Toxicology and applied pharmacology最新文献

{"title":"Aurocyanide, an active metabolite of auranofin, exerts cytoprotective effects via ROS-mediated Nrf2 activation in HepG2 cells","authors":"Undarmaa Otgontenger,&nbsp;Seokwon Yang,&nbsp;Eun Kyung Kim,&nbsp;Young-Mi Kim","doi":"10.1016/j.taap.2025.117656","DOIUrl":"10.1016/j.taap.2025.117656","url":null,"abstract":"<div><div>Auranofin, an FDA-approved oral gold(I) compound for rheumatoid arthritis, is being repurposed due to its established clinical safety and emerging therapeutic potential. Given its extensive <em>in vivo</em> metabolism, identifying active metabolites and characterizing their biological activities are critical for understanding its therapeutic mechanisms. Here, we evaluated the cytoprotective effects of seven potential auranofin metabolites against <em>tert</em>-butylhydroperoxide-induced oxidative injury in HepG2 cells. Among them, only aurocyanide markedly improved cell viability, as demonstrated by MTT and live-cell imaging assays. This study is the first to elucidate the molecular mechanisms underlying the cytoprotective effects of aurocyanide, with a focus on Nrf2 signaling. Aurocyanide suppressed <em>tert</em>-butylhydroperoxide-induced intracellular and mitochondrial ROS production and significantly increased antioxidant responsive element (ARE)-luciferase activity, comparable to that of sulforaphane. It also promoted nuclear accumulation of Nrf2, leading to upregulation of Nrf2-regulated antioxidant enzymes (GCL, HO-1, NQO1). Induction of Nrf2 target genes was confirmed in both HepG2 cells and primary mouse hepatocytes. Aurocyanide elevated intracellular GSH levels and alleviated <em>tert</em>-butylhydroperoxide-induced GSH depletion. Importantly, the cytoprotective effect of aurocyanide was significantly reduced in Nrf2-knockdown cells, highlighting the essential role of Nrf2. Pretreatment with <em>N</em>-acetyl-L-cysteine (NAC) abolished aurocyanide-induced Nrf2 activation and HO-1 upregulation, indicating the involvement of ROS in Nrf2/ARE pathway activation. Aurocyanide induced mild ROS production, which was reduced by NAC, and NAC also diminished the protective effects of aurocyanide against oxidative injury. In conclusion, aurocyanide, an active metabolite of auranofin, exerts antioxidant and hepatoprotective effects <em>via</em> ROS-mediated activation of the Nrf2 signaling pathway, broadening our understanding of its pharmacological actions in liver pathology.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117656"},"PeriodicalIF":3.4,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588199","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":"Exploring the role of metformin in high fluoride ingestion-induced bone lesions","authors":"Wenshu Xu,&nbsp;Ningning Jiang,&nbsp;Zhongyuan Zhang,&nbsp;Hui Xu","doi":"10.1016/j.taap.2025.117653","DOIUrl":"10.1016/j.taap.2025.117653","url":null,"abstract":"<div><div>This study was to investigate the potential mechanisms of metformin administration against skeletal fluorosis by mitigating bone turnover. Rats were treated with fluoride via intragastric gavage to develop a model of skeletal fluorosis, and half of them were concurrently treated with metformin for 12 weeks. The cells involved in the process of bone turnover, including osteoclasts, osteoblast, and osteocyte were exposed to varying concentrations of fluoride with or without metformin. Results showed that excessive fluoride treatment increased levels of bone turnover markers in the serum and the expression of bone turnover-related factors in the femur. Additionally, fluoride treatment damaged the trabecular microstructure and mechanical function in long bone. Concurrent treatment of metformin reduced the serum levels of bone turnover markers and protein expression of bone turnover-related factors in the femurs of fluorotic rats. Furthermore, metformin cotreatment restored the trabecular microstructure of and mechanical function of the long bones of fluorotic rats. In vitro studies demonstrated that low-dose fluoride stimulated osteoclastic viability and upregulated osteoclastic differentiation proteins, but metformin inhibited the stimulatory effect of fluoride on them. Though fluoride exposure increased the apoptosis rate of osteoclasts and osteoblasts, and metformin aggravated fluoride-induced osteoclastic apoptosis but alleviated osteoblastic apoptosis. Additional, metformin stimulated SOST expression and inhibited RANKL expression in osteocytes exposed to fluoride. This is consistent with the KEGG enriched pathway in metformin-treated osteocytes, such as the osteoclast differentiation and Wnt signaling pathways. These results suggested that metformin counteracted high bone turnover that occurred in skeletal fluorosis by inhibiting osteoclastogenesis and regulating osteocytes to delay osteogenesis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117653"},"PeriodicalIF":3.4,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582563","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 potential amelioration of oxaliplatin-induced peripheral neuropathy in Sprague Dawley rats by sodium butyrate via targeting neuro-immuno-inflammatory axis","authors":"Alaa R. AlKady,&nbsp;Maaly A. Abd Elmaaboud,&nbsp;Asmaa Fawzy Eltantawy,&nbsp;Amany A. Abdin","doi":"10.1016/j.taap.2025.117651","DOIUrl":"10.1016/j.taap.2025.117651","url":null,"abstract":"<div><div>Oxaliplatin is widely used as one of the first-line treatments for colorectal carcinoma. Oxaliplatin-induced peripheral neuropathy (OIPN) is the most common dose-limiting adverse effect leading to discontinuation of treatment. This work aimed to investigate the potential ameliorative effect of sodium Butyrate (NaB) on OIPN via assessment of neurotrophic factors and the immune-inflammatory axis, either before induction (PRE) or WITH the induction of OIPN in Sprague Dawley rats. In this study, OIPN was induced by oxaliplatin in a dose of 2.4 mg/kg once daily for 5 consecutive days/ week for 3 weeks by i.p. injection. Behavioral tests were performed, and the sciatic nerves were dissected and processed for further assessment of biochemical parameters and the histopathological picture. NaB has a marked neurotrophic, anti-inflammatory and immunomodulatory effect represented by a significant decrease in mechanical and cold allodynia scores and tissue levels of TNF-α and a significant increase in tissue levels of nerve growth factor (NGF) and IL-10 with a significant improvement in the histopathological changes by H&amp;E and Toluidine blue as well as a significant increase in the IHC expression of FOXP-3 and PPAR-γ. NaB-PRE OIPN showed more improvement in the neurotrophic, anti-inflammatory, and immunomodulatory properties than NaB WITH OIPN. These elaborated data indicated that NaB is a potential neuroprotective candidate for OIPN treatment due to its immunomodulatory, anti-inflammatory, and neurotrophic effects, particularly when used before the initiation of chemotherapeutic cycles to improve the clinical aspects of OIPN.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117651"},"PeriodicalIF":3.4,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145574638","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":"Artesunate attenuates pulmonary fibrosis by suppressing fibroblast senescence through inhibition of the STAT3/p53 signaling pathway","authors":"Jianyi Ding ,&nbsp;Zhile Chen ,&nbsp;Jiaqin Yu ,&nbsp;Yangjun Xu ,&nbsp;Ting Zhu ,&nbsp;Bin Wang ,&nbsp;Zhuyang Feng ,&nbsp;Xinhuo Li ,&nbsp;Xiumin Qian ,&nbsp;Bingqian Jin ,&nbsp;Guangmao Yu ,&nbsp;Chu Zhang ,&nbsp;Aixia Chen","doi":"10.1016/j.taap.2025.117646","DOIUrl":"10.1016/j.taap.2025.117646","url":null,"abstract":"<div><div>Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and lethal lung disease with elusive pathogenesis. Accumulating evidence implicates cellular senescence as a key mechanism in IPF. Current therapies (pirfenidone/nintedanib) reduce acute exacerbation risk and delay lung function decline in mild-to-moderate IPF, but adverse effects often limit their use. The JAK/STAT pathway is critically involved in the pathogenesis of IPF. While artesunate (Art) alleviates pulmonary fibrosis in rats through anti-inflammatory actions, its effects on fibrosis via STAT3 inhibition—particularly in murine models and human tissues—remain underexplored.</div><div>Objective: To determine whether and how Art attenuates pulmonary fibrosis by suppressing lung fibroblast senescence.</div><div>Methods: Pulmonary fibrosis was induced in vivo in mice through intratracheal bleomycin administration. In vitro senescence models included TGF-β-stimulated primary mouse lung fibroblasts and cultured human lung tissue explants. Fibrosis was assessed via hematoxylin and eosin, Masson's trichrome, immunohistochemistry (IHC), immunofluorescence (IF), and Western blot. The expression of senescence-associated markers was analyzed by Western blotting and immunofluorescence (IF).</div><div>Results: Art significantly attenuated bleomycin-induced pulmonary fibrosis in mice. It downregulated senescence markers (p53, p21), myofibroblast markers (α-SMA), and collagen-deposition proteins (fibronectin, collagen I). Mechanistically, Art inhibited STAT3 phosphorylation, subsequently suppressing p53-mediated fibroblast senescence.</div><div>Conclusion: Art demonstrates therapeutic potential for IPF by inhibiting fibroblast senescence through STAT3/p53 signaling axis suppression.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117646"},"PeriodicalIF":3.4,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145574632","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":"Integrative network toxicology and experimental validation reveal novel molecular mediators of omeprazole-induced nephrotoxicity","authors":"Qian Huang ,&nbsp;Yuqian Li ,&nbsp;Zhiliang Gao ,&nbsp;Yiming Shao","doi":"10.1016/j.taap.2025.117649","DOIUrl":"10.1016/j.taap.2025.117649","url":null,"abstract":"<div><div>Omeprazole, a widely used proton pump inhibitor, has been increasingly linked to adverse renal outcomes such as acute kidney injury (AKI) and chronic kidney disease (CKD), yet its nephrotoxic mechanisms remain unclear. In this study, we utilized an integrative network toxicology approach, combined with molecular docking and in vitro validation, to elucidate potential mechanisms underlying omeprazole-induced renal toxicity. By intersecting omeprazole-related genes with those implicated in AKI and CKD, we identified 73 overlapping targets enriched in the PI3K-Akt signaling pathway, EGFR inhibitor resistance, and xenobiotic response. A protein–protein interaction network and topological analysis revealed six hub targets (CASP3, CCND1, EGFR, MMP9, PARP1, PPARG), all showing strong binding affinities to omeprazole in molecular docking simulations. Functional validation in HK-2 cells demonstrated that omeprazole reduced cell viability, induced morphological damage, and increased apoptosis in both acute (300 μM, 24 h) and chronic (20 μM, 7 days) exposure models. qPCR analysis confirmed significant upregulation of <em>CASP3</em>, <em>EGFR</em>, <em>MMP9</em>, <em>PARP1</em>, and <em>PPARG</em>, with <em>CCND1</em> exhibiting model-dependent expression changes. These findings provide new insights into the molecular basis of omeprazole-associated nephrotoxicity and suggest potential biomarkers and therapeutic targets for mitigating renal injury.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117649"},"PeriodicalIF":3.4,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145565502","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":"Endometriosis lesion growth inhibition and immune modulation function of thymol in vitro and in vivo","authors":"Hyewon Jang ,&nbsp;Wonhyoung Park ,&nbsp;Hee Seung Kim ,&nbsp;Gwonhwa Song ,&nbsp;Whasun Lim ,&nbsp;Sunwoo Park","doi":"10.1016/j.taap.2025.117648","DOIUrl":"10.1016/j.taap.2025.117648","url":null,"abstract":"<div><div>Thymol, a phenolic monoterpene derivative found in the essential oil of <em>Thymus vulgaris L., Lamiaceae</em>, is currently under investigation for potential applications in pharmaceuticals, functional foods, and cosmetics. Despite ongoing research in these areas, the potential therapeutic effects of thymol on endometriosis remain unconfirmed. Endometriosis, characterized by the growth of endometrial tissue outside the uterus. Available treatment options, including medications and surgery, have limitations and are no curative. To address these limitations, our study aimed to explore the therapeutic potential of thymol in endometriosis, through simultaneous in vitro and in vivo investigations. Our results indicate that thymol induces antioxidant activity and regulate intracellular calcium ions. Further thymol administration reduced the size of endometriosis lesions in animal models and modulated immune responses, resulting in alterations in spleen populations of CD4⁺ T and CD8⁺ T cells and macrophages, as well as changes in the expression of cytokine-related genes. Overall, our findings suggest that thymol holds promise as a therapeutic agent for endometriosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117648"},"PeriodicalIF":3.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557939","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":"mTOR mediates airway epithelial E-cadherin disruption in toluene diisocyanate-induced asthma","authors":"Lin Fu ,&nbsp;Lichang Chen ,&nbsp;Xianru Peng ,&nbsp;Changyun Yang ,&nbsp;Jiamin Sun ,&nbsp;Zemin Chen ,&nbsp;Sudan Gan ,&nbsp;Shiyue Li ,&nbsp;Haixiong Tang ,&nbsp;Yidan Lin ,&nbsp;Lihong Yao","doi":"10.1016/j.taap.2025.117647","DOIUrl":"10.1016/j.taap.2025.117647","url":null,"abstract":"<div><div>E-cadherin is a critical adheren junctional protein for maintaining airway epithelial integrity. Downregulation of E-cadherin is commonly seen in asthma. Mammalian target of rapamycin (mTOR), a central regulator of metabolism, is implicated in asthma pathogenesis. This study was aimed to elucidate the role of mTOR signaling pathway on airway epithelial E-cadherin dysfunction in toluene diisocyanate (TDI)-induced asthma. Male BALB/c mice and in vitro cultured airway epithelial cell line BEAS-2B were exposed to TDI for modeling, and treated with rapamycin, an inhibitor of the mTOR signaling. We observed increased phosphorylation of mTOR and its downstream molecule p70s6k in TDI-exposed mice and cultured epithelia, indicating activation of mTOR signaling. In vivo, treatment with rapamycin dramatically alleviated TDI-induced airway hyperreactivity, decreased airway neutrophilia and eosinophilia, and suppressed the release of IL-4, IL-5 and IL-17 in the bronchoalveolar lavage fluid (BALF), suggesting a central role for mTOR in the development of TDI-induced asthma. Moreover, the TDI-induced downregulated E-cadherin expression in the lung was also significantly recovered by rapamycin, accompanied by less production of soluble E-cadherin (sE-cadherin), which is a marker of E-cadherin disruption and epithelial injury. Similar results were observed in cultured airway epithelial cells. Taken together, our data demonstrated that mTOR mediates airway epithelial E-cadherin disruption in TDI-induced asthma.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117647"},"PeriodicalIF":3.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557342","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":"Aucubin directly targets β-catenin to co-suppress Wnt and HIF-1 pathways in ovarian cancer: Computational and experimental validation","authors":"Zhijian Pan ,&nbsp;Han Wu ,&nbsp;Yancai Liu ,&nbsp;Haoyang Yu ,&nbsp;Jiayi Shu ,&nbsp;Changyan Yang ,&nbsp;Jianglong Wang ,&nbsp;Fengxia Du ,&nbsp;Min Shao ,&nbsp;Hefeng Zhou","doi":"10.1016/j.taap.2025.117645","DOIUrl":"10.1016/j.taap.2025.117645","url":null,"abstract":"<div><div>OV is a highly lethal malignancy plagued by chemoresistance, necessitating the development of novel therapeutic agents. The Wnt/β-catenin pathway, driven by its central component β-catenin (CTNNB1), is a key oncogenic axis in OV, making it an attractive therapeutic target. We employed an integrated strategy combining <em>in vitro</em> assays (MTT, Western blot), <em>in silico</em> analyses (network pharmacology, WGCNA, molecular docking, molecular dynamics simulations), and biophysical validation assays (CETSA, DARTS) to systematically investigate the anti-cancer mechanism of the natural compound AU. AU potently inhibited the viability of A2780 OV cells by inducing apoptosis. Our comprehensive bioinformatic analysis identified CTNNB1 as a high-confidence direct target of AU. Clinical data confirmed that CTNNB1 is overexpressed in OV and correlates with poor patient prognosis. Molecular docking and dynamics simulations predicted a stable AU-CTNNB1 interaction, which was then experimentally validated by both CETSA and DARTS, confirming direct target engagement in a cellular context. Mechanistically, AU treatment resulted in the dose-dependent suppression of key proteins in the Wnt/β-catenin and HIF-1 signaling pathways. AU exerts its anti-OV activity by directly binding to CTNNB1. This interaction inhibits the oncogenic Wnt/β-catenin pathway, leading to the concurrent suppression of the HIF-1 pathway and the induction of apoptosis. Our study provides a complete mechanistic rationale for the development of AU as a novel targeted therapy for ovarian cancer.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117645"},"PeriodicalIF":3.4,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534759","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":"Letter to the editor related to: Huang et al. Effect of parental perinatal exposure to L-glutamate monosodium salt monohydrate on developmental neurotoxicity in rat offspring","authors":"Ivonne M.C.M. Rietjens","doi":"10.1016/j.taap.2025.117633","DOIUrl":"10.1016/j.taap.2025.117633","url":null,"abstract":"<div><div>This is a letter to the Editor related to: Huang et al. Effect of parental perinatal exposure to L-Glutamate Monosodium Salt Monohydrate on developmental neurotoxicity in rat offspring published in 2025 in Toxicol. Appl. Pharmacol., 502; 117,450. The content provides an addition to the discussion on the safety evaluation of glutamates.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117633"},"PeriodicalIF":3.4,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534848","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":"Paeoniflorin attenuates ASA-induced enteropathy in simulated high-altitude hypoxia in rats by regulating intestinal inflammation, intestinal barrier, and intestinal flora","authors":"Ailifeire Tuerxuntayi ,&nbsp;Wenhui Shi ,&nbsp;Tian Shi ,&nbsp;Kudelaiti Abudukelimu ,&nbsp;Beiyao Gao ,&nbsp;Paziliya Abulaiti ,&nbsp;Kailibinuer Nuermaimaiti ,&nbsp;Najimangu Rehemutula ,&nbsp;Shenglong Xue ,&nbsp;Yingying Xing ,&nbsp;Weidong Liu ,&nbsp;Zhuoshuyi Liu ,&nbsp;Jiangwei Liu ,&nbsp;Feng Gao","doi":"10.1016/j.taap.2025.117641","DOIUrl":"10.1016/j.taap.2025.117641","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aimed to investigate whether high-altitude hypoxia exacerbates non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal injury and to evaluate the protective effects of Paeoniflorin (PF).</div></div><div><h3>Methods</h3><div>Male Sprague-Dawley rats were orally administered 300 mg/kg aspirin (ASA) to induce NSAID enteropathy, followed by 3 weeks of 5500 m high-altitude hypoxia exposure. Rats were divided into normoxic control (Con), hypoxic control (Hcon), hypoxic ASA model (HAsa), and PF treatment groups (25/50/100 mg/kg/day, LPF/MPF/HPF). The body weight changes, oxidative stress markers (MPO, SOD), inflammatory factors (IL-1β, TNF-α, IL-10), intestinal histology, tight junction proteins (ZO-1, Occludin), TLR4/NF-κB pathway activation, and gut microbiota composition (16S rRNA sequencing) were evaluated.</div></div><div><h3>Results</h3><div>The HAsa group exhibited the most severe intestinal damage, characterized by significant villus injury and inflammatory cell infiltration (<em>P</em> &lt; 0.05). Mechanistically, this damage was driven by TLR4/NF-κB pathway activation, accompanied by significantly increased pro-inflammatory cytokines (IL-1β, TNF-α) and decreased anti-inflammatory cytokine IL-10 (<em>P</em> &lt; 0.05). Oxidative stress was concurrently heightened, as evidenced by significantly elevated MPO levels and reduced SOD activity (<em>P</em> &lt; 0.05). Consequently, the expression of tight junction proteins (ZO-1, Occludin) was significantly downregulated (<em>P</em> &lt; 0.05), indicating compromised intestinal barrier function. Furthermore, 16S rRNA sequencing revealed gut microbiota dysbiosis, characterized by a decline in beneficial bacteria like <em>Lactobacillus</em> and <em>Bifidobacterium</em> and an expansion of harmful genera like <em>Romboutsia</em> and <em>Turicibacter</em> (<em>P</em> &lt; 0.05). PF intervention dose-dependently reversed these alterations by effectively suppressing the TLR4/NF-κB pathway (<em>P</em> &lt; 0.05), ameliorating inflammation and oxidative stress, and restoring mucosal barrier integrity. Concurrently, PF supplementation reshaped the gut microbiota, thereby normalizing the balance between beneficial and pathogenic bacteria (<em>P</em> &lt; 0.05).</div></div><div><h3>Conclusion</h3><div>High-altitude hypoxia synergistically exacerbates NSAID-induced intestinal injury. PF protects against this injury primarily via modulating the TLR4/NF-κB pathway, highlighting its therapeutic potential for high-altitude populations on NSAIDs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117641"},"PeriodicalIF":3.4,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534805","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}