Toxicology and applied pharmacology最新文献

{"title":"Integrated assessment of the effects of PFOA exposure on hepatic transcriptome and lipid profiles in mice expressing human PPARα","authors":"G. Nielsen ,&nbsp;E. Reed ,&nbsp;B. Lara ,&nbsp;D.H. Sherr ,&nbsp;W.J. Heiger-Bernays ,&nbsp;T. Hyötyläinen ,&nbsp;T.F. Webster ,&nbsp;J.J. Schlezinger","doi":"10.1016/j.taap.2025.117658","DOIUrl":"10.1016/j.taap.2025.117658","url":null,"abstract":"<div><div><em>Per</em>- and polyfluoroalkyl substances (PFAS) are a family of persistent chemicals that continue to be released pervasively into the environment, leading to widespread human exposure. Emerging epidemiological evidence shows adverse effects on liver lipids; however, past toxicological studies have been limited by a focus on peroxisome proliferator activated receptor α (PPARα) driven effects on triglycerides in rodent systems. Here, we use a more agonostic approach incorporating lipidomics and transcriptomics to test the hypothesis that activation of human PPARα by perfluorooctanoic acid (PFOA), disrupts liver lipid homeostasis, broadly, similar to that seen in human liver diseases. Female and male mice expressing human PPARα or that were PPARα null were fed a What We Eat In America diet and exposed to PFOA via drinking water for 6 weeks. Serum PFOA concentrations averaged 48 ± 9 μg/mL. PFOA changed the expression of ∼2000 hepatic genes with changes in expression of a larger number of genes in hPPARα versus PPARα null mice. In this occupational level PFOA exposure scenario, less than 60 % of transcriptional changes induced by PFOA depended on hPPARα expression. CAR was another major molecular initiating event, with other transcription factors pathways more likely to be modulated downstream of hPPARα activation. In hPPARα mice of both sexes, PFOA increased total liver lipids. In addition to triacylglycerides, lipid classes strongly altered by PFOA exposure predominantly belong to the phosphatidylcholine and sphingolipid classes. PFOA significantly decreased sphingomyelin abundance and increased ceramide abundance regardless of genotype, which coincided with an increase in expression of <em>SMase</em>, the enzyme that converts sphingomyelin to ceramide. These results highlight the ability of PFOA to modulate liver lipids beyond triacylglycerides in both an hPPARα-dependent and -independent manner.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117658"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145623892","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":"Integrated in silico and in vitro assessment of estrogen and androgen receptor activity of 10 selected PFAS within an Integrated Approach to Testing and Assessment (IATA)","authors":"Darlene Mae D. Ortiz ,&nbsp;Handule Lee ,&nbsp;Ngoc Minh-Hong Hoang ,&nbsp;Hyun Jun Lee ,&nbsp;Jinhee Choi ,&nbsp;Kwangsik Park","doi":"10.1016/j.taap.2025.117628","DOIUrl":"10.1016/j.taap.2025.117628","url":null,"abstract":"<div><div>The potential of <em>per</em>- and polyfluoroalkyl substances (PFAS) to disrupt endocrine systems continues to be a regulatory concern. However, effectively prioritizing these structurally diverse chemicals remains challenging due to inconsistencies in predictive and experimental data. In this study, we employed a multi-tiered evaluation strategy that combines <em>in silico</em> modeling, <em>in vitro</em> assays, and curated mechanistic data within the OECD's Integrated Approach to Testing and Assessment (IATA) framework. Molecular docking using AutoDock Vina, CB-Dock2, and Endocrine Disruptome consistently revealed strong binding affinities of long-chain PFAS, particularly PFDA, PFOA, and 10:2 FTOH, to estrogen and androgen receptors. These predictions were corroborated by ER and AR transactivation assays (OECD TG 455/458), which demonstrated ER agonist and AR antagonist activity for the same compounds. In contrast, short-chain and sulfonated PFAS (PFHxA, PFBS, PFOS) exhibited limited to no activity across platforms. To enhance the biological relevance of the prioritization, we compiled supporting mechanistic evidence by applying the IATA framework to organize data along the adverse outcome pathway from molecular initiating events, through key events, to predicted adverse outcomes. Literature-reported alterations in steroidogenic enzymes and hormone levels were included to enrich mechanistic depth. All lines of evidences were systematically integrated into a weight-of-evidence matrix, enabling a transparent and biologically plausible ranking of PFAS based on receptor interaction, functional activity, and endocrine-disruptive potential. This combined approach identified PFDA and PFOA as high-priority endocrine disruptors and offers a scalable, non-<em>in vivo</em> strategy for the screening and risk-based prioritization of environmentally persistent chemicals.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117628"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459870","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":"Mechanism of auranofin toxicity: Inhibition of tetrahydrobiopterin metabolism","authors":"Shaojun Yang ,&nbsp;Yi-Hua Jan ,&nbsp;Jason R. Richardson ,&nbsp;Diane E. Heck ,&nbsp;Jeffrey D. Laskin","doi":"10.1016/j.taap.2025.117615","DOIUrl":"10.1016/j.taap.2025.117615","url":null,"abstract":"<div><div>Auranofin is a gold-containing anti-inflammatory drug used for the treatment of rheumatoid arthritis. Recent studies indicate that auranofin targets cellular antioxidants including the thioredoxin system and the ubiquitin–proteasome system, which can result in cellular oxidative stress. In the present studies, we identified a novel mechanistic site of action of auranofin, namely tetrahydrobiopterin (BH4) biosynthesis. BH4 is an essential cofactor required for aromatic amino acid hydroxylases, nitric oxide synthase and alkylglycerol monooxygenase, enzymes that produce mediators important in regulating inflammation. It is synthesized <em>de novo</em> from GTP via the action of GTP cyclohydrolase I, 6-pyruvoyl-tetrahydrobiopterin synthase and sepiapterin reductase (SPR), which leads to the production of dihydrobiopterin (BH2). Further metabolism of BH2 to BH4 is mediated by dihydrofolate reductase (DHFR). We discovered that auranofin causes a rapid depletion of cellular BH4 in several different cell types; PC12 cells were most sensitive to auranofin followed by Jurkat cells, BeWo cells, HaCaT cells, SKNMC cells, RAW246.7 cells and CX-1 cells. This was due to the inhibition of both SPR and DHFR. BH4 is required for tyrosine hydroxylase and tryptophan hydroxylase, enzymes mediating the synthesis of dopamine and serotonin, respectively. In PC12 cells, blocking BH4 biosynthesis with auranofin correlated directly with inhibition of serotonin and dopamine production indicating that the drug targeted aromatic amino acid hydroxylase activity. Our findings provide novel insights into the metabolic consequences of treating inflammatory diseases or cancer cell growth and metastasis with auranofin.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117615"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145419437","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":"2026-01-01","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":"Comparative assessment of female reproductive toxicity from PFOA and its alternative GenX in mice and human granulosa cells","authors":"Yangyang Yuan ,&nbsp;Binhui Wang ,&nbsp;Yuyu Fan ,&nbsp;Meiling Le ,&nbsp;Lihai Wu ,&nbsp;Shiyi Deng ,&nbsp;Jian Huang ,&nbsp;Dalei Zhang","doi":"10.1016/j.taap.2025.117639","DOIUrl":"10.1016/j.taap.2025.117639","url":null,"abstract":"<div><div>Perfluorooctanoic acid (PFOA) is a legacy perfluoroalkyl substance (PFAS) with various detrimental health effects, prompting its replacement by hexafluoropropylene oxide dimer acid (GenX). However, the female reproductive toxicity and underlying mechanism of GenX remain inadequately understood. In this study, we comparatively evaluated the impacts of PFOA and GenX on ovarian function using integrated <em>in vivo</em> mouse and <em>in vitro</em> human granulosa cell models. Our experimental findings indicated that oral exposure to PFOA significantly reduced ovarian weight, impaired follicular development, disrupted estrous cyclicity, decreased estradiol level, and induced ovarian oxidative stress and apoptosis in mice. However, GenX did not display significant toxic effects on the ovaries at the doses tested, except for reducing ovarian GPX4 expression and serum estradiol level. Notably, both PFOA and GenX at high-concentration treatment <em>in vitro</em> dramatically impaired the viability and proliferation, elicited ROS overproduction and mitochondrial injury, and suppressed NRF2 and HO-1 expression in cultured KGN cells. Nevertheless, at equivalent exposure doses, GenX elicited markedly decreased adverse influences on KGN cells compared to PFOA. Molecular docking simulation indicated a stronger interaction of PFOA with NRF2 than GenX. In addition, treatment with PFOA also diminished estradiol secretion and induced apoptosis in KGN cells. In summary, PFOA exposure resulted in female reproductive impairment by inducing oxidative stress and apoptosis in mouse ovaries and human granulosa cells. Although GenX exhibited comparatively low ovarian detriment relative to PFOA, its potential risk of reproductive toxicity remains a nonnegligible concern.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117639"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145514063","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":"Leonurine alleviates retinal ischemia-reperfusion injury by inhibiting microglia activation","authors":"Jingchang Yuan ,&nbsp;Miao Wei ,&nbsp;Xiaochen Wang,&nbsp;Sisi Tan,&nbsp;Yujia Huo,&nbsp;Ruotong Ouyang,&nbsp;Xiao Fan,&nbsp;Hong Li","doi":"10.1016/j.taap.2025.117616","DOIUrl":"10.1016/j.taap.2025.117616","url":null,"abstract":"<div><div>Retinal ischemia-reperfusion (RIR) injury is a critical pathological process in glaucoma. However, the effective treatments on glaucoma induced by RIR injury are limited. This study investigated the protective effects of Leonurine (Leo) against RIR injury in rats and explored its role in modulating microglial activation. The rat RIR model was established, and Leo was administered via intraperitoneal injection. Structural and cellular changes were assessed using H&amp;E staining, optical coherence tomography (OCT), and immunofluorescence, which revealed that Leo alleviated retinal thinning and reduced retinal ganglion cell (RGC) loss. Additionally, Leo suppressed microglial activation and downregulated the expression of inflammatory cytokines. In oxygen-glucose deprivation/reperfusion (OGD/R)-treated HMC3 microglial cells, Leo inhibited M1 polarization and changed microglial migratory and proliferative capacities, as shown by cell viability, wound healing, and EdU assays. Transcriptome sequencing and Western blot analysis further indicated that Leo downregulated key proteins in the TGF-β2/Smad2/3 and MAPK signaling pathways. Leo reduces RIR-induced inflammation, oxidative stress, and RGC loss by inhibiting microglial M1 polarization via the TGF-β2/Smad and MAPK signaling pathways. These findings demonstrate that Leo alleviated RIR injury by inhibiting microglial M1 polarization via the TGF-β2/Smad and MAPK pathways, suggesting its potential as a therapeutic agent for ischemic retinal diseases.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117616"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145419438","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":"Shared and divergent neurotoxic mechanisms of Bisphenol A and Di(2-ethylhexyl) phthalate with implication for Alzheimer's disease: Insights from network toxicology and in vitro validation","authors":"Qiwei Zhang,&nbsp;Siqi Long,&nbsp;Na Zhang,&nbsp;Guohui Sun,&nbsp;Lijiao Zhao,&nbsp;Rugang Zhong","doi":"10.1016/j.taap.2025.117637","DOIUrl":"10.1016/j.taap.2025.117637","url":null,"abstract":"<div><div>Bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP) are widely recognized environmental neurotoxicants implicated in Alzheimer's disease (AD). However, the shared and divergent mechanisms by which BPA and DEHP induce neurotoxicity in AD remain largely unexplored. In this study, we conducted the first systematic comparative analysis of overlapping and distinct neurotoxic pathways of BPA and DEHP by integrating network toxicology and in vitro experimental validation. Five shared core targets (MMP9, PPARG, MAPK14, BCL2, and BCL2L1) were identified from multiple databases. Experimental validation confirmed that BPA and DEHP significantly upregulated MMP9, PPARG, and phosphorylated MAPK14, while downregulating BCL2 and BCL2L1 at both transcriptional and protein levels. KEGG pathway enrichment revealed both shared and divergent pathways, with the lipid and atherosclerosis pathway emerging as a common AD-relevant pathway, whereas BPA and DEHP showed compound-specific involvement in PI3K-Akt, MAPK, and other signaling cascades. Molecular docking analysis further demonstrated favorable binding of both BPA and DEHP to the shared core targets. Collectively, this study provides novel mechanistic insights into both overlapping and distinct neurotoxic effects of BPA and DEHP in AD, offering a theoretical basis for future mechanistic research and environmental risk assessment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117637"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145514137","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":"Polystyrene nanoplastics and lung cancer: Insights from network toxicology and mechanistic in vitro studies","authors":"Thai-Khuong Le ,&nbsp;Chia-Hung Kuo ,&nbsp;Chih-Chung Wu ,&nbsp;Ya-Ting Chen ,&nbsp;Shu-Ling Hsieh","doi":"10.1016/j.taap.2025.117618","DOIUrl":"10.1016/j.taap.2025.117618","url":null,"abstract":"<div><div>The correlation between exposure to polystyrene nanoplastics (PNs), an emerging environmental pollutant, and cancer processes has attracted heightened attention. However, the potential effects of PNs exposure on the processes of lung cancer have been yet inadequately comprehended. Our current study investigated the effects and mechanisms of PNs on lung cancer based on network toxicity analysis and in vitro tests. The integrated network toxicology analysis identified 189 possible targets of PNs-induced lung cancer, primarily associated with oxidative stress, apoptosis, inflammation, mitochondrial outer membranes, and cancer pathways. The 10 primary targets extracted from protein-protein interaction (PPI) analysis exhibited strong binding affinities with PNs (−8.7 to −5.2 kcal/mol) via molecular docking. The A549 human lung adenocarcinoma cells exhibited cytotoxicity after exposure to PNs via cell morphology analysis, MTT assay, and LDH assay. Additionally, treatment with PNs in A549 cells induced cell death, diminished mitochondrial membrane potential, elevated ROS and MDA levels, activated the cellular antioxidant defense system by enhancing SOD and GST activity, excited the release of IL-6, IL-1β, and TNF-α, and captured the cell cycle in the G0/G1 phase. This study suggests that PNs not only elicit cytotoxicity but also contribute to lung cancer progression, providing critical insights into the potential carcinogenic hazards linked to PNs and underscoring the pressing necessity for regulatory oversight of PNs exposure to protect public health and environmental risks associated with nanoplastics pollution.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117618"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145402071","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":"CDKN3 promoted triple-negative breast cancer by inhibiting ferroptosis through the upregulation of HSP90","authors":"Qiqi Zhao ,&nbsp;Yufang Wang","doi":"10.1016/j.taap.2025.117629","DOIUrl":"10.1016/j.taap.2025.117629","url":null,"abstract":"<div><h3>Purpose</h3><div>The study aimed to investigate CDKN3 as a potential target for triple negative breast cancer (TNBC) and its mechanism in this type of cancer.</div></div><div><h3>Methods</h3><div>After lentiviral transfection, various assays, including CCK8, clonogenic assay, flow cytometry, transwell, and scratch tests were conducted. Additionally, we examined CDKN3's impact on iron-induced cell death through various cellular markers and iron-related proteins. To assess CDKN3's impact on ferroptosis, we utilized the ferroptosis inhibitor Ferrostatin-1 and activator Erastin. To examine CDKN3's involvement in iron-induced cell death in TNBC, we repeated the previous experiment after introducing an HSP90 inhibitor. A 4T1 mammary fat pad graft tumor model was also conducted to validate the results of our in vitro cellular experiments.</div></div><div><h3>Results</h3><div><em>In vitro</em> experiments demonstrated that overexpression of CDKN3 promoted the growth, invasion, and migration of breast cancer cells. It also facilitated cell cycle progression from G0/G1 phase to S phase and suppressed apoptosis in TNBC cells. The knockdown of CDKN3 was the exact opposite. Overexpression of CDKN3 increased HSP90 expression, while CDKN3 knockdown decreased HSP90 expression. The impact of CDKN3 on the proliferation, migration, invasion, and ferroptosis of TNBC cells was associated with HSP90. The <em>in vivo</em> and <em>in vitro</em> experimental results were consistent, showing that CDKN3 overexpression promoted tumor growth and inhibited ferroptosis.</div></div><div><h3>Conclusion</h3><div>CDKN3 was an oncogene whose overexpression promoted the initiation and progression of TNBC by inhibiting HSP90-mediated ferroptosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117629"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482991","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":"High-density lipoprotein cholesterol protects against delayed encephalopathy after acute carbon monoxide poisoning","authors":"Yuhang Mu ,&nbsp;Nan Gao ,&nbsp;Yutao Wang ,&nbsp;Shaokun Wang ,&nbsp;Li Pang","doi":"10.1016/j.taap.2025.117663","DOIUrl":"10.1016/j.taap.2025.117663","url":null,"abstract":"<div><div>High-density lipoprotein cholesterol (HDL-C) plays a crucial role in neurological disorders. In this study, we aimed to elucidate the role of HDL-C in delayed encephalopathy after acute carbon monoxide poisoning (DEACMP), which presents with both neurological and psychiatric symptoms. Two-sample Mendelian randomization was employed on 201 lipid summary statistics to investigate potential causality. Data from the FinnGen database of 306,787 individuals were used. Mendelian randomization analysis results were screened using Bayesian model averaging. The results were validated in a multicenter cohort of 1368 patients, and the role of the antioxidant properties of high-density lipoprotein in DEACMP was examined. Mendelian randomization analysis identified six high-density lipoprotein-related variants significantly associated with DEACMP, with the cholesterol to total lipids ratio in medium high-density lipoprotein showing the strongest effect (marginal inclusion probability = 0.51, <em>p</em> = 1.00 × 10⁻³, false discovery rate = 6.00 × 10⁻³). Clinical validation confirmed HDL-C as an independent protective factor. Patients without DEACMP had higher high-density lipoprotein oxidant index values (1.23 [interquartile range: 1.02–1.36]) than those who developed DEACMP (0.84 [interquartile range: 0.66–0.90]); the high-density lipoprotein oxidant index declined significantly in postmenopausal women (<em>p</em> = 0.023). These findings demonstrate that HDL-C mitigates the risk of DEACMP through its antioxidant capacity. The integration of genetic evidence, clinical validation, and functional assays provides robust support for HDL-C as a predictive biomarker of neural recovery after carbon monoxide poisoning.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"506 ","pages":"Article 117663"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145639885","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}