Toxicology and applied pharmacology最新文献

{"title":"Vericiguat as a novel PPARα ligand alleviates pressure-overload-induced heart failure.","authors":"Peng Zhang, Chenxin Yuan, Zhujing Zhan, Jianghua Zhou, Pan Huang, Wenhan Wang, Jinfu Qian, Peiren Shan","doi":"10.1016/j.taap.2025.117473","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117473","url":null,"abstract":"<p><p>Heart failure (HF) remains a critical global health challenge with limited therapeutic options. Vericiguat, a novel soluble guanylate cyclase (sGC) stimulator, has demonstrated clinical potential in HF management. This study aimed to investigate the cardioprotective effects of vericiguat and its underlying mechanism in pressure-overload-induced HF. Using a transverse aortic constriction (TAC) mouse model, we demonstrated that vericiguat significantly improved cardiac function and attenuated myocardial hypertrophy, fibrosis, and oxidative stress. In vitro, vericiguat mitigated isoproterenol (ISO)-induced hypertrophy and oxidative stress in HL-1 cardiomyocytes. RNA sequencing and pathway enrichment analysis revealed that vericiguat exerts its protective effects by modulating metabolic pathways, particularly through the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Vericiguat upregulated PPARα expression at both mRNA and protein levels, with no significant effect on PPARβ or PPARγ. CETSA and DARTS assays confirmed a direct interaction between vericiguat and PPARα, further supported by molecular docking showing stable hydrogen bonding and hydrophobic interactions, notably with residue SER280. Pharmacological inhibition of PPARα with GW6471 abolished vericiguat's protective effects, underscoring the central role of PPARα activation. In conclusion, vericiguat alleviates pressure-overload-induced HF by directly binding to, upregulating and activating PPARα, offering a novel therapeutic approach for the treatment of HF.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117473"},"PeriodicalIF":3.3,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627154","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":"Unfixed light pattern-related circadian disruption impairs circadian-orexinergic-serotoninergic system and induces depression-like behaviors in mice.","authors":"Qianyi Liu, Qinghe Meng, Jingbo Qi, Jiaqi Cheng, Jianjun Jiang, Lanqin Shang, Xuetao Wei, Weidong Hao","doi":"10.1016/j.taap.2025.117464","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117464","url":null,"abstract":"<p><p>Unfixed light pattern (ULP) occurring in shift work can lead to circadian disruption (CD), which has been linked to the increasing risk of depression. However, whether ULP-related CD is a risk factor for depression has remained elusive and the underlying mechanism is poorly understood. In this study, mice were subjected to ULP-related CD and we found that CD mice showed prolonged immobility time in the tail suspension test and forced swimming test. This affective damage effect was exacerbated with a longer duration of CD and was reversed by recovery of CD. Mechanistically, it was demonstrated that expression of clock genes in the suprachiasmatic nucleus (SCN), lateral hypothalamus area (LHA), and dorsal raphe nucleus (DRN) showed different degrees of phase shift and arrhythmicity in CD mice during desynchronization period. Furthermore, we found phase shift but normal amplitude for the expression of SCN cFOS, and mesor decrease and phase shift for the expression of the downstream of SCN--LHA OX-A, DRN OX-A, and DRN 5-HT in mice during desynchronization period, which worsened with longer CD duration and restored after recovery of CD. Altogether, this study suggests that ULP-related CD may be a risk factor for depression and the circadian-orexinergic-serotoninergic pathway might involve in it, which may provide new insights for the prevention and treatment of depression induced by ULP-related CD occurring in shift work.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117464"},"PeriodicalIF":3.3,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627153","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":"Cadmium-induced apoptosis of granulosa cells is mediated by excessive activation of mitophagy and ROS-mediated mitochondrial dysfunction.","authors":"Wenqian Li, Mengqi Wu, Haotian Shi, Muran He, Junyue Wang, Yichao Huang, Dexiang Xu, Jun Zhang","doi":"10.1016/j.taap.2025.117462","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117462","url":null,"abstract":"<p><p>Cadmium (Cd), a pervasive environmental and occupational toxicant, has raised significant public health concerns due to its detrimental effects on human health. Emerging evidence highlights its capacity to impair the female reproductive system, notably through induction of follicular cell apoptosis. However, the underlying mechanism of Cd-induced apoptosis of granulosa cells remains unclear. In this study, thirty female mice were randomly allocated into three groups and exposed to CdCl₂ (0, 1.0, or 4.0 mg/kg) for 12 h, while 40 mice were divided into four groups and treated with CdCl₂ (4 mg/kg) for varying durations (0, 6, 12, or 24 h). Ovarian injury, apoptosis and mitophagy were observed in mice. To further elucidate the mechanism, human ovarian granulosa-like tumor cells (KGN cells) were treated with CdCl₂ (0-40 μM). Cd triggered apoptosis and excessive mitophagy in KGN cells, accompanied by reduced adenosine triphosphate (ATP) levels, diminished mitochondrial membrane potential (MMP), and elevated total reactive oxygen species (ROS) and mitochondrial ROS (mtROS). Pharmacological inhibition of autophagy using 3-methyladenine (3-MA) attenuated Cd-induced apoptosis and mitochondrial dysfunction, whereas autophagy activation via rapamycin exacerbated these detrimental effects. Our findings demonstrate that Cd disrupts mitochondrial homeostasis by over activating mitophagy, which subsequently amplifies apoptotic signaling in ovarian granulosa cells. These results provide mechanistic insights into Cd-associated ovarian pathologies and highlight the therapeutic potential of targeting mitophagy to mitigate reproductive toxicity.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117462"},"PeriodicalIF":3.3,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627152","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":"Preclinical pharmacokinetic and toxicokinetic profiles of AY-1001 (IsoLiPro), a novel small molecule lithium-organic coordination compound","authors":"Yi Guo ,&nbsp;Bingjie Zhang ,&nbsp;Chuanbin Cai ,&nbsp;Qinmin Tang ,&nbsp;Zhifeng Lei ,&nbsp;Jiang Chen ,&nbsp;Xiaojiang Zheng ,&nbsp;Shaowei Lei ,&nbsp;Weidi Zhang ,&nbsp;Dan Zi ,&nbsp;Jun Tan ,&nbsp;Song Li","doi":"10.1016/j.taap.2025.117459","DOIUrl":"10.1016/j.taap.2025.117459","url":null,"abstract":"<div><div>Lithium is recommended as a first-line option for maintenance therapy of bipolar disorder (BD), due to its reliable mood-stabilizing property and benefits for relapse and suicide prevention. However, its clinical applications are still facing challenges, considering the relatively narrow therapeutic window, poor ability to cross the blood-brain barrier, and various side-effects ranging from mild nonspecific to life threatening symptoms. To overcome these challenges, the discovery and development of novel lithium-containing candidates with better kinetics profiles is urgently needed. We previously synthesized and patented a novel lithium-containing coordination compound AY-1001 (C₉H₁₆LiNO₄), which shows antimanic activity in animal model. In this study, the pharmacokinetic and toxicokinetic properties of AY-1001 were further determined. Pharmacokinetic data demonstrated that AY-1001 has a faster onset of action, a shorter half-life, and a higher blood-brain barrier transmission rate, compared with the traditional inorganic lithium carbonate. In addition, toxicological data indicated that AY-1001 exhibits low toxicity in SD rats and beagle dogs. These findings suggest that AY-1001 has the potential to improve therapeutic effects and reduce side effects, providing a strong scientific basis and promising strategy for the further development of organic lithium-containing mood stabilizers.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117459"},"PeriodicalIF":3.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144609629","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":"Hinokitiol induces developmental and cardiovascular toxicity in zebrafish larvae and potential mechanisms","authors":"Chenkai Ge ,&nbsp;Ziang Wang ,&nbsp;Weitao Hu ,&nbsp;Qinyuan Shen ,&nbsp;Weirong Li ,&nbsp;Wenwen Zha ,&nbsp;Zhonghao Xiao ,&nbsp;Jingrong Tang ,&nbsp;Ling Huang ,&nbsp;Huimin Li ,&nbsp;Zigang Cao ,&nbsp;Jianjun Chen","doi":"10.1016/j.taap.2025.117461","DOIUrl":"10.1016/j.taap.2025.117461","url":null,"abstract":"<div><div>Hinokitiol is a natural compound collected from the trunk of cypress, belonging to the tropolone family of compounds. It has anti-inflammatory, anti-tumour and antibacterial activities, making it a natural product with a wide range of applications. It is used as an additive in hair growth agents, toothpaste, make-up and furniture wood. However, the toxicity of hinokitiol remains poorly understood. Therefore, the cardiovascular and developmental toxicity of hinokitiol in organisms was investigated in zebrafish larvae. In the study, zebrafish embryos were exposed to hinokitiol for 3 days to study the developmental and cardiovascular toxicity of hinokitiol. Concentrations for the hinokitiol toxicity test were set at 0, 0.4, 0.8, 1.2, 1.6, 2.0 and 2.2 mg/L. The experimental concentrations of 0, 0.8, 1.2 and 1.6 mg/L were subsequently determined based on phenotype. The results showed that exposure to hinokitiol resulted in increased mortality, changes in hatching rates and abnormalities in the apparent morphology of zebrafish embryos/larvae (shortened body length, reduced eye area, pericardial edema, and abnormal heart rate). In addition, hinokitiol impaired the cardiovascular system of zebrafish larvae, as evidenced by the absence of morphological features of the atria and ventricles, linearization of the heart, and reduction in the area and abundance of blood vessels. In addition, hinokitiol affects mitochondrial function by affecting iron ion levels and generates oxidative stress leading to apoptosis and which then generates cardiovascular toxicity. Our findings suggest that hinokitiol causes mitochondrial dysfunction and oxidative stress through iron chelation, which in turn triggers apoptosis, ultimately leading to cardiovascular and developmental toxicity in zebrafish larvae. The study provides new insights into the safety of hinokitiol and natural products.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117461"},"PeriodicalIF":3.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144596642","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":"Gallium maltolate and cisplatin co-treatment effectively targets triple-negative breast cancer in spheroid and mouse models","authors":"Ya-Wen Yang ,&nbsp;Yu-Chen Hsieh ,&nbsp;Ching-Yu Liu ,&nbsp;Chun-Kai Pan ,&nbsp;Zi-Yu Pan ,&nbsp;Kai-Yin Lo","doi":"10.1016/j.taap.2025.117460","DOIUrl":"10.1016/j.taap.2025.117460","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks targeted therapies and is characterized by high invasiveness and metastatic potential. Our previous work demonstrated that GaM (gallium maltolate) blocks cell cycle progression and impairs ribosomal synthesis in TNBC cells. Moreover, GaM treatment promotes ferroptosis activation, and its combination with cisplatin exhibits synergistic effects. To further evaluate the efficacy of these treatments, we applied them to three-dimensional spheroid and mouse models. Two types of spheroids were generated: one composed solely of TNBC cells (MDA-MB-231) and the other a co-culture with normal breast cells (MCF10A). In both MDA/MCF10A and MDA-MB-231 spheroids, we observed enhanced p53 activation and increased p21 expression, with the effects being more pronounced in the MDA-MB-231 spheroids. These effects were stronger with the combination treatment than with either treatment alone. Similar results were observed in a xenograft model, where tumors formed from MDA-MB-231 cells in nude mice. The combination therapy reduced tumor size to a similar extent as cisplatin alone and did not cause adverse effects in mice. The combination therapy induced apoptosis, nucleolar stress, and ferroptosis. Additionally, the treatment inhibited cell migration and metastasis - by increasing E-cadherin levels and reducing metalloproteases. These findings provide a strong foundation for further mechanistic studies and potential clinical applications.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117460"},"PeriodicalIF":3.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144596194","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":"Vitamin D alleviates silica-induced pulmonary fibrosis partly by inhibiting STAT3/hexokinase 2-mediated fibroblast glycolysis","authors":"Huanyu Yang ,&nbsp;Li Zhang ,&nbsp;Guanming Chen ,&nbsp;Qiongxiao Wu ,&nbsp;Mingyi Li ,&nbsp;Chengye Zhang ,&nbsp;Mengjia Han ,&nbsp;Qi Xu","doi":"10.1016/j.taap.2025.117456","DOIUrl":"10.1016/j.taap.2025.117456","url":null,"abstract":"<div><div>Pulmonary fibrosis is defined by the excessive accumulation of extracellular matrix proteins, with few treatment options currently available. Notably, emerging evidence indicates that vitamin D may provide benefits for fibrotic lesions across various tissues. However, the underlying molecular mechanisms have not yet been fully elucidated. In our study, we observed that glycolysis levels increased during the fibroblast-to-myofibroblast transition (FMT) in both MRC-5 cells and mouse primary lung fibroblasts, however, vitamin D treatment inhibited fibroblasts' activation, proliferation, and glycolysis <em>in vitro</em>. We further identified signal transducer and activator of transcription 3 (STAT3) as a crucial downstream effector of vitamin D, with the expression of phosphorylated STAT3 (p-STAT3) being negatively regulated by vitamin D. In MRC-5 cells and mouse primary lung fibroblasts, ectopic expression of STAT3 enhanced fibroblast activation and blocked the anti-fibrotic effects of vitamin D. Mechanistic studies revealed that vitamin D reduces p-STAT3 levels, which inhibits the expression of hexokinase-II (HK2), a key enzyme in the glycolytic pathway, consequently blocking fibroblast glycolysis and activation. <em>In vivo</em> experiments demonstrated that vitamin D administration significantly mitigated silica-induced fibrogenesis, while a deficiency in vitamin D exacerbated the progression of pulmonary fibrosis. Collectively, our findings suggest that vitamin D alleviates silica-induced pulmonary fibrosis by inhibiting fibroblast glycolysis in a STAT3/HK2-dependent manner, indicating that vitamin D supplementation may serve as a promising antifibrotic agent.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"503 ","pages":"Article 117456"},"PeriodicalIF":3.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144596584","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":"Novel NLRP3 inhibitors mitigate acute radiation-induced lung injury by suppressing pyroptosis in alveolar epithelial cells","authors":"Yupeng Zhi ,&nbsp;Huijia Chen ,&nbsp;Yihao Huang ,&nbsp;Lipeng Li ,&nbsp;Zibin Chen ,&nbsp;Hongzhao Huang ,&nbsp;Fang Ke ,&nbsp;Yansong Guo ,&nbsp;Chun Chen","doi":"10.1016/j.taap.2025.117458","DOIUrl":"10.1016/j.taap.2025.117458","url":null,"abstract":"<div><h3>Objective</h3><div>Radiation-induced lung injury (RILI), a severe complication of thoracic tumor radiotherapy, is driven by NLRP3-mediated pyroptosis triggered by irradiation. This study aimed to design novel NLRP3 inhibitors targeting pyroptosis in alveolar epithelial cells to alleviate RILI and elucidate underlying mechanisms.</div></div><div><h3>Methods</h3><div>Quinoxalinone derivatives (QK-3A – QK-3E) targeting the NACHT domain of NLRP3 were synthesized. Their effects on the NLRP3/GSDMD pathway and cytokines (IL-1β, IL-18) were evaluated in irradiated A549 and MLE-12 cells using high-content Screening. A C57BL/6 mouse RILI model assessed compound efficacy via HE staining, Western blot, immunofluorescence. Safety was evaluated.</div></div><div><h3>Results</h3><div>Single-cell sequencing datasets analysis revealed a marked reduction in alveolar type 2 (AT2) cell proportion (from 12.41 % to 4.02 %) during early RILI, with pyroptosis-related genes showing heightened activity in AT2 cells. Molecular docking demonstrated QK-3E's strong binding to NLRP3 residues ARG351 and PHE575, inhibiting its activation. In vitro, QK-3D and QK-3E reduced radiation-induced cleaved-caspase-1/GSDMD-N expression(about 30 %–75 %), and IL-1β/IL-18 releases(about 30 %–50 %), suppressing AT2 pyroptosis. In vivo, QK-3D and QK-3E attenuated lung index elevation(about 25 %), mitigated pulmonary and systemic inflammation, and outperformed dexamethasone. They downregulated GSDMD-N(about 20 %-30) and cleaved-caspase-1(about 50 %–60 %) in SPC⁺ AT2 cells, blocking pyroptosis without cardiotoxicity, hepatotoxicity, or nephrotoxicity.</div></div><div><h3>Conclusion</h3><div>The NLRP3 inhibitors QK-3D and QK-3E effectively alleviate RILI by suppressing AT2 pyroptosis via NLRP3/GSDMD pathway inhibition, offering a potent and safe therapeutic candidate for early intervention. This study advances pyroptosis-targeted strategies for inflammatory diseases.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117458"},"PeriodicalIF":3.3,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144572241","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":"Machine learning-driven prediction of eye irritation toxicity: Integration of in silico and in vitro study","authors":"Shanshan Chen ,&nbsp;Jiaxin Wang ,&nbsp;Lu Hao ,&nbsp;Ying Wan ,&nbsp;Yang Yu ,&nbsp;Yiwei Wang","doi":"10.1016/j.taap.2025.117457","DOIUrl":"10.1016/j.taap.2025.117457","url":null,"abstract":"<div><div>Eye irritation (EI) toxicity poses critical challenges in chemical safety assessment, demanding alternatives to ethically contentious animal testing. We present the first integrative framework combining computational prediction with experimental validation for EI evaluation. Utilizing 5220 compounds characterized by 11 molecular fingerprints and 13 molecular descriptors (MDs), six machine learning (ML) algorithms generated 252 models through rigorous five-fold cross-validation. The optimized model demonstrated exceptional predictive accuracy (0.977 test-set performance), surpassing comparable approaches. Experimental validation assessed model-predicted compounds through <em>in vitro</em> corneal epithelial assays, with benchmarked biological responses confirming prediction reliability. This closed-loop methodology establishes a paradigm for ethical chemical safety assessment, achieving three critical advancements: replacement of animal testing through computational-experimental synergy, enhanced prediction reliability <em>via</em> machine learning-optimized feature selection, and accelerated developmental timelines through early-stage toxicity screening. The validated approach addresses interspecies extrapolation limitations while aligning with global 3Rs (Replacement, Reduction, Refinement) initiatives, offering transformative potential for next-generation risk assessment in chemical development.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117457"},"PeriodicalIF":3.3,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563563","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":"NLRP3 inflammasome regulates doxorubicin-induced cardiotoxicity by modulating the abundance of gut microbiota","authors":"Jinsong Yin ,&nbsp;Yuyun You ,&nbsp;Juncong Mao ,&nbsp;Jialong Qi ,&nbsp;Xin Zhang ,&nbsp;Yunfei Hong","doi":"10.1016/j.taap.2025.117455","DOIUrl":"10.1016/j.taap.2025.117455","url":null,"abstract":"<div><div>Doxorubicin (DOX) is a widely used anthracycline whose dose-dependent cardiotoxicity limits its clinical efficacy. However, the mechanisms underlying its toxicity, particularly the regulatory network involving the Nod-like receptor protein 3 (NLRP3) inflammasome-gut-heart axis, remain incompletely understood. This study aimed to establish cellular and animal models of doxorubicin-induced cardiotoxicity (DIC) and investigate the role of the inflammasome in DIC-associated alterations in gut microbiota abundance. Rat cardiomyocytes (H9c2 cells) were treated with DOX 1, 10, 25, and 50 μmol/L concentrations to assess dose-dependent cardiotoxicity. In vivo, C57BL/6 J and NLRP3/MLKL/RIPK3 knockout (KO) mice received DOX (5 mg/kg, intravenous, every 2 days for 3 doses, cumulative 15 mg/kg) to establish a DIC model. We measured the physiological and biochemical parameters of mice peripheral blood using an automatic biochemical analyzer. Additionally, we quantified the mRNA expression levels of inflammatory factors using a reverse transcription polymerase chain reaction and observed cardiomyocyte apoptosis. Fecal samples were collected from each group for 16S recombinant DNA sequencing to analyze gut microbiota. DOX-induced H9c2 cell damage and inflammatory factor release activated the NLRP3 inflammasome and upregulated autophagy-associated proteins LC3I/II. NLRP3 KO attenuated DOX-induced cardiac damage, modulated the immune environment in mouse blood, and mitigated DIC. NLRP3 KO lowered the abundance of mucinophilic <em>Akkermansia muciniphila</em> and suppressed the cardiotoxic effects of DOX. The cardiotoxic effects of DOX were mediated via the NLRP3 inflammasome. NLRP3 inflammasome may mediate DIC by regulating the abundance of gut <em>Akkermansia muciniphila</em>.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"502 ","pages":"Article 117455"},"PeriodicalIF":3.3,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144555030","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}