α-Arbutin is a skin-lightning agent that has been widely used in cosmetic and pharmaceutical formulations to treat hyperpigmentation disorders such as melasma and solar lentigo. It has fewer reported adverse effects in h...α-Arbutin is a skin-lightning agent that has been widely used in cosmetic and pharmaceutical formulations to treat hyperpigmentation disorders such as melasma and solar lentigo. It has fewer reported adverse effects in humans than hydroquinone and greater efficacy than β-Arbutin. However, few studies have focused on evaluating its toxicity profile, particularly its genetic toxicity. The aims of this study were to evaluate the cytotoxic, genotoxic, and mutagenic effects of α-Arbutin following a preliminary in silico analysis of toxicity-related parameters. Cytotoxicity and genotoxicity were assessed using the MTT and comet assays, respectively, whereas mutagenic activity was examined with the cytokinesis-block micronucleus cytome assay (CBMN-Cyt) and the Salmonella/microsome assay (Ames test). In the MTT assay, α-Arbutin exhibited an IC (24 h) of 43.5 ± 0.02 μM and displayed genotoxic activity in L929 fibroblast cells treated for 3 h, regardless of a 21 h recovery period. Despite the observed genotoxic effects in the comet assay, no mutagenic activity was detected in either the Ames test or the CBMN-Cyt assay, in agreement with the in silico analysis, indicating that α-Arbutin did not induce gene or chromosomal mutations under the tested conditions.
Copper oxide nanoparticles (CuO NPs) are widely used in agriculture, medicine, food, and electronic materials, raising increasing concerns about their potential health risks. Nanoparticles (NPs) can cross biological barr...Copper oxide nanoparticles (CuO NPs) are widely used in agriculture, medicine, food, and electronic materials, raising increasing concerns about their potential health risks. Nanoparticles (NPs) can cross biological barriers and enter the bloodstream, making the cardiovascular system a potential target of toxicity. However, the endothelial toxicity of CuO NPs and the size dependent mechanisms underlying their effects remain unclear. In this study, the cytotoxicity of CuO NPs with different sizes in human umbilical vein endothelial cells (HUVECs) and the underlying mechanisms were investigated. CuO NPs reduced cell viability, increased LDH release, and inhibited cell proliferation in a size dependent manner (5 nm > 20 nm > 80 nm). Smaller CuO NPs induced higher ROS levels, disrupted the antioxidant system, and caused mitochondrial dysfunction, ultimately resulting in cuproptosis in HUVECs, as evidenced by DLAT aggregation and Fe-S proteins loss. In addition, CuO NPs activated the MAPK, NF-κB NLRP3 inflammasome and DNA damage response (DDR) pathway. Overall, CuO NPs induced size-dependent endothelial injury through oxidative stress, inflammation, DNA damage, and cuproptosis by activating MAPK/NF-κB/NLRP3 and the DDR pathway. These findings provide mechanistic insights into the cardiovascular toxicity of CuO NPs and support risk assessment of nanomaterial exposure.
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. Polybrominated diphenyl ethers (PBDEs) are persistent environmental pollutants, yet whether the dominant hu...Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. Polybrominated diphenyl ethers (PBDEs) are persistent environmental pollutants, yet whether the dominant human congener, 2,2',4,4',5,5'-hexabromodiphenyl ether (BDE-153), drives IPF-related molecular changes remains unclear. Here, we integrated network toxicology, machine learning, immune infiltration analysis, molecular docking, and targeted in vitro validation to explore molecular links between BDE-153 and IPF. A total of 436 overlapping targets were identified from 1185 BDE-153-related targets and 5787 IPF-associated genes. Functional enrichment highlighted AGE-RAGE, sphingolipid signaling, and apoptosis. Three core genes (BCL2, ESR1, and MAPK1) were prioritized as candidates and exhibited differential expression in IPF tissues, with area under the curve values of 0.777-0.917. Transcriptome-based immune infiltration analysis revealed associations of these core genes with altered infiltration of multiple immune cell types. Molecular docking suggested favorable BDE-153 binding to the three core proteins, especially ESR1. BDE-153 upregulated the expression of ESR1, α-SMA, IL-6, IL-8, and IL-1β in vitro, while ESR1 antagonist intervention further increased IL-8 secretion, indicating context-dependent inflammatory regulation. Collectively, these findings indicate that BDE-153 may modulate pro-inflammatory and fibrotic remodeling responses closely relevant to IPF pathogenesis, providing a hypothesis-generating basis for further mechanistic investigation.
Polystyrene microplastics (PS-MPs), recognized as widespread environmental contaminants, have been identified within human articular tissues. However, their contribution to the pathogenesis of osteoarthritis (OA) remains...Polystyrene microplastics (PS-MPs), recognized as widespread environmental contaminants, have been identified within human articular tissues. However, their contribution to the pathogenesis of osteoarthritis (OA) remains incompletely understood. In this study, a combination of network toxicology and transcriptomic profiling was employed to pinpoint 30 core targets implicated in PS-MP-induced OA. Functional enrichment analyses indicated significant associations with inflammatory processes, endoplasmic reticulum (ER) stress, and apoptotic pathways. Through machine learning algorithms, six potential diagnostic biomarkers for early-stage OA were identified. Among these, NFKB1 emerged as a core target, with both molecular docking and dynamic simulations confirming its stable interaction with PS-MPs. Subsequent in vitro assays and single-cell RNA sequencing revealed that PS-MPs upregulate NFKB1 expression, thereby intensifying inflammation, ER stress, and chondrocyte apoptosis. Notably, pharmacological inhibition of NFKB1 using MD-1 mitigated these deleterious effects and preserved extracellular matrix integrity. These findings elucidate a mechanistic pathway by which PS-MPs contribute to OA progression through NFKB1-driven ER stress and apoptosis, providing novel perspectives on environmentally induced OA pathology and identifying a potential therapeutic target for countering PS-MP-related chondrotoxicity.
The establishment of the primordial follicle pool during embryogenesis determines the reproductive lifespan of female mammals, and disturbances during meiotic prophase I (MPI) can permanently compromise ovarian reserve....The establishment of the primordial follicle pool during embryogenesis determines the reproductive lifespan of female mammals, and disturbances during meiotic prophase I (MPI) can permanently compromise ovarian reserve. Perfluorobutanesulfonic acid (PFBS), a short-chain replacement for legacy perfluoroalkyl substances (PFAS), is increasingly used in industrial and consumer products, yet its effects on fetal oocyte development remain insufficiently understood. In this study, pregnant ICR mice were orally exposed to PFBS (20 or 200 mg/kg) from 13.5 to 17.5 days post coitum, corresponding to the critical period of meiotic initiation. Maternal PFBS exposure delayed meiotic progression, reflected by the accumulation of pachytene-stage oocytes, without apparent disruption of synapsis. However, PFBS-exposed oocytes showed increased γ-H2A.X, DMC1, and RAD51 foci, indicating impaired DNA double-strand break repair and homologous recombination. Consequently, the number of diplotene-stage oocytes and postnatal primordial follicles was significantly reduced. These findings suggest that prenatal PFBS exposure interferes with homologous recombination-mediated DNA repair during fetal oocyte meiosis, resulting in a diminished ovarian reserve. This work provides mechanistic evidence supporting the potential reproductive toxicity of emerging short-chain PFAS.
The use of read-across is established for assessing toxicological hazards based on structural and biological similarities. Toxicokinetic (TK) read-across extends this concept to infer in vivo TK of target compounds from...The use of read-across is established for assessing toxicological hazards based on structural and biological similarities. Toxicokinetic (TK) read-across extends this concept to infer in vivo TK of target compounds from source analogs with available data, but its application to non-pharmaceutical chemicals remains limited. Here, we evaluated TK read-across for non-pharmaceutical compounds, focusing on cosmetic ingredients across multiple administration routes and diverse TK properties, including poor oral bioavailability. A TK analog workflow was applied to identify analogs, with suitability ratings assigned based on structure, reactivity, metabolism, and physicochemical properties. Case studies showed that "suitable" pairs exhibited comparable in vivo TK and in vitro absorption, distribution, metabolism and excretion (ADME) characteristics, typically within 0.5-2-fold differences. Pairs rated "suitable with interpretation" displayed >2-fold TK differences, consistent with structural or ADME dissimilarities. "Suitable with pre-condition" pairs were poor TK analogs, as analogs were often metabolites or metabolic precursors of targets, with >5-fold differences in clearance. "Not suitable" pairs showed divergent TK profiles and structures. A human study using a "suitable" pair demonstrated that terpinolene TK aligned with limonene data within two-fold. Overall, this workflow supports evidence-based analog selection and enables TK read-across to inform safety and TK assessments when human data are limited.
Traditional cigarettes remain a major global health threat due to their high content of toxic substances and well-established links to cardiovascular, respiratory, and oncological diseases. In recent years, a variety of...Traditional cigarettes remain a major global health threat due to their high content of toxic substances and well-established links to cardiovascular, respiratory, and oncological diseases. In recent years, a variety of novel nicotine products have emerged and are often promoted as potentially less harmful alternatives to conventional smoking. However, growing evidence indicates that these products are not risk-free. Their increasing popularity, particularly among adolescents, raises additional public health concerns driven by attractive flavors and marketing strategies. Chemical analyses demonstrate that both traditional and emerging nicotine products may contain toxic substances, including heavy metals such as mercury, cadmium, lead, arsenic, nickel, and chromium. Despite its well-documented toxicity, mercury remains one of the least investigated metals in nicotine products and is rarely included in toxicological assessments. In this interpretative review, we synthesize and critically analyze current evidence on heavy metal contamination in cigarettes, electronic nicotine delivery systems, snus, and tobacco-free nicotine pouches. Although alternative nicotine products may reduce exposure to combustion-related toxicants, users may still be exposed to harmful levels of heavy metals. These findings highlight the need for comprehensive monitoring, standardized analytical protocols, and strengthened regulatory strategies.
Late-onset silicosis is characterized by the progression of pulmonary fibrosis long after cessation of silica exposure, yet its underlying mechanisms remain poorly understood. This study aimed to determine whether a brie...Late-onset silicosis is characterized by the progression of pulmonary fibrosis long after cessation of silica exposure, yet its underlying mechanisms remain poorly understood. This study aimed to determine whether a brief silica exposure could initiate a sustaining fibrotic process and to characterize the associated pathological and molecular alterations. A rat model of silicosis was established by short-term silica inhalation for two weeks, followed by a recovery period of up to 46 weeks. Histopathological and micro-CT analyses demonstrated progressive fibrotic development even after exposure cessation. Notably, fibrotic pulmonary dust foci (fPDFs) emerged as a predominant lesion, characterized by alveolar remodeling and diffuse collagen deposition distinct from classical silicotic nodules. These lesions were associated with alveolar type II (AT2) cell dysfunction, evidenced by aberrant differentiation, loss of homeostatic markers such as ATP-binding cassette subfamily A member 3 (ABCA3), lysophosphatidylcholine acyltransferase 1 (LPCAT1), and fatty acid synthase (FAS), and gain of transitional markers keratin 8 (KRT8) and stratifin (SFN). Integrated proteomic and lipidomic analyses revealed profound metabolic reprogramming, with significant dysregulation of lipid metabolism pathways. Key enzymes involved in lipid synthesis and remodeling were identified in AT2 cells and downregulated in fPDF regions. Our findings establish that short-term silica exposure initiates a sustaining fibrotic cascade, highlight fPDFs as a critical pathological entity, and suggest that AT2 cell dysfunction and metabolic reprogramming are closely associated with the progression of silicosis, highlighting them as potential key correlates of the sustaining fibrotic cascade. These insights provide a novel framework for understanding disease progression and identifying therapeutic targets.
Api AM, Bartlett A, Belsito D
… +31 more, Botelho D, Bruze M, Bryant-Friedrich A, Burton GA, Cancellieri MA, Chon H, Cronin M, Crotty S, Dagli ML, Dekant W, Deodhar C, Farrell K, Fryer AD, Jones L, Joshi K, Lapczynski A, Laskin DL, Lavelle M, Lee I, Moustakas H, Muldoon J, Penning TM, Piersma AH, Ritacco G, Sadekar N, Schember I, Schultz TW, Siddiqi F, Sipes IG, Sullivan G, Thakkar Y
Non-nutritive sweeteners (NNS) are increasingly consumed during pregnancy, yet their distinct metabolic fates obscure a unified mechanism for developmental programming. We tested whether maternal NNS exposure acts upstre...Non-nutritive sweeteners (NNS) are increasingly consumed during pregnancy, yet their distinct metabolic fates obscure a unified mechanism for developmental programming. We tested whether maternal NNS exposure acts upstream of metabolism by targeting the oral-submandibular gland (SMG) axis. Wistar Han dams received saccharin, acesulfame-K or rebaudioside A from gestation day 0 through lactation. Offspring were followed from weaning to adulthood and assessed by repeated two-bottle choice tests, meal-microstructure metrics, SMG histomorphometry and targeted transcript profiling. Maternal exposure did not alter litter outcomes, growth, fasting glycaemia or detectable sweet preference under the present high-preference paradigm. By contrast, rebaudioside A and acesulfame-K remodelled SMG architecture, reducing granular convoluted tubule representation, expanding striated ducts and attenuating sexual dimorphism. Unsupervised clustering of expression profiles separated rebaudioside A/acesulfame-K from control/saccharin glands and revealed coordinated suppression of trophic factors (Egf and kallikrein transcripts) with selective induction of amylase or cystatin genes, without evidence of an inflammatory transcriptional signature. These findings support sex-dependent, structural and transcriptional remodeling of the SMG after perinatal NNS exposure. However, because salivary protein output and downstream physiology were not measured, the SMG should be viewed here as a candidate pre-metabolic target rather than proof of a defined causal mechanism."
Platinum-based drugs, such as cisplatin, carboplatin, and oxaliplatin, are increasingly being used to treat a variety of cancers, including lung, ovarian, testicular, and bladder cancer, as well as a secondary treatment...Platinum-based drugs, such as cisplatin, carboplatin, and oxaliplatin, are increasingly being used to treat a variety of cancers, including lung, ovarian, testicular, and bladder cancer, as well as a secondary treatment for other types of cancer. These drugs primarily act by targeting the DNA of cancer cells, causing DNA damage that inhibits cell division and slows cancer progression. However, the mechanism can also lead to specific side effects, such as neuropathy. Chemotherapy-induced peripheral neuropathy (CIPN) caused by platinum drugs is a common and severe toxicity issue that significantly impacts the quality of life of affected patients. CIPN manifests as damage to the peripheral nerves, resulting in impaired sensation, movement limitations, and disruptions in autonomic function. While the exact mechanisms underlying CIPN are not entirely understood, it is believed to involve complex pathways, including oxidative stress, inflammation, and disruption of neuronal function. Identifying effective interventions to mitigate CIPN is crucial, as current management strategies have had limited success. Recent research has focused on plant-based compounds, which have shown promising results in both preclinical and clinical studies. To this end, our review highlights key toxic mechanisms of CIPN caused by platinum-based drugs and identifies effective natural compound-based interventions, offering valuable insights into treatment strategies for CIPN management.
Api AM, Bartlett A, Belsito D
… +31 more, Botelho D, Bruze M, Bryant-Friedrich A, Burton GA, Cancellieri MA, Chon H, Cronin M, Crotty S, Dagli ML, Dekant W, Deodhar C, Farrell K, Fryer AD, Jones L, Joshi K, Lapczynski A, Laskin DL, Lavelle M, Lee I, Moustakas H, Muldoon J, Penning TM, Piersma AH, Ritacco G, Sadekar N, Schember I, Schultz TW, Siddiqi F, Sipes IG, Sullivan G, Thakkar Y
T-2 toxin, a potent trichothecene mycotoxin, exposes humans to its toxicity through chronic ingestion of contaminated food. As a key environmental risk factor for cartilage damage, its precise mechanism of disrupting mit...T-2 toxin, a potent trichothecene mycotoxin, exposes humans to its toxicity through chronic ingestion of contaminated food. As a key environmental risk factor for cartilage damage, its precise mechanism of disrupting mitochondrial homeostasis in chondrocytes remains unclear. This study employed transcriptome sequencing to identify core targets and validated findings using both in vitro and in vivo models. We demonstrate that T-2 toxin and its metabolite HT-2 toxin suppress the expression of mitochondrial transcription factor A (TFAM) and 8-oxoguanine DNA glycosylase-1 (OGG1). This suppression reduces mitochondrial membrane potential (ΔΨm), accelerates reactive oxygen species (ROS) accumulation, and aggravates mitochondrial DNA (mtDNA) oxidative damage, culminating in mitochondrial dysfunction with consequent adenosine triphosphate (ATP) depletion. This bioenergetic collapse ultimately leads to chondrocyte death and articular tissue degeneration. These findings suggest that T-2 toxin impairs mitochondrial integrity through disruption of the TFAM-OGG1 functional axis, highlighting a potential mechanistic link and promising intervention strategy for cartilage damage caused by T-2 toxin.
Microplastics (MPs), as an emerging pollutant, have drawn much attention due to the possibility that they may be released from certain food packaging and pose potential risks to human health. This study systematically in...Microplastics (MPs), as an emerging pollutant, have drawn much attention due to the possibility that they may be released from certain food packaging and pose potential risks to human health. This study systematically investigated the effects of three storage temperature, mechanical agitation, and light exposure on the release behavior of MPs from commercially soft beverages (soda water, cola, and mineral water), and assessed their toxicity in vitro and in vivo. Light exposure was identified as the most critical factor promoting MP release, with the highest abundance reaching 92.79 ± 7.53 μg/g in cola after UV-A treatment, which significantly altered the surface functional groups of the bottles, enhancing CO groups. Toxicological assessments demonstrated that the MPs isolated from the beverages induced concentration-dependent toxic effects, with MPs released under UV-A treatment reducing Caco-2 cell viability to 58.39 ± 3.99% at 200 μg/mL, and significantly triggering apoptosis and oxidative stress. MPs derived from cola exhibited stronger cytotoxicity compared to those from other beverages. Zebrafish embryo experiments confirmed that MPs led to increased mortality and an imbalance in oxidative stress levels (reactive oxygen species (ROS) and superoxide dismutase (SOD), decreased glutathione (GSH)). Although the zebrafish larvae showed some elimination capacity, MPs remained detectable after the clearance period.
BACKGROUND: Accelerated aging is linked to a higher risk of chronic diseases. Some emerging environmental toxicants have also been reported to be associated with chronic diseases. However, the relationship between accele...BACKGROUND: Accelerated aging is linked to a higher risk of chronic diseases. Some emerging environmental toxicants have also been reported to be associated with chronic diseases. However, the relationship between accelerated aging and environmental toxicants remains unclear. OBJECTIVE: Our study seeks to investigate the association between accelerated aging and environmental toxicants via exposome-wide association study and further evaluated whether systemic inflammation may partially explain the association. METHODS: Accelerated aging was calculated by the Klemera-Doubal method (KDM) biological age. Exposome-wide association study (ExWAS), the deletion-substitution-addition (DSA) algorithm, and exposure-class risk scores (ERS) were used to investigate these associations. In addition, we applied a mediation analysis framework to examine whether systemic inflammation statistically accounted for part of these associations. Finally, we also attempted to conduct a mixed-effects analysis on the selected chemicals. RESULTS: ExWAS analysis identified 27 environmental toxicants as risk factors for accelerated aging, with copper (OR = 2.56, 95%CI:1.82-3.59), tungsten (OR = 2.37, 95%CI:1.30-4.31), and N-Acetyl-S-(phenyl)-l-cysteine (OR = 1.47,95%CI:1.25-1.72) being particularly notable. Stratified analyses suggested that sex and BMI may modify the effect of environmental toxicants on accelerated aging, with more nominally significant associations observed in males than in females. Formal interaction testing of the 8 core chemicals confirmed statistically significant effect modification by sex or BMI for key exposures including copper and total cotinine, with the exception of MHBMA3. Mediation analysis showed that SII was statistically associated with the exposure-outcome relationship and may partially explain these associations of several environmental toxicants on accelerated aging, including metals, nicotine metabolites, and polycyclic aromatic hydrocarbons. The ERS analysis showed that three categories yielded statistically significant indirect effects, including acrylamide & glycidamide, nicotine metabolites and metals. Additionally, a positive correlation was observed between the mixture and accelerated aging in the WQS model, with copper showing the greatest contribution. The results of the subsequent Qgcomp and BKMR analyses also corroborated this finding. IMPACT: Our study systematically investigated the associations between environmental toxicants and accelerated aging, identifying multiple environmental toxicants as risk factors. Our findings demonstrate that males and individuals with overweight status exhibit heightened susceptibility to key environmental pollutants. These findings highlight the importance of targeted strategies to reduce environmental exposures in susceptible populations.
Cannabidiol (CBD) is known to activate aryl hydrocarbon receptor (AhR) and expression of cytochromes P450 (CYP) 1A. This study examined the effect of cannabigerol (CBG) on the AhR/CYP1A pathway in HepG2 cells, human hepa...Cannabidiol (CBD) is known to activate aryl hydrocarbon receptor (AhR) and expression of cytochromes P450 (CYP) 1A. This study examined the effect of cannabigerol (CBG) on the AhR/CYP1A pathway in HepG2 cells, human hepatocytes, and normal human epidermal keratinocytes (NHEK cells), and the action of CBG was compared to that of CBD. The results confirmed CBD activated both AhR and CYP1A1 transcription in transfected HepG2 cells, and it increased the levels of CYP1A1 mRNA in HepG2 and NHEK cells, and the levels of CYP1A1 and CYP1A2 mRNA in hepatocytes. Moreover, CBD upregulated the protein levels of CYP1A1 and CYP1A2 in HepG2 cells and hepatocytes, respectively, but these effects were only accompanied by a slight increase in the activity of CYP1A enzymes. In contrast to CBD, CBG had a negligible effect on AhR activity and CYP1A1 transcription. Despite this, CBG elevated the CYP1A mRNA levels in all three cell models, but this effect was weaker than that of CBD, and it did not result in relevant changes in the protein levels or activity of CYP1A. We conclude that CBG is a poor modulator of the AhR/CYP1A pathway in vitro, and its effect on the pathway in vivo remains to be explored.
Dietary and environmental chemical exposures including food contact materials, pesticide residues, heavy metals, mycotoxins, and synthetic food additives are increasingly recognized as contributors to endocrine and metab...Dietary and environmental chemical exposures including food contact materials, pesticide residues, heavy metals, mycotoxins, and synthetic food additives are increasingly recognized as contributors to endocrine and metabolic disease via mitochondrial mechanisms not captured by classical receptor-based screening. Mitochondria function as central integrators of metabolism, redox signaling, and stress responses, extending beyond bioenergetics to regulate endocrine function. These chemicals disrupt oxidative phosphorylation, mitochondrial dynamics, and metabolite fluxes, inducing metabolic reprogramming in hormone-sensitive tissues. Consequences include impaired ATP production, altered reactive oxygen species signaling, and epigenetic dysregulation, leading to defects in hormone synthesis, secretion, and tissue responsiveness. Developmental vulnerability and genetic variation in mitochondrial and nuclear-encoded genes further modulate susceptibility. Mechanistically, a cascade progresses from oxidative damage and impaired biogenesis to disrupted dynamics and mitophagy, followed by retrograde metabolite signaling that epigenetically stabilizes endocrine dysfunction. This underlies insulin resistance, steroidogenic impairment, thyroid imbalance, and neuroendocrine dysregulation. Tissue-specific mitochondrial vulnerabilities align with distinct chemical classes across endocrine cell types. While pharmacological and lifestyle interventions show promise, limitations in bioavailability and safety of food-derived bioactives remain. This review integrates causal evidence, chemical classification, and tissue-specific mapping to provide a translational framework for food toxicology and regulatory assessment.
The co-contamination of T-2 and HT-2 mycotoxins in food poses significant health risks to humans. Our previous studies demonstrated that combined exposure to T-2 and HT-2 induces inflammatory responses and damage of inte...The co-contamination of T-2 and HT-2 mycotoxins in food poses significant health risks to humans. Our previous studies demonstrated that combined exposure to T-2 and HT-2 induces inflammatory responses and damage of intestinal barrier functions. However, the involvement of ferroptosis remains poorly understood together with other potential pathways. In this study, we investigated the combined toxic effects of T-2 and HT-2 and explored the mechanisms of action focusing on excessive reactive oxygen species (ROS)-induced ferroptosis in colorectal cancer (Caco-2) cells. In general, significantly elevated levels of ROS, lipid reactive oxygen species (L-ROS), iron content, and mitochondrial structural damage, and altered expression of six ferroptosis-related marker genes and proteins were observed in cells treated with T-2 and HT-2 individually and in combination. Furthermore, supplementation with the ferroptosis inhibitor Ferrostatin-1 (Fer-1) and ferroptosis suppressor protein 1 inhibition (iFSP1) effectively modulated oxidative stress imbalance, mitochondrial injury, and ferroptotic responses. These findings indicate that combined exposure to T-2 and HT-2 induces ferroptosis, primarily through the Cystine/GPX4 and NAD(P)H/FSP1/CoQ10 regulatory pathways. This study provides a theoretical basis for understanding mycotoxin-induced ferroptosis and offers valuable insights into the potential health risks associated with the combined toxicity of T-2 and HT-2.
Alpha 5 nicotinic acetylcholine receptor (α5-nAChR) is involved in nicotine-induced lung adenocarcinoma (LUAD) cell proliferation. Ribonucleotide Reductase Subunit M2 (RRM2) plays an important role in the development of...Alpha 5 nicotinic acetylcholine receptor (α5-nAChR) is involved in nicotine-induced lung adenocarcinoma (LUAD) cell proliferation. Ribonucleotide Reductase Subunit M2 (RRM2) plays an important role in the development of LUAD and resistance to chemotherapy drugs. Cyclin-dependent kinase 1 (CDK1) is a potential downstream effector of RRM2. Notably, our gene expression profile shows that α5-nAChR was positively correlated with the expression of RRM2 and CDK1. However, little is known about the link between α5-nAChR and RRM2 in nicotine-related LUAD. Here, we identified a link between α5-nAChR and RRM2 in LUAD. α5-nAChR expression was associated with RRM2 expression, smoking status, and poor prognosis. In vitro experiments demonstrated that α5-nAChR mediates nicotine-induced CDK1, RRM2 expression via STAT3, thereby enhancing LUAD cell proliferation and migration. Furthermore, the functional link among α5-nAChR, RRM2, and CDK1 was confirmed both in mouse xenograft tissues and human LUAD tissues. These findings uncover a novel role of α5-nAChR/RRM2 axis involved in nicotine-related LUAD progression.