Toxicology and applied pharmacology最新文献

{"title":"PM_2.5 enhances DRP1-mediated mitochondrial fission to induce ferroptosis and exacerbate asthma through the AHR-HSP90-PKM2 pathway.","authors":"Simiao Qiao, Fanshu Li, Jia Huang, Xiaoqian Wu, Xiaoying Cao, Xifeng Zhang, Zhifeng Wei","doi":"10.1016/j.taap.2025.117590","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117590","url":null,"abstract":"<p><p>This study was designed to clarify the reason for PM_2.5 to induce the ferroptosis of bronchial epithelial cells and worsen asthma in detail, advancing the development of relevant drugs. Results displayed that PM_2.5 mainly induced ferroptosis but not apoptosis of bronchial epithelial cells, indicating by the changes of lipid reactive oxygen species (ROS), iron, malondialdehyde, lactic dehydrogenase, nuclear receptor coactivator 4, glutathione and glutathione peroxidase 4 levels, and further confirmed by using in combination with the ferroptosis and apoptosis inhibitors. It also caused the mitochondrial disturbance, reduced the level of mitochondrial membrane potential, up-regulated the level of mitochondrial ROS, and mechanisms were subsequently ascribed to dynamin-related protein 1 (DRP1)-related mitochondrial fission. Furthermore, the up-regulation on ubiquitination of pyruvate kinase M2 (PKM2) but not macrophage stimulating 1 or interferon regulatory factor 1, the transcriptional regulators locating at the upstream of DRP1, was showed by PM_2.5via controlling \"aryl hydrocarbon receptor (AHR)-heat shock protein 90 (HSP90)\" axis. In addition, isoliquiritigenin (ISL), the main active ingredients in licorice, was demonstrated to prevent the PM_2.5-induced activation of AHR-PKM2-ferroptosis in asthma. In conclusion, PM_2.5 activated \"AHR-HSP90\" axis to disturb DRP1-related mitochondrial fission, induced ferroptosis of bronchial epithelial cells, and worsened asthma. Conversely, ISL restored the above-mentioned signals, ferroptosis and asthma mediated by PM_2.5, and was suggested as a potential compound to combat the exacerbation of asthma.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117590"},"PeriodicalIF":3.4,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239760","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":"C-Fos protein expression in the mouse brain: effects of nicotine aerosol.","authors":"Ying Li, Shanshan Du, Jingping Sun, Xiaodong Guo, Qidong Zhang, Pu Fan, Yufei Hu, Jian Mao, Wu Fan, Qingzhao Shi, Guobi Chai, Jianping Xie","doi":"10.1016/j.taap.2025.117588","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117588","url":null,"abstract":"<p><p>Tobacco products are predominantly consumed through inhalation of nicotine-containing aerosols, with nicotine producing significant sensory stimulation effects. Existing research indicates that organic acid components can modulate the neurostimulatory properties of tobacco products. This study aimed to investigate the combined effects of nicotine and citric acid aerosols on neural activity in the male mouse brain. By establishing a group aerosol exposure protocol and utilizing c-Fos protein as a neuronal activity marker, we demonstrated that nicotine aerosol exposure significantly enhanced c-Fos expression in several brain regions including the hypothalamus, amygdala, midbrain, and olfactory-related areas. Notably, citric acid effectively attenuated the nicotine-induced enhancement of neuronal activity, with significantly reduced c-Fos expression observed in specific brain regions including the amygdalopiriform transition area (APir), basolateral amygdaloid nucleus (BLA), anterior medial amygdalar (MeA), lateral preoptic nucleus (LPO), medial habenular nucleus (MHb), and accumbens nucleus (NAc) compared to the nicotine group. This study reveals the regulatory role of organic acids on the neurostimulatory effects of nicotine, providing a theoretical basis for modulating the sensory characteristics of tobacco products.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117588"},"PeriodicalIF":3.4,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239797","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":"Generation and distribution of cyanide in rats and humans following sodium cyanoborohydride exposure.","authors":"Zhenshuo Guo, Yiling Tang, Ruilin Zhang, Yu Ma, Ruxin Luo, Ping Xiang, Hui Yan, Wenjia Duan","doi":"10.1016/j.taap.2025.117592","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117592","url":null,"abstract":"<p><p>Sodium cyanoborohydride (NaBH₃CN) is a commonly used reducing agent. However, its metabolism and mechanism of toxicity are still unclear. In this study, we first demonstrated that NaBH₃CN underwent rapid hydrolysis in aqueous solution and produced hydrocyanic acid. Cyanide was detected in the gastric contents of rats following oral administration of NaBH₃CN, and cyanide poisoning symptoms such as tachypnea, limb convulsions, and opisthotonos were observed. Combined with a gas chromatography-mass spectrometry (GC-MS) method and rat poisoning models, we systematically investigated the metabolism and distribution of cyanide generated from NaBH₃CN and validated the findings through a human poisoning case. In vitro experiments demonstrated that NaBH₃CN hydrolyzed to produce hydrogen cyanide in acidic, neutral, and alkaline aqueous solutions, as well as in simulated gastric fluid. Animal experiments revealed that NaBH₃CN can metabolize to release cyanide in vivo, with a dose-dependent distribution profile. The cyanide concentration in the blood and tissues peaked at 20 min after exposure and then rapidly decreased within 2 h. Under various exposure doses, peak blood cyanide concentrations (9.57 ± 1.01-47.57 ± 3.35 μg/mL) consistently exceeded tissue concentrations by 2- to 6-fold. Finally, we reported a clinical poisoning case involving an adolescent male with depression, who experienced generalized convulsions after oral intake of sodium cyanoborohydride. Laboratory tests confirmed the presence of cyanide in both blood and urine specimens. In addition, the blood cyanide concentrations decreased from 2.43 ± 0.05 to 0.45 ± 0.03 μg/mL, while urine levels decreased from 1.26 ± 0.04 to 0.22 ± 0.03 μg/mL within 24 h after antidote administration. In conclusion, our research demonstrated for the first time that oral exposure to NaBH₃CN leads to generation of cyanide in the stomach and resulted in symptoms consistent with cyanide poisoning. The distribution profile of cyanide after oral NaBH₃CN exposure in rats suggested that blood samples were optimal for identifying acute NaBH₃CN poisoning, with liver tissue as an alternative. More importantly, our findings provided an experimental basis for identifying NaBH₃CN poisoning and were validated through a clinical poisoning case.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117592"},"PeriodicalIF":3.4,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239742","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":"10-Hydroxy-2-decenoic acid ameliorates LPS-induced acute lung injury through targeting MD2-mediated inflammatory signaling pathways.","authors":"Cong Shu, Chen Li, Huamin Liu, Zengxian Zhou, Chenghao Qian, Zhuohui Xie, Fenfen Lin, Yuxiao Jiang, Ruping Chen, Yue Liu, Xin Liu, Gaozhi Chen, Lili Fu","doi":"10.1016/j.taap.2025.117589","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117589","url":null,"abstract":"<p><strong>Background: </strong>Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are life-threatening conditions with high mortality, characterized by excessive inflammatory responses. Lipopolysaccharide (LPS) is widely used to mimic ALI by activating myeloid differentiation factor 2 (MD2)/Toll-like receptor 4 (TLR4)-mediated inflammatory pathways. Royal jelly-derived 10-hydroxy-2-decenoic acid (10-HDA) exhibits anti-inflammatory properties, but its role in ALI remains unexplored.</p><p><strong>Objective: </strong>This study aimed to investigate the therapeutic potential of 10-HDA against LPS-induced ALI and elucidate its underlying mechanism.</p><p><strong>Methods: </strong>In vitro, mouse peritoneal macrophages (MPMs) were pretreated with 10-HDA before LPS stimulation. In vivo, ALI was induced in mice via intratracheal LPS, with 10-HDA administered intraperitoneally. Cytokine levels were measured via ELISA and qPCR. Signaling pathways were analyzed by Western blot and immunofluorescence. Lung injury, inflammatory cell infiltration, and edema were assessed via histopathology, BALF analysis, and wet/dry ratio. Immunoprecipitation, molecular docking, and drug affinity-responsive target stability (DARTS) assays were used to identify the interaction between 10-HDA and MD2.</p><p><strong>Results: </strong>10-HDA significantly suppressed LPS-induced proinflammatory cytokine secretion in MPMs and ALI mice, and inhibited phosphorylation of TAK1, MAPKs, TBK1 and NF-κB nuclear translocation. It attenuated lung histopathological damage, neutrophil infiltration, and edema. Mechanistically, 10-HDA disrupted MD2/TLR4-mediated inflammatory pathways by directly binding MD2, as confirmed by immunoprecipitation, DARTS, and molecular docking.</p><p><strong>Conclusion: </strong>10-HDA alleviates LPS-induced ALI by targeting MD2 to block TLR4 signaling, thereby suppressing both MyD88-dependent (MAPKs/NF-κB) and TRIF-dependent (TBK1/IRF3) pathways. These findings highlight 10-HDA as a promising therapeutic candidate for ALI/ARDS.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117589"},"PeriodicalIF":3.4,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239816","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":"Proteomic profiling and bioinformatics insights into lung tissue damage following whole-body exposure to sulfur mustard vapor.","authors":"Meital Charni-Natan, Maayan Cohen, Shlomi Baranes, Hila Gutman, Ariel Gore, Vered Horwitz, Shlomit Dachir","doi":"10.1016/j.taap.2025.117587","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117587","url":null,"abstract":"<p><p>Sulfur mustard (SM) is a chemical warfare agent that causes severe cellular damage by alkylating DNA and proteins, with the skin, eyes, and respiratory system being the most affected. Acute respiratory injury is the primary cause of long-term lung damage following exposure. Despite its long history of use, SM's mechanism of action remains poorly understood, and no effective treatments exist. Proteomics enables systematic identification and characterization of proteins in specific tissues, yet no comprehensive proteomic studies have examined lungs exposed to SM. This study presents the first in vivo, time-resolved proteomic characterization of rat lungs at multiple time points after whole-body exposure to SM vapor (155 μg/L/10 min). Using mass spectrometry, differentially expressed proteins were categorized into four groups reflecting different phases of injury: naive (unexposed), 4 days post-exposure (early acute injury), 1 week post-exposure (advanced acute injury), and 4 weeks post-exposure (recovery). Bioinformatics integration of these data revealed stage-specific molecular pathways involved in inflammation, tissue remodeling, oxidative stress, and immune regulation. Importantly, several identified proteins overlapped with known markers of SM-induced damage in human samples, reinforcing their translational relevance. By linking protein groups to disease associations and drug databases, we proposed a dynamic therapeutic framework tailored to the evolving phases of injury. This included specific regimens and identified FDA-approved drugs that target key proteins. By focusing on proteomic profiling changes in response to SM exposure, this study provides novel insights into SM's mechanism of action and supports the development of targeted treatments customized to each stage of injury.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117587"},"PeriodicalIF":3.4,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233464","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":"Development and reproductive safety of AdCLD-CoV19, an adenoviral vector-based COVID-19 vaccine, in female Sprague-Dawley rats and their offspring.","authors":"Sang-Jin Park, Seonghyeon Kim, Sangyun Kim, Kwang-Soo Shin, Chang-Yuil Kang, Eui-Ju Hong, Wan-Jung Im, Ji-Seong Jeong, Wook-Joon Yu, Kyong-Cheol Ko, Yong-Bum Kim","doi":"10.1016/j.taap.2025.117503","DOIUrl":"10.1016/j.taap.2025.117503","url":null,"abstract":"<p><p>The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in over 180 million cases and 4 million deaths by mid-2021. Vaccine hesitancy, particularly among women, stems from limited safety data in vulnerable populations. Therefore, we evaluated the developmental and reproductive safety of AdCLD-CoV19, an adenoviral vector-based coronavirus 2019 (COVID-19) vaccine, in pregnant Sprague-Dawley rats and their offspring. Female rats received AdCLD-CoV19 (5 × 10¹⁰ viral particles/head/d, 0.5 mL intramuscularly) twice before mating, thrice during gestation, and once postnatally. We assessed general toxicity, fertility, embryo-fetal development, postnatal development, maternal function, and immunogenicity through embryo-fetal development and pre- and postnatal development studies. AdCLD-CoV19 produced no significant toxicological effects on fetuses or neonates. No treatment-related effects were observed in maternal animals or F1 offspring, including body weight, food consumption, fertility, developmental, or behavioral endpoints. No malformations were detected in fetuses or pups. Vaccinated dams and offspring exhibited significantly elevated anti-spike IgG titers, confirming effective maternal antibody transfer through placental and lactational routes. These findings support the safety profile of AdCLD-CoV19 in pregnant and lactating females. Further clinical studies are needed to confirm translational relevance in humans.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117503"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804918","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":"The different impacts of ambient air pollution exposure on the risks of gestational hypertension and preeclampsia in twin pregnancies.","authors":"Wei-Zhen Tang, Hong-Yu Xu, Qin-Yu Cai, Yun-Ren Pan, Hao-Wen Chen, Ya-Ting Jia, Tai-Hang Liu, Yong Heng Wang, Fei Han, Niya Zhou","doi":"10.1016/j.taap.2025.117505","DOIUrl":"10.1016/j.taap.2025.117505","url":null,"abstract":"<p><p>Air pollution may raise hypertension risk, but its effects on gestational hypertension and preeclampsia in twin pregnancies are unclear. This retrospective study of 3670 twin pregnancies divided participants into three groups: gestational hypertension, preeclampsia, and no hypertension. The preeclampsia group was further split into mild and severe preeclampsia. The effects of air pollutants (PM_2.5, PM₁₀, SO₂, NO₂, CO, and O₃) on the risks of gestational hypertension and preeclampsia were assessed during preconception, the first and second trimesters, and the first 20 weeks using multivariate logistic regression, trend regression, and restricted cubic spline (RCS) analysis. Dual-pollutant models were used for validation. In both single-pollutant and dual-pollutant models, exposure to PM_2.5 and PM₁₀ during early pregnancy (first 20 weeks and the first trimester) showed a significant protective effect against gestational hypertension. However, no significant association was found between PM_2.5 and PM₁₀ exposure and the risk of preeclampsia or Severe preeclampsia. Further analysis revealed that SO₂, NO₂, and CO exposure during the 3 months preconception were identified as risk factors for preeclampsia. For gestational hypertension, the protective effects of SO₂ and NO₂ exposure during the 3 months preconception and the first trimester disappeared after adjusting for some pollutants, but remained protective in most cases. An association was found between O₃ exposure during the 3 months preconception and gestational hypertension risk in twin pregnancies, but not with preeclampsia or severe preeclampsia risk. Air pollutants have significantly different impacts on gestational hypertension and preeclampsia in twin pregnancies, particularly during the 3 months preconception.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117505"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804920","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":"Copper ionophore enhanced cisplatin efficiency through DLAT-cuprotosis.","authors":"Jun Tang, Lingling Zhao, Xiujuan Qiu, Qitian Chen","doi":"10.1016/j.taap.2025.117496","DOIUrl":"10.1016/j.taap.2025.117496","url":null,"abstract":"<p><p>Breast cancer is the most prevalent cancer among women globally, and triple-negative breast cancer (TNBC) lacks effective therapeutic strategies. Cuproptosis-related genes (CRGs) are implicated in the progression of breast cancer. Thirteen CRGs have been identified in previous studies. RNA sequencing data from TCGA-BRCA and protein data from the HAP databases indicated that DLAT expression is lower in breast tumor tissues compared to normal tissues. Conversely, high DLAT expression is associated with poor prognosis in patients. However, the specific role and underlying mechanisms of dihydrolipoamide S-acetyltransferase (DLAT) in breast cancer remain largely unexplored. Differential gene and enrichment analyses showed that elevated DLAT expression is involved in the cell cycle, cellular senescence, and the p53 signaling pathway. Furthermore, DLAT expression correlates with immune scores and cellular infiltration. Knockdown of DLAT in breast cancer cells significantly inhibits proliferation, migration and invasion capabilities. Additionally, DLAT positively regulates the expression of genes involved in cell proliferation and epithelial-mesenchymal transition (EMT). Drug sensitivity assays and breast tumor xenograft models demonstrate that the copper ionophore ES-Cu could reverse cisplatin resistance in breast cancer cells by promoting DLAT oligomerization, inducing cuproptosis, and increasing intracellular ROS levels. Therefore, DLAT holds promise as a valuable molecular marker in immunotherapy and as a mediator of cuproptosis, with the potential to enhance the clinical efficacy of breast cancer chemotherapy.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117496"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765578","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":"Hyperoside protects human osteoblasts from phthalate-induced mitochondrial dysfunction, oxidative stress, and apoptosis.","authors":"Ekramy M Elmorsy, Huda A Al Doghaither, Ayat B Al-Ghafari, Neven A Ebrahim, Mohamed E Mohamed, Samah F Ibrahim, Farouk S Elgendy, Ahmed Abdeen","doi":"10.1016/j.taap.2025.117491","DOIUrl":"10.1016/j.taap.2025.117491","url":null,"abstract":"<p><p>Butyl cyclohexyl phthalate (BCP), an emerging environmental contaminant, impairs osteoblast function via oxidative stress, mitochondrial dysfunction, and apoptosis. This study evaluated hyperoside (HYP), a flavonoid, for its protective effects against BCP-induced toxicity in human osteoblasts. Molecular docking showed strong binding of BCP and HYP to oxidative stress- and apoptosis-related proteins. In vitro assays revealed BCP's dose-dependent cytotoxicity, marked by decreased ATP production, mitochondrial membrane potential, mitochondrial complexes I and III activities, and suppressed mitophagy (PINK1/PARKIN downregulation), elevated oxidative stress biomarkers, and activated apoptosis (Cas-3/-8/-9, Bax/Bcl2 imbalance). HYP co-treatment restored osteoblast viability, secretory function, and mitophagy while reducing oxidative stress via Nrf2/HO-1 activation. HYP also inhibited caspases and normalized Bax/Bcl2 ratios, preventing apoptosis. These findings demonstrate HYP's dual cytoprotective role: enhancing mitochondrial quality control and mitigating BCP-induced oxidative/apoptotic damage. The study unveils BCP's osteotoxic mechanisms and positions HYP as a promising therapeutic to counteract environmental bone toxicity by targeting mitophagy, redox balance, and apoptotic pathways, highlighting the potential of flavonoid-based interventions in osteotoxicity management.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117491"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800288","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":"Hederagenin exerts anti-tumor effects in pancreatic cancer by impairing DRP1 mediated-mitophagy via VDAC1-HK2-PINK1/PARKIN pathway.","authors":"Fang Su, Jianhua Yu, Shenhao Xu, Huanjun Tong, Jiandong Li, Fangfang Tao, Baochun Lu","doi":"10.1016/j.taap.2025.117586","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117586","url":null,"abstract":"<p><p>Pancreatic cancer (PC) is widely regarded as the deadliest form of malignancy with a notably bleak prognosis. Although survival rates have shown gradual improvements, the pace of advancement remains slower when compared to other forms of cancer. Mitophagy suppression has surfaced as a novel approach for cancer treatment. Hederagenin (HDG), a triterpenoid extracted from the Hedera helix, has been identified as a potent inhibitor of mitophagy in PC. HDG has demonstrated the capacity to suppress the growth of BXPC-3 and PANC-1 cells in vitro, while also showing efficacy in diminishing tumor expansion in vivo. Furthermore, HDG promoted the opening of mitochondrial permeability transition pores, and enhance the accumulation of ROS. In addition, HDG led to a disruption in autophagic flux and an increase in autophagosomes within PC cells. Western blot analysis suggested that HDG hindered the fusion of lysosomes and autophagosomes by downregulating the expression of SNAP29, LAMP1, and Rab7. HDG also altered mitochondrial morphology in PC cells by suppressing the expression of dynamin-related protein 1 (DRP1), a crucial element in mitochondrial division machinery. This inhibition subsequently triggered voltage-dependent anion-selective channel protein 1 (VDAC1) oligomerization, mitochondrial hexokinase 2 (HK2) dissociation, and downregulation of the PINK1/PARKIN pathway, ultimately inhibiting the proliferation of PC cells in vitro. Moreover, the anti-mitophagy impact of HDG was reversed by DRP1 overexpression, while DRP1 knockdown produced the opposite results. These findings collectively suggest that HDG exerts anti-tumor activity by inhibiting mitophagy in PC cells. The underlying mechanism may involve the suppression of the DRP1-VDAC1-HK2-PINK1/PARKIN signaling pathway.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117586"},"PeriodicalIF":3.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145213818","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}