Bettinsoli V, Erlacher M, Galbiati V
… +3 more, Marinovich M, Corsini E, Wilflingseder D
Arch Toxicol
· 2026 Jul · PMID 41984094
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RNA therapeutics hold strong potential for treating genetic disease, yet progress is often limited by delivery, stability, and safety concerns. Here, we profile respiratory safety and cellular uptake of an inhaled siRNA...RNA therapeutics hold strong potential for treating genetic disease, yet progress is often limited by delivery, stability, and safety concerns. Here, we profile respiratory safety and cellular uptake of an inhaled siRNA targeting the cardiac RyR2 gene, which is responsible for catecholaminergic polymorphic ventricular tachycardia (CPVT), delivered via inhalation with calcium phosphate nanoparticles (CaP NPs). Barrier integrity, cytotoxicity, siRNA uptake, and immune activation, were assessed using a human 3D normal bronchial epithelial model (NHBE) under Air-Liquid Interphase (ALI) and dendritic cells (DCs), tested in monoculture and in co-culture. Barrier function, measured by transepithelial electrical resistance (TEER), remained stable after 48 h of exposure to 400 nM siRNA RyR2, scramble control, or CaP NPs, indicating preserved epithelial performance. Confocal imaging showed efficient internalization of Cy5-labeled siRNA in both mono- and co-cultures. Cytokine profiling revealed IL-8 release across all conditions in NHBE and NHBE + DC models, with IL-6 and TNF-α limited to immune-competent co-cultures; IFN-γ was below the limit of detection. No cytotoxicity was observed. Together, these data demonstrate that CaP NP-mediated delivery achieves robust siRNA uptake without compromising airway barrier integrity, while eliciting only modest, context-dependent immune responses (primarily IL-8 and TNF-α in the presence of DCs). This work supports the respiratory safety and translational potential of inhaled RyR2-targeting siRNA for CPVT.
The development of new approach methodologies (NAMs) is increasingly enabling the replacement and reduction of animal use in research, complementing the ethical framework provided by the 3Rs (replacement, refinement, and...The development of new approach methodologies (NAMs) is increasingly enabling the replacement and reduction of animal use in research, complementing the ethical framework provided by the 3Rs (replacement, refinement, and reduction) of animal research. The European Commission has supported these approaches by embedding 3R requirements in policy frameworks and providing dedicated funding for 3Rs/NAMs-related research. However, a systematic and comprehensive overview on European Union (EU) research funding of these projects is lacking. In this study, projects funded under Framework Programme 7 (2007-2013), Horizon 2020 (2014-2020) and Horizon Europe (2021-2027, extracted until March 2025) were analysed using the EU Community Research and Development Information Service database (CORDIS). A 2-tiered artificial intelligence-based data retrieval approach was applied, combining supervised text classification and semantic search followed by expert review, yielding a total of 539 relevant projects. Approximately 40% of these projects were toxicology-related, while the remainder pertained to areas such as disease research or technology scaling. Across the portfolio, oncology and neuroscience emerged as major application areas, with a strong representation of in vitro methodologies, including 3D cell culture methods and engineered models such as organs-on-chip, alongside in silico technologies. In terms of country participation and collaboration, Western European countries occupied central positions in obtaining funding and leading research efforts in this field. Overall, these findings demonstrate that EU framework programmes have provided substantial and sustained support for 3Rs/NAMs research and innovation, while also highlighting thematic and geographic imbalances that can inform future research and policy initiatives.
Chlorfenapyr (CFP) is a halogenated pyrrole insecticide that requires metabolic activation to exert toxicity and has been associated with severe poisoning in humans. However, the metabolic pathways underlying CFP bioacti...Chlorfenapyr (CFP) is a halogenated pyrrole insecticide that requires metabolic activation to exert toxicity and has been associated with severe poisoning in humans. However, the metabolic pathways underlying CFP bioactivation and detoxification in humans remain poorly defined. In this study, we systematically investigated the metabolic fate of CFP and its toxic metabolite tralopyril (TLP) using in vitro human drug-metabolizing enzyme systems. Screening of ten human cytochrome P450 (CYP) isoforms at 5 and 50 µM CFP indicated that CYP2B6 is the major contributor to CFP bioactivation, which was further supported by selective inhibition and correlation analyses. CFP metabolism by CYP2B6 followed Michaelis-Menten kinetics, with showing a K of 1.80 ± 0.57 μM, a V of 0.24 ± 0.02 pmol/min/pmol P450, and an CL of 139.78 ± 33.70 nL/min/pmol P450. In addition, incubations using 50 or 100 µM TLP and varying concentrations of glutathione (0.1 to 1 mM GSH) showed the formation of a novel GSH conjugate of TLP (TLP-GSH), of which level was markedly enhanced by human glutathione S-transferases (GSTs). Among six recombinant human GST isoforms tested, GSTA1, GSTA2, GSTM1, and GSTP1 showed significant catalytic activity in TLP-GSH formation compared with non-enzymatic reactions. Moreover, extracellular flux analysis revealed that TLP dose-dependently inhibited basal and maximal oxygen consumption rates, an effect exacerbated by GST inhibition, indicating a protective role of GSTs in TLP-induced mitochondrial toxicity. Together, these findings delineated metabolic enzymes-mediated bioactivation and detoxification pathways governing CFP toxicity in humans and provided a new perspective on clinical management strategies for CFP poisoning.
Batke M, Damm G, Foth H
… +11 more, Freyberger A, Hengstler JG, Mangerich A, Mielke H, Partosch F, Schupp T, Sonnenburg A, Vom Brocke J, Wollin KM, Algharably EA, Gundert-Remy U
Arch Toxicol
· 2026 Jul · PMID 41984091
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Toxicological animal studies are essential to risk assessment. The reliability of the studies depends on the extent to which study design, conduct, and analysis have a high internal validity. Several tools exist for asse...Toxicological animal studies are essential to risk assessment. The reliability of the studies depends on the extent to which study design, conduct, and analysis have a high internal validity. Several tools exist for assessing the internal validity of human and animal studies, however, a dedicated tool for animal toxicokinetic studies is lacking. We developed a questionnaire to systematically assess toxicokinetic animal studies. The questionnaire consists of seven main domains with questions for which points are given by the assessor multiplied by fixed weighting factors (WF). The scores are then aggregated at both the domain and overall levels and expressed as a percentage of the maximum score. We established four confidence tiers based on the percentage of the achieved score. Experts were able to discriminate studies based on internal validity (overall assessment rating between 37.6% and 86.9%, n = 7 studies). The questionnaire was also a helpful tool for less experienced scientists (master students, postgraduates) helping them to assess the internal validity in a systematic way. By implementing a WF into the calculation and performing the assessment at the domain level, both innovative steps in the assessment process, the transparency of the assessment is increased. In a limited exploratory study, we found that Large Language Models (AI) were able to complete the questionnaire, however, failing to discriminate studies' quality. This newly developed questionnaire provides a transparent, granular, and effective framework for assessing the internal validity of animal toxicokinetic studies, offering reliable discrimination across quality tiers for both experienced and toxicologists in training.
The management of N-nitrosamine impurities challenges pharmaceutical development and regulation worldwide. Because most medicinal exposures are shorter than lifetime and absolute impurity exclusion is impossible, reliabl...The management of N-nitrosamine impurities challenges pharmaceutical development and regulation worldwide. Because most medicinal exposures are shorter than lifetime and absolute impurity exclusion is impossible, reliable approaches to define duration-specific intake limits are essential. On the premise that carcinogenic risk is proportional to cumulative dose, the 'Less-Than-Lifetime' (LTL) Threshold of Toxicological Concern (TTC) framework defines progressively lower intake limits for mutagenic impurities over longer exposures. However, N-nitrosamines are currently treated as a 'cohort of concern', necessitating compound-specific evaluation placing reliance on in vivo mutagenicity assays for impurity qualifications. To better understand durational potency relationships and the application domain of the LTL-TTC, we applied benchmark dose (BMD) modelling to cumulative-dose-scaled transgenic rodent (TGR), error-corrected sequencing and rodent carcinogenicity datasets for N-nitrosodimethylamine (NDMA) obtained from the published literature. For TGR, cumulative-dose scaling better resolved liver as the most sensitive organ and reduced interstudy variability: liver BMDs spanned ~ 80-fold in daily-dose units but only ~ 20-fold when scaled to cumulative dose. Among closely-matched mouse liver gavage studies, cumulative-dose BMDs only varied by ~ 2.5-fold across 1 to 28-day treatment regimens. Error-corrected sequencing also demonstrated parity, with acute-dose regimens producing mutation burdens near-identical (< 1.2-fold) to those cumulated from 28-day repeat-dose regimens. Comparable results were obtained from carcinogenicity datasets confirming proportionality-of-effect to cumulative dose. These findings empirically support the validity of the LTL-TTC concept. More broadly, they demonstrate that short-term in vivo mutagenicity assays can serve as reliable surrogates for lifetime carcinogenicity studies, strengthening the scientific and regulatory basis for duration-adjusted acceptable intakes for N-nitrosamine impurities.
Per- and polyfluoroalkyl substances (PFASs) are pervasive in airborne particles and aerosols, making inhalation a critical exposure pathway; however, the lack of inhalation toxicity data hinders accurate risk assessment...Per- and polyfluoroalkyl substances (PFASs) are pervasive in airborne particles and aerosols, making inhalation a critical exposure pathway; however, the lack of inhalation toxicity data hinders accurate risk assessment and public health protection. In this study, we developed quantitative structure-activity relationship (QSAR) and quantitative read-across structure-activity relationship (q-RASAR) models to predict the acute inhalation toxicity of PFASs. The models were constructed using mechanistically interpretable two-dimensional molecular descriptors, and the integration of similarity-based descriptors enhanced predictive performance while maintaining model simplicity and interpretability. All validated models were applied to untested PFASs for toxicity prediction and priority ranking. In addition, interspecies toxicity (iST) models were established to explore toxicity relationships between rats and mice, enabling cross-species extrapolation. Collectively, these QSAR, q-RASAR, and iST models address the critical data gap in PFAS inhalation toxicology, providing a rapid and reliable tool for regulators and researchers to support science-driven risk assessment and public health protection against airborne PFAS exposure.
Guidarelli A, Spina A, Buffi G
… +2 more, Fiorani M, Cantoni O
Arch Toxicol
· 2026 Jul · PMID 41975125
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Clinically relevant concentrations of arsenic trioxide (ATO) induce apoptosis in NB4 cells through a complex, yet poorly defined interplay between endoplasmic reticulum-derived Ca signalling and mitochondrial oxidative s...Clinically relevant concentrations of arsenic trioxide (ATO) induce apoptosis in NB4 cells through a complex, yet poorly defined interplay between endoplasmic reticulum-derived Ca signalling and mitochondrial oxidative stress. This study enhances our understanding of these mechanisms by demonstrating that exposure to 1 µM ATO initiates a biphasic Ca release: an initial flux from inositol 1,4,5-trisphosphate receptors (IP₃Rs), followed by a secondary release via ryanodine receptors (RyRs). Unlike IPR-derived Ca, the fraction of the cation released through RyRs is subsequently taken up by mitochondria. Notably, IPR-derived Ca uniquely activates NADPH oxidase 2 (NOX 2), a key event leading to the downstream generation of mitochondrial superoxide (mitoO). Importantly, mitochondrial Ca accumulation itself is not required for mitoO emission. ATO-induced genomic DNA strand breaks are mediated by NOX 2-derived reactive oxygen species (ROS), both directly and indirectly, through the subsequent induction of mitochondrial ROS formation. Furthermore, mitochondrial uptake of RyR-derived Ca is essential for triggering the mitochondrial permeability transition and the ensuing apoptotic cell death. Although sodium arsenite elicited comparable effects on Ca homeostasis, it promoted mitoO generation via a distinct, NOX 2-independent pathway that relied on RyR-mediated mitochondrial Ca accumulation. Thus, in NB4 cells, ATO exposure orchestrates a functional crosstalk between discrete Ca sources to regulate a cascade of events culminating in NOX 2 activation, mitoO production, and initiation of the mitochondrial apoptotic pathway.
Arch Toxicol
· 2026 Jul · PMID 41915199
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Mycotoxins are secondary fungal metabolites which have toxic effects on other organisms. The trichothecenes mycotoxins deoxynivalenol (DON) and T2/HT2 are secreted by Fusarium species and are found across the globe. They...Mycotoxins are secondary fungal metabolites which have toxic effects on other organisms. The trichothecenes mycotoxins deoxynivalenol (DON) and T2/HT2 are secreted by Fusarium species and are found across the globe. They are under surveillance in many jurisdictions. The main toxic effect of DON and T2/HT2 is the inhibition of protein translation by toxin binding to the peptidyl transfer centre of the large ribosomal subunit. We have characterised the effects of DON and HT2 (at IC75) on the transcriptome of the lung fibroblast cell line V79 over a time course of 15, 30, 60, 90, 120, 180 min and 24 h. The data demonstrate that the gene expression changes found at 24 h post exposure are different to those found at earlier time points. The immediate, albeit transient, effect of DON and HT2 exposure is the activation of the p38-Fos/Jun MAP kinase stress signalling pathway. This rapid response also entails a substantial activation of histone genes; a response typically associated with cell cycle entry. The activation of the p38-Fos/Jun stress pathway peaks at 90 min post exposure in response to DON and at 120 min post exposure for HT2. Gene expression changes triggered by DON exposure during the first 60 min significantly overlap with those elicited by other chemicals. In contrast, longer term exposure to DON elicits transcriptome responses which are specific to treatment with inhibitors of translation.
Synthetic cathinones are increasingly popular new psychoactive substances (NPS), with new structures often designed to evade legal restrictions. Besides presenting challenges for drug policy, this also results in a poor...Synthetic cathinones are increasingly popular new psychoactive substances (NPS), with new structures often designed to evade legal restrictions. Besides presenting challenges for drug policy, this also results in a poor understanding of these compounds’ pharmacological effects, particularly concerning their interaction with monoamine transporters such as the serotonin transporter (SERT). Therefore, we optimized a previously developed SERT bioassay based on the TRACT (transporter activity through receptor activation) principle by developing a new human embryonic kidney (HEK) 293T cell line stably expressing SERT (HEK293T-SERT). The use of this cell line was evaluated in the TRACT protocol to determine uptake inhibition and SERT-mediated serotonin (5-HT) release. SERT effects are measured by means of a modified serotonin 2 A receptor (5-HT2AR), using functional complementation of a split-nanoluciferase. 5-HT2AR activation depends on extracellular serotonin levels, which are elevated either through inhibited or reversed 5-HT transport. The TRACT assay format for SERT inhibition with the new HEK293T-SERT cell line outperformed the transient transfection protocol. In addition, the use of the HEK293T-SERT cells in a fluorescence-based functional assay resulted in an identical ranking of the SERT inhibition activities of a set of eleven diversely substituted cathinones in both TRACT and fluorescence assays. These compounds carried key substitutions, including N-alkylation/arylation, ring substitution and α-alkylation. Furthermore, the TRACT assay format was suited to distinguish between SERT blockers and releasers, and allowed functional characterization. Overall, the dual functionality of the optimized TRACT assay provides a versatile tool for characterizing SERT-modulating NPS, with potential applications in therapeutic drug development.
Sündermann J, Reamon-Buettner SM, Wilde S
… +2 more, Bitsch A, Ziemann C
Arch Toxicol
· 2026 Jun · PMID 41915196
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β-Nitrostyrene, an important intermediate in chemical industry, shows relevant anti-proliferative and pro-apoptotic potential and has thus been suggested for potential use in tumor chemotherapy. If not derivatized, β-nit...β-Nitrostyrene, an important intermediate in chemical industry, shows relevant anti-proliferative and pro-apoptotic potential and has thus been suggested for potential use in tumor chemotherapy. If not derivatized, β-nitrostyrene is however, highly reactive and possess (geno)toxic potential. To decipher structural elements relevant for biological activity, crucial for both, chemical risk assessment and potential drug development, a panel of nine structural derivatives of β-nitrostyrene, was put together. It included structures with and without nitrovinyl moiety and was based on fingerprint similarity, QSAR-based mutagenicity alerts, and literature reports. It comprised simple structures like styrene and more complex structures such as 2-methoxy-5-[(E)-2-nitroethenyl]phenol. In vitro experiments in human WS1 and mouse L5178/TK cells demonstrated that the nitrovinyl moiety of β-nitrostyrene seems vital for its cytotoxic (membrane damage, metabolic competence) and genotoxic (clastogenicity, mutagenicity) properties. The extent of adversity varied with modification of structural elements. For example 1-nitro-2-[(E)-2-nitroethenyl]benzene led to 2.3-fold higher mean tail intensities in the alkaline comet assay than β-nitrostyrene. Notably, all derivatives with a nitrovinyl moiety, except 5-[(E)-2-nitroethenyl]-1,3-benzodioxole, induced DNA double-strand breaks, as judged by γH2A.X induction. In conclusion, our study identified structural elements responsible for the cyto- and genotoxic potential of β-nitrostyrene, demonstrating that minor structural changes can significantly alter its adverse biological activity.
Amaral Bueno Azevedo C, Miniskiskosky G, Guimarães Del Amo MV
… +4 more, Povala Theisen V, Cavichiolo Franco CR, Stafim da Cunha R, Marques Stinghen AE
Arch Toxicol
· 2026 Jul · PMID 41915194
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Endothelial dysfunction induced by the accumulation of uremic toxins is a key contributor to cardiovascular disease (CVD) in patients with chronic kidney disease (CKD), as increased endothelial permeability represents an...Endothelial dysfunction induced by the accumulation of uremic toxins is a key contributor to cardiovascular disease (CVD) in patients with chronic kidney disease (CKD), as increased endothelial permeability represents an early and critical event in vascular injury and disease progression. This study evaluated the effects of trimethylamine N-oxide (TMAO), a low-molecular-weight uremic toxin, on endothelial junction integrity. Endothelial cells (EA.hy 926) were treated with TMAO at normal (2.83 mg/L) and uremic (7.49 mg/L) concentrations for 24 h. Cell viability was assessed using the MTT assay. VE-cadherin expression and phosphorylation were analyzed by western blotting and confirmed by confocal immunofluorescence. Endothelial permeability was determined by FITC-dextran passage across transwell inserts, and cell adhesion to extracellular matrix proteins was evaluated using fibronectin-coated plates. Our results demonstrate that TMAO reduced cell viability and disrupted endothelial cell-cell junctions by decreasing VE-cadherin protein levels and increasing its phosphorylation at tyrosine 658, resulting in increased endothelial permeability. TMAO also reduced endothelial adhesion to fibronectin, a key extracellular matrix protein. Notably, TMAO did not alter the expression of VE-cadherin-associated proteins, including p120-catenin and β-catenin. These findings provide mechanistic insight into the direct toxic effects of TMAO on endothelial barrier function and identify endothelial junctions as potential therapeutic targets to mitigate cardiovascular risk in CKD.
Gounder S, Mhlongo N, Ghazi T
… +1 more, Chuturgoon A
Arch Toxicol
· 2026 Jun · PMID 41915193
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The increasing prevalence of mycotoxin toxicity poses significant health risks, contributing to various diseases. Among these, fumonisin B1 (FB) alters sphingolipid biosynthesis, induces oxidative stress, apoptosis, mito...The increasing prevalence of mycotoxin toxicity poses significant health risks, contributing to various diseases. Among these, fumonisin B1 (FB) alters sphingolipid biosynthesis, induces oxidative stress, apoptosis, mitochondrial dysfunction, and inflammation. This study investigated the impact of acute FB exposure on inflammation and epigenetics changes in hearts of C57BL/6 mice. Molecular docking was performed to identify potential interactions between FB and key inflammatory proteins (TNF-α, iNOS, NF-κB p65, and NF-κB p50). Excised C57BL/6 mice heart tissue was analysed for gene expression (qPCR), protein expression (Western blotting), nitric oxide levels (NOS assay), cytokine levels (ELISA), and global DNA methylation (ELISA). Molecular docking suggested FB interacted with key residues in TNF-α, iNOS, and NF-κB, potentially influencing their activity. Gene expression analysis (TNF-α, NF-κB, IL-6, NLRP3 Inflammasome, IL-18, caspase 1, IL-1β, GSDMD, caspase 3, CT-1, IL-10, MBD2, DNMT1, DNMT3A, and DNMT3B) revealed that FB significantly dysregulated inflammatory cytokines and DNA methylation-related genes. Protein expression analysis showed significant upregulation of pro-inflammatory cytokines (TNF-α, NF-κB, IL-6, IL-1β, IL-18, IL-10, and TGF-β1). Global DNA methylation levels were significantly increased, with notable upregulation of DNMT1. In conclusion, acute exposure of C57BL/6 mice to FB significantly impacted inflammatory and DNA methylation pathways, leading to cardiac distress complications.
Edizcan Z, Schaller S, Kuepfer L
… +1 more, Geci R
Arch Toxicol
· 2026 Jun · PMID 41915192
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High-throughput physiologically based kinetic (HT-PBK) modelling provides a mechanistic framework for predicting systemic pharmacokinetics (PK) from in vitro and in silico data, supporting non-animal chemical safety asse...High-throughput physiologically based kinetic (HT-PBK) modelling provides a mechanistic framework for predicting systemic pharmacokinetics (PK) from in vitro and in silico data, supporting non-animal chemical safety assessment within next generation risk assessment (NGRA). Here, we applied HT-PBK modelling to dermal exposure, a key route of human contact with chemicals. Using the skin permeation model of the Open Systems Pharmacology Suite, we simulated systemic PK profiles of 52 compounds based solely on physicochemical properties predicted by quantitative structure-activity relationship (QSAR) models and without any compound-specific in vitro measurements. We systematically compared different QSAR tools for lipophilicity, solubility, and other parameters to identify optimal model parameterisation strategies. Across all compounds, the best-performing HT-PBK strategy predicted 73% of compounds' Cmax and 75% of AUC values within a tenfold range of observed human plasma data extracted from published clinical studies. A systematic tendency toward overprediction of systemic PK was observed, likely due to missing study metadata and the default assumption of fully hydrated skin. Prediction errors were larger for dermal than for oral exposure, reflecting the greater complexity and variability of dermal absorption processes. Nevertheless, key exposure metrics were reproduced within acceptable limits. These results demonstrate the feasibility of fully in silico, non-animal HT-PBK modelling for dermal absorption and support its use as a pragmatic tool for exposure-driven safety assessment within NGRA frameworks.
Alker W, Tsiros P, Sarimveis H
… +2 more, Braeuning A, Buhrke T
Arch Toxicol
· 2026 May · PMID 41915190
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Per- and polyfluoroalkyl substances (PFAS) are a large family of persistent environmental contaminants. Some PFAS are known to bioaccumulate, are frequently detected in human serum, and are associated with several advers...Per- and polyfluoroalkyl substances (PFAS) are a large family of persistent environmental contaminants. Some PFAS are known to bioaccumulate, are frequently detected in human serum, and are associated with several adverse effects on the immune system, the endocrine system, and the liver. PFAS-mediated activation of the peroxisome proliferator-activated receptor alpha (PPARα), which plays a key role in lipid and cholesterol homeostasis, is suggested to be an important molecular initiating event triggering PFAS toxicity. The aim of this study was to evaluate the PPARα activation potential of a diverse panel of 34 PFAS congeners, consisting of both legacy and novel compounds, using a PPARα-dependent transactivation assay in transfected HEK293T cells. The resulting concentration-response data were analyzed using benchmark dose (BMD) modelling to quantify PPARα activation potency. A key finding was that PFAS with a sulfonic acid group showed a lower potency compared to those with a carboxylic group. The most potent activators belonged to the perfluoroalkylether carboxylic acid (PFECA) subgroup. Computational descriptors were generated to characterize each congener, and quantitative structure-activity relationship (QSAR) modelling was applied to relate molecular features to in vitro PPARα activation potency, as expressed by BMD estimates. For prioritization purposes in the context of PFAS hazard characterization, the QSAR model was used to screen about 10,000 PFAS congeners. Of these, roughly 10% were within the defined applicability domain of the developed QSAR model. Predicted BMD concentrations for PPARα activation were in the range between 0.3 µM and 420 µM.
Micro- and nano-plastics (MNPs) contamination has recently become a widespread concern. These particles have been detected in multiple human organs. MNPs can enter the human body through three ways: diet intake, inhalati...Micro- and nano-plastics (MNPs) contamination has recently become a widespread concern. These particles have been detected in multiple human organs. MNPs can enter the human body through three ways: diet intake, inhalation and skin contact, subsequently entering the bloodstream and distributing throughout the body's tissue systems. The health risks posed by MNPs exposure are believed to be linked to cellular senescence, a state of stable cell growth arrest that significantly increases the risk of age-related diseases. The mechanisms of MNPs-induced cellular senescence are primarily associated with oxidative stress and DNA damage, and involve signaling pathways such as eNOS/SIRT1, cGAS-STING, and NF-κB. In this review, we examine the exposure pathways and distribution of MNPs in the human body, the characteristics and mechanisms of MNPs-induced cellular senescence, and potential therapeutic interventions to counteract these effects. We aim to provide state-of-the-art information on the mechanism of MNPs-induced cellular senescence and preventive and curative measures, thereby stimulating future research to minimize the health hazards of their exposure.