMT进展。在cxcl12刺激的细胞中，GKB7I-53显著减少了细胞迁移和侵袭，同时降低了促进转移扩散的关键酶MMP-2/9的活性。在机制上，GKB7I-53抑制了mnsod诱导的STAT3激活，从而阻断了对转移至关重要的JAK/STAT3信号通路。分子对接研究证实了与EMT和癌症进展相关的靶蛋白有很强的结合亲和力。这些发现提示GKB7I-53可能作为结直肠癌抗转移特性的潜在先导化合物。GKB7I-53不是诱导一般的细胞毒性，而是选择性地调节emt相关途径，这表明其抗转移作用的机制基础。然而，需要进一步的体内验证和临床前研究来确定其治疗相关性。

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引用次数: 0

Paclitaxel impairs mitochondrial dynamics in human sensory-like neuron cells 紫杉醇损害人感觉样神经元细胞的线粒体动力学

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-12 DOI: 10.1016/j.taap.2026.117715

Mariana Caprio Schiess , Gessica Sabrina de Assis Silva , Natália Gabriele Hösch , Vitória Carvalho Troitiño , Marcelo Medina de Souza , Carlos DeOcesano-Pereira , Talita Glaser , Henning Ulrich , Ana Marisa Chudzinski-Tavassi , Michelle Cristiane Bufalo , Vanessa Olzon Zambelli

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.

紫杉烷被认为是治疗实体癌的一线化疗药物。紫杉醇（PTX）是一种常用的紫杉烷，虽然有效，但在约60-70%的患者中引起周围慢性神经病变。研究表明，生物能量代谢障碍与神经病变的发展之间存在相关性。然而，感觉神经元中线粒体融合-裂变过程与神经变性和疼痛的发展之间的相关性仍然知之甚少。考虑到神经元具有高代谢需求和大量线粒体，并且化疗诱导的神经病变通常伴有线粒体功能障碍，我们研究了线粒体可塑性在紫杉醇培养的感觉样神经元细胞中的作用。我们的研究结果表明，紫杉醇的神经毒性浓度通过下调融合蛋白（如mitofusin-1和- 2 (MFN1和MFN2)）和上调裂变蛋白（如动力蛋白相关蛋白1 (Drp1)）诱导线粒体断裂。此外，通过激活转录因子3 （ATF-3）表达、P物质释放和前列腺素E2 （PGE2）诱导的钙内流来测量，紫杉醇增加超氧化物释放，损害神经生成，并激活促伤害信号。值得注意的是，用P110 （Drp1的药理抑制剂）阻断过度裂变，ptx诱导的感觉神经元样细胞毒性被阻止。总之，我们的数据表明，感觉神经元线粒体动力学的损伤有助于紫杉醇神经毒性，从而导致伤害感觉。因此，防止线粒体分裂可能是预防ptx诱导的神经毒性的一种策略，为理解ptx诱导的神经病变的发生机制开辟了新的视角。

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引用次数: 0

GSDMD inhibitor GI-Y1 alleviates doxorubicin-induced cardiotoxicity via the inhibition of mitochondrial dysfunction GSDMD抑制剂GI-Y1通过抑制线粒体功能障碍减轻阿霉素诱导的心脏毒性。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-10 DOI: 10.1016/j.taap.2026.117713

Yucong Zhang , Ruihan Zheng , Minne Xie , Yunxuan Chen , Binbin Xia , Zexin Yang , Zhuoning Li , Yuzheng Li , Li Luo , Weijian Huang , Shanshan Dai , Bozhi Ye , Wenli Zhang

Objective

This study aimed to explore GI-Y1's (a GSDMD inhibitor) protective effect against doxorubicin (Dox)-induced cardiotoxicity (DIC) and clarify its molecular mechanisms.

Methods

In vivo, wild-type and Gsdmd⁻/⁻ mice received Dox (5 mg/kg/week for 4 weeks) and GI-Y1 (10 or 20 mg/kg/day). AAV9-mediated GSDMD overexpression verified target specificity. Cardiac function was assessed by echocardiography; myocardial injury via H&E staining, TUNEL assay, and serum biomarkers (CK-MB, LDH, cTnT). In vitro, HL-1 cardiomyocytes were treated with Dox (0.5 μg/mL) and GI-Y1 (10 or 20 μM). Pyroptosis markers (GSDMD cleavage, IL-1β secretion, LDH release) and mitochondrial function were measured using Western blot, ELISA, JC-1 staining, and TEM.

Results

GI-Y1 improved survival and cardiac function in Dox-treated mice. It reduced serum cardiac injury biomarkers and alleviated myocardial histological damage. In vivo and in vitro, GI-Y1 inhibited Dox-induced cardiomyocyte pyroptosis, shown by reduced GSDMD cleavage, less IL-1β secretion, and decreased cell death. Mechanistically, GI-Y1 bound GSDMD, impairing its lipid-binding and pore-forming abilities. It also relieved Dox-induced mitochondrial dysfunction by reducing mitochondrial GSDMD-N, restoring MMP, boosting ATP, and inhibiting mtDNA release.

Conclusion

GI-Y1 alleviates DIC by directly targeting GSDMD, inhibiting pyroptosis and mitochondrial damage. This study highlights GI-Y1 as a promising therapy for chemotherapy-related cardiac injury and a valuable tool to study pyroptosis in cardiovascular diseases.

目的：探讨GI-Y1 （GSDMD抑制剂）对多柔比星（Dox）诱导的心脏毒性（DIC）的保护作用，并阐明其分子机制。方法：在体内，野生型和Gsdmd-/-小鼠分别给予Dox（5 mg/kg/周，持续4 周）和GI-Y1（10或20 mg/kg/天）。aav9介导的GSDMD过表达证实了目标特异性。超声心动图评估心功能；通过H&E染色、TUNEL试验和血清生物标志物（CK-MB、LDH、cTnT）检测心肌损伤。在体外，用Dox（0.5 μg/mL）和GI-Y1（10或20 μM）处理HL-1心肌细胞。采用Western blot、ELISA、JC-1染色和TEM检测焦亡标志物（GSDMD裂解、IL-1β分泌、LDH释放）和线粒体功能。结果：GI-Y1改善了dox处理小鼠的存活率和心功能。降低血清心肌损伤生物标志物，减轻心肌组织学损伤。在体内和体外，GI-Y1抑制dox诱导的心肌细胞焦亡，表现为GSDMD切割减少，IL-1β分泌减少，细胞死亡减少。在机制上，GI-Y1结合GSDMD，损害其脂质结合和成孔能力。它还通过降低线粒体GSDMD-N、恢复MMP、促进ATP和抑制mtDNA释放来缓解dox诱导的线粒体功能障碍。结论：GI-Y1通过直接靶向GSDMD减轻DIC，抑制热亡和线粒体损伤。本研究强调GI-Y1是化疗相关心脏损伤的一种有前景的治疗方法，也是研究心血管疾病焦亡的一种有价值的工具。

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引用次数: 0

Norcantharidin inhibits the EZH2-mediated JAK2/STAT3 signaling pathway to inhibit the proliferation of non-small cell lung cancer 去甲斑蝥素抑制ezh2介导的JAK2/STAT3信号通路抑制非小细胞肺癌的增殖。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-09 DOI: 10.1016/j.taap.2026.117714

Shuang Wu , Wei Zhang

Objective

The purpose of this study was firstly to investigate the anti-tumor effects of NCTD on NSCLC cell proliferation, apoptosis, migration, and invasion. Secondly, it aimed to explore whether these effects were associated with the modulation of the EZH2/JAK2/STAT3 signaling axis.

Methods

This study employed a series of in vitro experiments, including CCK-8, Edu staining, colony formation, flow cytometry, and Transwell assays, to evaluate the effects of NCTD on the proliferation, apoptosis, migration, and invasion of NSCLC cells. The in vivo anti-tumor efficacy was evaluated using an A549 xenograft mouse model. Underlying mechanisms were explored via western blot and genetic perturbation (knockdown and overexpression) of EZH2.

Results

The results of the in vitro experiments demonstrated that NCTD significantly inhibited NSCLC cell proliferation, colony formation, migration, and invasion, while promoting apoptosis. Furthermore, NCTD effectively suppressed tumor growth in the xenograft mouse model. The molecular mechanism study revealed that NCTD treatment was associated with downregulation of EZH2 and concomitant suppression of JAK2/STAT3 phosphorylation and activation of the JAK2/STAT3 signaling pathway. Genetic knockdown of EZH2 mimicked the anti-tumor effects of NCTD, whereas overexpression of EZH2 partially reversed its efficacy.

Conclusion

The anti-tumor activity of NCTD is associated with the downregulation of EZH2 protein expression and concomitant inhibition of the JAK2/STAT3 signaling pathway. These findings provide novel insights into the molecular mechanisms underlying NCTD's anti-tumor activity.

目的：本研究首先探讨NCTD对非小细胞肺癌细胞增殖、凋亡、迁移和侵袭的抗肿瘤作用。其次，旨在探讨这些影响是否与EZH2/JAK2/STAT3信号轴的调制有关。方法：本研究采用CCK-8、Edu染色、集落形成、流式细胞术、Transwell等一系列体外实验，评价NCTD对NSCLC细胞增殖、凋亡、迁移和侵袭的影响。采用A549异种移植小鼠模型评价其体内抗肿瘤效果。通过western blot和基因扰动（敲低和过表达）探讨EZH2的潜在机制。结果：体外实验结果表明，NCTD显著抑制NSCLC细胞增殖、集落形成、迁移和侵袭，促进细胞凋亡。此外，NCTD在异种移植小鼠模型中有效抑制肿瘤生长。分子机制研究表明，NCTD治疗与EZH2下调，同时抑制JAK2/STAT3磷酸化和激活JAK2/STAT3信号通路有关。基因敲低EZH2可模拟NCTD的抗肿瘤作用，而过表达EZH2可部分逆转其抗肿瘤作用。结论：NCTD的抗肿瘤活性可能与下调EZH2蛋白表达并同时抑制JAK2/STAT3信号通路有关。这些发现为NCTD抗肿瘤活性的分子机制提供了新的见解。

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引用次数: 0