Toxicol. Appl. Pharmacol. [JOURNAL]
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200 papers
Corrigendum to 'Human-relevant exposure to mixtures of rare earth elements disrupts T3 homeostasis through impaired synthesis and conversion in human Thyrocytes' [Toxicology and Applied Pharmacology volume 514 (2026) 117929].
Chen Y, Teng M, Chen Y … +7 more , Qu Y, Crabbe MJC, Cao Z, Andersen ME, Zhang Q, Zhao F, Qu W
Toxicol Appl Pharmacol · 2026 Jul · PMID 42398789 · Publisher ↗
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Per- and polyfluoroalkyl substances and the risk of thyroid and breast cancer: Evidence from a meta-analysis and computational toxicology.
Shen HY, Jin MH, Wu ZC … +2 more , He TT, Gao CJ
Toxicol Appl Pharmacol · 2026 Jul · PMID 42392276 · Publisher ↗
Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants with endocrine-disrupting and carcinogenic effects, but epidemiological evidence linking PFAS exposure to cancer remains inconsistent. We...
Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants with endocrine-disrupting and carcinogenic effects, but epidemiological evidence linking PFAS exposure to cancer remains inconsistent. We conducted a meta-analysis to systematically evaluate associations between PFAS exposure and risks of thyroid and breast cancer. Relevant literature published between January 2003 and May 2025 was retrieved from Web of Science and PubMed. The analysis showed that the pooled odds ratios (ORs) for perfluorooctanoic acid (PFOA) and perfluorohexane sulfonate (PFHxS) in relation to thyroid cancer were 0.87 (95% CI: 0.77-0.98) and 0.84 (95% CI: 0.75-0.94), respectively. In contrast, the pooled OR for overall PFAS exposure and breast cancer was 1.04 (95% CI: 1.00-1.09, I = 62.2%), indicating no statistically significant association but suggesting a borderline trend. Notably, PFAS exposure was inversely associated with invasive breast cancer (OR = 0.45, 95% CI: 0.26-0.76). Computational toxicology analyses indicated that PFAS may interact with endocrine- and growth factor-related pathways involving EGFR, AKT1, and ESR1, providing supportive but hypothesis-generating mechanistic context. This study highlights specific PFAS compounds that may be associated with altered risks of thyroid and breast cancer. Future high-quality prospective studies with standardized exposure assessments are warranted to clarify the potential carcinogenic effects of PFAS.
High expression of Tbx15 in lung adenocarcinoma cells facilitates bone metastasis by suppressing IL-25 secretion and reducing MVP expression in osteoclasts.
Xu Y, Xu L, Li J … +1 more , Xu F
Toxicol Appl Pharmacol · 2026 Jul · PMID 42392275 · Publisher ↗
Bone is a primary site for lung cancer metastasis, and T-box transcription factor 15 (Tbx15) is aberrantly expressed in multiple cancers. It aims to investigate the role of Tbx15 in lung cancer bone metastasis and its po...
Bone is a primary site for lung cancer metastasis, and T-box transcription factor 15 (Tbx15) is aberrantly expressed in multiple cancers. It aims to investigate the role of Tbx15 in lung cancer bone metastasis and its potential mechanisms. TCGA and cellular analyses revealed elevated Tbx15 lung adenocarcinoma tissues and cells (MLE-12, CMT64, LA795, LLC), while recombinant IL-25 (rIL-25) expression was low in supernatants and lysates. And Pearson analysis showed a negative correlation between Tbx15 and IL-25. The CCK-8 and EdU assays showed that Tbx15 knockdown inhibited LA795 cell proliferation, migration, and invasion. In vivo, simultaneous Tbx15 knockdown and rIL-25 administration promote tumor cell growth and accelerate bone metastasis in mice. Mechanistically, Tbx15 knockdown upregulates IL-25 expression, thereby promoting apoptosis of osteoclasts (OCs) and suppressing bone metastasis. Besides, OCs were treated with rIL-25 and the apoptosis inhibitor Z-VAD-FMK, and found that extracellular IL-25 protein promoted apoptosis of OCs by upregulating major vault protein (MVP) expression. In conclusion, our study demonstrates that knockdown of Tbx15 upregulates IL-25 expression to promote apoptosis of OCs, while exogenous supplementation of IL-25 promotes proliferation and bone metastasis of lung adenocarcinoma cells. The dual role of IL-25 in Tbx15-positive lung adenocarcinoma cells and its potential regulatory mechanism were elucidated.
Corrigendum to "Nitazoxanide reverses pulmonary vascular remodeling in pulmonary hypertension by targeting the IMPA1-RAGE signaling axis" [Toxicology and Applied Pharmacology 507 (2026) 117657].
Wang D, Huang N, Cai M … +3 more , Huang R, Zhu X, Hu C
Toxicol Appl Pharmacol · 2026 Jul · PMID 42392274 · Publisher ↗
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Time-resolved transcriptomic responses delineate liver injury, immune-mediated clearance, and regeneration following microcystin-LR exposure in whitefish: implications for an uptake-limiting defense response (autokleisis).
Woźny M, Jastrzębski JP, Lewczuk B … +7 more , Szyryńska N, Ziółkowska N, Florczyk M, Gomułka P, Bittner M, Różyński R, Brzuzan P
Toxicol Appl Pharmacol · 2026 Jul · PMID 42392273 · Publisher ↗
Microcystin-LR (MC-LR), a potent cyanobacterial hepatotoxin, enters hepatocytes via active transport and inhibits protein phosphatases. However, the temporal organization of hepatic injury, immune-mediated clearance, and...
Microcystin-LR (MC-LR), a potent cyanobacterial hepatotoxin, enters hepatocytes via active transport and inhibits protein phosphatases. However, the temporal organization of hepatic injury, immune-mediated clearance, and regenerative repair after MC-LR exposure, as well as the associated transcriptomic signature, remain incompletely understood. Here, we exposed juvenile whitefish (Coregonus lavaretus) to MC-LR (100 μg·kg, intraperitoneally) on day 0 and re-exposed them on day 7. Across a 1-14-day time course, we integrated histology and ultrastructure, immunohistochemistry, plasma biochemistry, and bulk RNA-seq with gene set enrichment at selected timepoints. The response to MC-LR exposure consisted of three partially overlapping phases: (i) early hepatocyte injury accompanied by stress-response transcriptional signatures; (ii) an intermediate phase dominated by macrophage-associated clearance, cytoskeletal/trafficking remodeling, and suppressed glucose metabolism; and (iii) a late regenerative phase with proliferative programs, bile-duct-associated epithelial proliferation and re-emergence of immature hepatocytes. Despite re-dosing, hepatic MC-LR immunoreactivity decreased and became confined to discrete degenerating cell clusters, suggesting reduced effective toxin entry and/or retention during regeneration. Together, these findings provide a phase-resolved framework for MC-LR hepatoxicity and recovery in a teleost liver and suggest an uptake-limiting recovery state as a candidate protective component of regeneration.
Ranolazine is associated with attenuation of lipopolysaccharide-induced acute kidney injury via modulation of inflammatory, oxidative, and vascular markers.
Altuntas A, Kolay O, Tepebasi MY … +6 more , Ilhan I, Yurt DS, Donmez N, Baltik M, Asci H, Ozmen O
Toxicol Appl Pharmacol · 2026 Jul · PMID 42386134 · Publisher ↗
Sepsis triggers acute kidney injury (AKI) through inflammatory, oxidative, apoptotic, and microvascular mechanisms. This study investigated the renoprotective effects of ranolazine (RAN) in a lipopolysaccharide (LPS)-ind...
Sepsis triggers acute kidney injury (AKI) through inflammatory, oxidative, apoptotic, and microvascular mechanisms. This study investigated the renoprotective effects of ranolazine (RAN) in a lipopolysaccharide (LPS)-induced AKI model. Thirty-two male Wistar albino rats were allocated to four groups: Control, LPS (5 mg/kg, intraperitoneal), LPS + RAN (100 mg/kg orally, twice daily for three days), and RAN. Six hours after LPS administration, kidney tissues were collected for histopathological and immunohistochemical analysis of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor alpha (TNF-α), and caspase 3 (Cas-3). Biochemical assessments included total antioxidant status (TAS), total oxidative status (TOS), oxidative stress index (OSI), and serum blood urea nitrogen (BUN) and creatinine levels. Gene expression of interleukin-1 beta (IL-1β), sirtuin 1 (SIRT-1), heme oxygenase-1 (HO-1), hypoxia-inducible factor-1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), fms-related tyrosine kinase-1 (FLT-1), and aquaporin 2 (AQP-2), sodium channel epithelial 1 alpha subunit (SCNN1A), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM1) was analyzed. LPS induced renal injury, evidenced by increased NF-κB, TNF-α, Cas-3, TOS, OSI, BUN, creatinine, and FLT-1, SCNN1A, NGAL, and KIM1 expression, together with decreased TAS, SIRT-1, HO-1, HIF-1α, VEGF, and AQP-2. RAN treatment significantly attenuated these alterations, reducing inflammation, oxidative stress, and apoptosis, tubular injury and tubular transport-related signaling while partially restoring vascular and hypoxia-related signaling. Prophylactic RAN attenuated inflammation, oxidative stress, and tubular injury while preserving renal function and modulating vascular and tubular pathways in sepsis-associated AKI, supporting its potential as an adjunctive therapeutic strategy.
Human-relevant exposure to mixtures of rare earth elements disrupts T3 homeostasis through impaired synthesis and conversion in human Thyrocytes.
Chen Y, Teng M, Chen Y … +7 more , Qu Y, Crabb MJC, Cao Z, Andersen ME, Zhang Q, Zhao F, Qu W
Toxicol Appl Pharmacol · 2026 Jun · PMID 42364782 · Publisher ↗
Despite epidemiological links between rare earth elements (REEs) exposure and thyroid dysfunction, health risks of chronic, low-dose mixture exposure in populations remain unknown. We exposed human thyroid follicular epi...
Despite epidemiological links between rare earth elements (REEs) exposure and thyroid dysfunction, health risks of chronic, low-dose mixture exposure in populations remain unknown. We exposed human thyroid follicular epithelial cells Nthy-ori 3-1 to a biomimetic 14-REE mixture, encompassing light (La, Ce, Pr, Nd, Sm, and Eu) and heavy (Gd, Tb, Dy, Ho, Yb, Lu, Sc, and Y) elements, at concentrations reflecting human internal exposure from 1× to 1000× serum background concentration (SBC). REEs significantly inhibited triiodothyronine (T3) secretion without affecting thyroxine (T4). This disruption was associated with dysregulation of the dual oxidase 1 (DUOX1)/catalase (CAT)-mediated H₂O₂ redox system involved in thyroid hormone synthesis, together with impaired deiodinase-mediated T4-to-T3 conversion. Upregulation of DUOX1 and thyroid peroxidase (TPO), alongside NRF2-mediated defense activation, was significantly initiated at the 1× SBC level, indicating high sensitivity to background environmental concentrations. REE-induced oxidative stress triggered mitochondrial damage and ATP depletion, which may be mechanistically linked to the impaired deiodinase-mediated T4-to-T3 conversion. Antioxidant intervention effectively restored mitochondrial integrity, ATP levels, and deiodinase activities, thereby rescuing T3 secretion. This study revealed a thyrotoxic mechanism of REEs under realistic exposure scenarios, providing critical evidence for assessing their environmental health risks.
Integrative machine learning and experimental validation reveal the molecular mechanisms of 2-bromo-4,6-dinitroaniline nephrotoxicity: CD45 and cyclophilin C as early response biomarkers of renal tubular injury.
Zhao Y, Zhou L, Liu P … +4 more , Li D, Fan L, Ye Y, Qin G
Toxicol Appl Pharmacol · 2026 Jun · PMID 42364781 · Publisher ↗
2-Bromo-4,6-dinitroaniline (BDNA), a synthetic intermediate of brominated azo dyes, poses potential nephrotoxicity risks; however, its early molecular injury mechanisms remain elusive. This study integrated network toxic...
2-Bromo-4,6-dinitroaniline (BDNA), a synthetic intermediate of brominated azo dyes, poses potential nephrotoxicity risks; however, its early molecular injury mechanisms remain elusive. This study integrated network toxicology prediction, machine learning algorithms (least absolute shrinkage and selection operator [LASSO], support vector machine recursive feature elimination [SVM-RFE], and random forest), and transcriptomic data mining with a 90-day subchronic male Sprague-Dawley (SD) rat exposure model to identify early biomarkers of BDNA-induced nephrotoxicity. Cross-validation of three algorithms identified CD45 (protein tyrosine phosphatase receptor type C, PTPRC) and cyclophilin C (peptidylprolyl isomerase C, PPIC) as high-confidence core targets (training area under the curve [AUC] = 0.951; validation AUCs = 0.958 and 0.929). Single-gene gene set enrichment analysis (GSEA) revealed PTPRC enrichment in immune-inflammatory pathways and PPIC in protein homeostasis-related pathways. Single-cell analysis confirmed their cell type-specific expression patterns. Subchronic BDNA exposure induced dose-dependent renal tubular epithelial injury with significant upregulation of both targets, without interstitial fibrosis or glomerulosclerosis in male SD rats. PTPRC and PPIC may serve as potential early response biomarkers for BDNA-induced renal tubular injury, involving immune-inflammatory activation and proteostasis imbalance. This study establishes an integrative toxicological framework from computational prediction to experimental validation, while acknowledging that causal roles require further functional verification.
Dexmedetomidine antagonizes cisplatin-induced ototoxicity in Cochlear hair cells by alleviating endoplasmic reticulum stress via the PERK pathway.
Wen J, Fan X, Chen W … +2 more , Zhang X, Ma X
Toxicol Appl Pharmacol · 2026 Jun · PMID 42364780 · Publisher ↗
Cisplatin (CIS) is a chemotherapy drug of significant importance frequently used in the treatment of solid tumors. However, irreversible sensorineural hearing loss limits the clinical application of CIS. Endoplasmic reti...
Cisplatin (CIS) is a chemotherapy drug of significant importance frequently used in the treatment of solid tumors. However, irreversible sensorineural hearing loss limits the clinical application of CIS. Endoplasmic reticulum stress (ERS) is a cellular response mechanism to adverse stimuli, involving complex cellular activities that may play a crucial role in CIS ototoxicity. Dexmedetomidine (DEX) is a widely used sedative and analgesic agent with independent cytoprotective effects; however, its ability to protect cochlear hair cells from CIS-induced injury remains to be fully elucidated. Therefore, we aimed to develop experimental frameworks using the HEI-OC1 cellular model and cochlear samples, investigate how DEX protects against CIS-induced cytotoxicity, and elucidate the molecular pathways involved. Transcriptomic analysis of the CIS-induced damage model established in HEI-OC1 cells revealed that CIS significantly induced the expression of genes closely associated with ERS. Furthermore, CIS enhanced the expression of ERS-related proteins in HEI-OC1 cells, including caspase 12, BiP, and CHOP. The addition of DEX significantly reduced the morphological damage caused by CIS to hair cells in cochlear explants. Additionally, DEX enhanced the survival of HEI-OC1 cells under CIS treatment. Subsequent investigation revealed that DEX significantly suppressed the increase in p-PERK, p-eIF2α, and ATF4 proteins, induced by CIS, thereby effectively counteracting CIS ototoxicity. The use of PERK pathway agonists and inhibitors further corroborated the hypothesis that DEX alleviates ERS via the PERK pathway, thereby counteracting CIS ototoxicity. Collectively, DEX demonstrated considerable potential as a means of safeguarding hair cells in the cochlea against ototoxic effects induced by CIS.
In vitro assessment of the osteotoxic potential of diuron in human BMSCs.
Xie Y, Chen Z, Wu X … +4 more , Du L, Chen Z, Fang D, Yu J
Toxicol Appl Pharmacol · 2026 Jun · PMID 42361913 · Publisher ↗
Osteoporosis (OP) is an age-related chronic skeletal disorder that has been increasingly linked to environmental chemical stressors. Diuron, a widely used substituted phenylurea herbicide with high environmental persiste...
Osteoporosis (OP) is an age-related chronic skeletal disorder that has been increasingly linked to environmental chemical stressors. Diuron, a widely used substituted phenylurea herbicide with high environmental persistence, has been extensively characterized for multi-organ toxicity; however, its potential impact on bone homeostasis remains insufficiently characterized. In this study, we combined network toxicology, molecular docking, and in vitro experiments to conduct an initial hazard-identification assessment of the osteotoxic potential of diuron and to explore candidate mechanisms. Network analysis identified 73 overlapping targets between diuron and OP, with EGFR, NFKB1, STAT1, PARP1, and PTGS2 as hub genes. Functional enrichment analysis suggested that calcium signaling and PI3K/Akt signaling may be involved. Analysis of the GSE230665 dataset provided exploratory supportive evidence that several predicted targets were differentially expressed in an OP-related disease context. Molecular docking further provided supportive in silico evidence for potential interactions between diuron and the predicted hub proteins, while experimental target engagement remains to be established. In vitro, diuron reduced the viability of bone marrow mesenchymal stem cells (BMSCs) in a dose-dependent manner and impaired osteogenic differentiation, as indicated by decreased ALP and ARS staining and downregulation of osteogenic marker genes. Diuron exposure was also associated with increased expression of the predicted hub genes in BMSCs. Western blot analysis demonstrated that diuron reduced the phosphorylation levels of PI3K and Akt, whereas treatment with the PI3K activator 740 YP partially restored pathway activity. Collectively, these results suggest that diuron exposure may compromise BMSC osteogenic potential under in vitro conditions, with PI3K/Akt suppression as a plausible contributing mechanism. These findings reveal a preliminary osteotoxic signal and warrant follow-up studies in vivo and in human-relevant models to evaluate real-world relevance.
Gastrodin inhibits the dephosphorylation of EGFR by DUSP3 to suppress oxidative stress-induced ferroptosis in astrocytes and alleviate cerebral ischemia-reperfusion injury.
Luo J, Zhang X, Dong S … +3 more , Yang C, Huang X, Yao X
Toxicol Appl Pharmacol · 2026 Jun · PMID 42341951 · Publisher ↗
Cerebral ischemia-reperfusion injury (CIRI) poses great challenges for drug development because of its complex pathogenesis. The involvement of astrocytes in the pathogenesis of CIRI has given rise to the development of...
Cerebral ischemia-reperfusion injury (CIRI) poses great challenges for drug development because of its complex pathogenesis. The involvement of astrocytes in the pathogenesis of CIRI has given rise to the development of novel drug strategies that target these cells. This study aims to investigate the effects of gastrodin, the main bioactive component of Gastrodia elata, on astrocytes during CIRI and the molecular mechanism. Gastrodin inhibited oxidative stress (OS) in astrocytes in a concentration-dependent manner and restored the neuroprotection of astrocytes. Gastrodin destabilized dual specificity protein phosphatase 3 (DUSP3) in astrocytes, leading to attenuation of its protein expression, which activated epidermal growth factor receptor (EGFR) phosphorylation and nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) antioxidant signaling. Inhibition of OS by gastrodin ameliorated ferroptosis in astrocytes during CIRI, increased GSH concentration, relieved mitochondrial damage, and reduced Fe content. The ameliorative effects of gastrodin on astrocyte OS and ferroptosis, and CIRI in mice, were reversed by restoring DUSP3 expression or by treatment with the EGFR phosphorylation inhibitor gefitinib. In summary, gastrodin demonstrated ameliorative effects on astrocyte OS and CIRI-induced neurological impairments, which were dependent on the inhibition of DUSP3 expression and EGFR dephosphorylation.
Salidroside suppresses hypoxia-induced ocular angiogenesis by modulating the acetylation of PFKFB3 protein in endothelial cells and regulating glycolytic activity.
Li N, Ma X, Jin Y … +3 more , Yan H, Yun Y, Tan D
Toxicol Appl Pharmacol · 2026 Jun · PMID 42336299 · Publisher ↗
BACKGROUND: Pathological ocular angiogenesis represents a leading cause of severe vision impairment, predominantly mediated by hypoxia-induced activation of endothelial glycolysis. Salidroside, the principal bioactive co...
BACKGROUND: Pathological ocular angiogenesis represents a leading cause of severe vision impairment, predominantly mediated by hypoxia-induced activation of endothelial glycolysis. Salidroside, the principal bioactive constituent of Rhodiola rosea, has exhibited protective effects in multiple retinal disorders; however, its direct regulatory role in glycolytic metabolism remains poorly understood. This study investigates whether salidroside exerts anti-angiogenic effects through targeting PFKFB3, a key regulator of glycolysis. METHODS: Potential molecular targets were identified via network pharmacology analysis, followed by experimental validation of the interaction between salidroside and PFKFB3 using molecular docking and cellular thermal shift assay (CETSA). In vivo therapeutic efficacy was assessed in an oxygen-induced retinopathy (OIR) mouse model, with evaluation of retinal neovascularization, glycolytic activity, and post-translational modifications of PFKFB3. In vitro studies employed hypoxic human umbilical vein endothelial cells (HUVECs) to elucidate underlying mechanisms through functional assays and metabolic profiling. PFKFB3 overexpression and pharmacological inhibition of deacetylases were performed to confirm target specificity. RESULTS: Network pharmacology analysis highlighted PFKFB3 as a central intersecting target with high binding affinity for salidroside, which was subsequently confirmed experimentally. In OIR mice, salidroside treatment significantly reduced pathological retinal neovascularization, suppressed glycolytic activation, and attenuated PFKFB3 acetylation, phosphorylation at serine 461 (S461), and cytosolic translocation. In vitro, salidroside ameliorated hypoxia-induced endothelial dysfunction and inhibited glycolytic flux-effects that were reversed upon PFKFB3 overexpression. Significantly, concurrent administration of the deacetylase inhibitor nicotinamide (NAM) effectively nullified the effects of salidroside, which is associated with the inhibition of PFKFB3 modifications and glycolytic activity. CONCLUSIONS: Salidroside directly binds to PFKFB3 and promotes its deacetylation, thereby inhibiting downstream phosphorylation, cytosolic translocation, and glycolytic activation in hypoxic endothelial cells. This mechanistic pathway underlies the anti-angiogenic effect of salidroside in the OIR model, supporting its potential as a promising therapeutic agent for neovascular ocular diseases.
Asiaticoside alleviates metabolic associated fatty liver disease via PI3K/AKT/mTOR signaling pathway.
Li M, Niu X, Zhang R … +3 more , Xing Y, Zhang Q, Ma H
Toxicol Appl Pharmacol · 2026 Jun · PMID 42336298 · Publisher ↗
Metabolic associated fatty liver disease (MAFLD) is a prevalent metabolic disorder worldwide, for which effective therapeutic options remain limited. Asiaticoside, a major bioactive compound derived from Centella asiatic...
Metabolic associated fatty liver disease (MAFLD) is a prevalent metabolic disorder worldwide, for which effective therapeutic options remain limited. Asiaticoside, a major bioactive compound derived from Centella asiatica, possesses anti-inflammatory and antioxidant properties; however, its role and underlying mechanisms in MAFLD remain incompletely understood. In the present study, the therapeutic effects and molecular mechanisms of asiaticoside were investigated using both in vivo and in vitro MAFLD models. MAFLD was induced in mice by a high-fat high-cholesterol diet, while palmitic acid-treated AML12 hepatocytes were used to establish an in vitro lipid metabolism disorder model. Asiaticoside treatment markedly alleviated hepatic injury, lipid accumulation, steatosis, and inflammation in vivo, and reduced lipid droplet accumulation, mitochondrial oxidative stress, and inflammatory responses in vitro. Target prediction approaches, including network pharmacology analysis, molecular docking, and cellular thermal shift assay, identified AKT as a key target, which was further validated by molecular experiments. Mechanistically, asiaticoside improved lipid metabolic homeostasis and attenuated mitochondrial dysfunction and inflammation primarily by inhibiting aberrant activation of the PI3K/AKT/mTOR signaling pathway. Collectively, these findings demonstrate that asiaticoside exerts protective effects against MAFLD and highlight its potential as a nutritional regulator for MAFLD prevention and treatment.
Improving biomarker robustness for in silico cardiac safety assessment through an excitation-contraction coupling model.
Hanum UL, Qauli AI, Ariyadi … +1 more , Lim KM
Toxicol Appl Pharmacol · 2026 Jun · PMID 42336297 · Publisher ↗
BACKGROUND AND OBJECTIVE: Predicting drug-induced cardiac toxicity remains a critical challenge in preclinical safety assessment, particularly for evaluating the risk of Torsade de Pointes (TdP). While the Comprehensive...
BACKGROUND AND OBJECTIVE: Predicting drug-induced cardiac toxicity remains a critical challenge in preclinical safety assessment, particularly for evaluating the risk of Torsade de Pointes (TdP). While the Comprehensive in vitro Proarrhythmia Assay (CiPA) framework enables biomarker-based risk stratification, the robustness of these biomarkers under ion-channel uncertainty remains insufficiently characterized. This study aims to systematically evaluate whether incorporating excitation-contraction (EC) coupling can improve biomarker robustness for TdP risk assessment. METHODS: Human ventricular electrophysiological models (CiPAORdv1.0 and ToR-ORd) were integrated with a Land-based electromechanical model. Eleven biomarkers were evaluated using ordinal logistic regression, with 12 drugs used for training and 16 drugs for testing. To account for uncertainty, model performance was assessed using 10,000 independent test-time iterations following the CiPA framework. RESULTS: Integration of EC coupling consistently increased the number of accepted biomarkers (CiPAORdv1.0: 4 to 6; ToR-ORd: 5 to 7). The most pronounced improvements were observed in calcium transient-based biomarkers (CaTD50, CaTD90), which transitioned from rejected to accepted. In addition, voltage-based biomarkers such as APD90 and qNet exhibited reduced variability and improved statistical stability, as reflected by narrower confidence intervals. CONCLUSIONS: These findings demonstrate that incorporating electromechanical coupling enhances biomarker robustness by improving the physiological representation of calcium dynamics under uncertain conditions. This study provides a structured computational evaluation of biomarker reliability and highlights the potential of electromechanical models to strengthen in silico TdP risk prediction within the CiPA framework.
Membrane-mediated mechanisms of NSAID-induced cardiotoxicity independent of cyclooxygenase selectivity: Evidence from rat and zebrafish models.
Jha AK, Subramaniyan V, Gupta S … +5 more , Kumari R, Tiwari KR, Gokulakrishnan M, Nair S, Kumar A
Toxicol Appl Pharmacol · 2026 Jun · PMID 42336296 · Publisher ↗
Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with cardiovascular adverse events that are not fully explained by cyclooxygenase (COX) inhibition. Here, we investigated the contribution of membrane-mediate...
Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with cardiovascular adverse events that are not fully explained by cyclooxygenase (COX) inhibition. Here, we investigated the contribution of membrane-mediated mechanisms to NSAID-induced toxicity using integrated in vivo, developmental, and biophysical approaches. Ketoprofen, indomethacin, and celecoxib were evaluated in rats (serum biomarkers and histopathology) and zebrafish embryos (cardiac function), alongside mechanistic studies in cardiac-mimicking lipid membranes using differential scanning calorimetry, NMR spectroscopy, and molecular dynamics simulations. Ketoprofen significantly increased serum creatine kinase and lactate dehydrogenase levels and induced moderate myocardial damage. Indomethacin produced minimal changes in circulating biomarkers but caused mild-to-moderate histological alterations. Celecoxib showed limited toxicity in adult tissues but significantly reduced zebrafish heart rate, indicating pronounced developmental cardiotoxicity. In membrane systems, ketoprofen increased transition temperature and enthalpy, consistent with bilayer condensation and enhanced lipid order. Celecoxib decreased transition enthalpy and increased vesicle heterogeneity, indicating membrane destabilization. Indomethacin reduced transition cooperativity with modest effects on bilayer structure. NMR and simulation data supported differential drug-insertion and lipid-interaction profiles. These findings demonstrate that NSAIDs exhibit compound-specific toxicity profiles that depend on biological context and are linked to distinct drug-membrane interactions. Membrane perturbation represents a COX-independent mechanism contributing to NSAID-associated cardiotoxicity and provides a framework for integrating molecular and organism-level toxicological responses.
Mechanism of auranofin toxicity: Inhibition of tetrahydrobiopterin metabolism.
Yang S, Jan YH, Richardson JR … +2 more , Heck DE, Laskin JD
Toxicol Appl Pharmacol · 2026 Jan · PMID 42334839 · Full text
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 ubiquiti...
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 de novo 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.
Dose-dependent modulation of mitochondrial physiology and nutrient secretion in Sertoli cells by l-carnitine.
Mateus FG, Martins AD, Moreira S … +4 more , Moreira RJ, de Lourdes Pereira M, Oliveira PF, Alves MG
Toxicol Appl Pharmacol · 2026 Jun · PMID 42314964 · Publisher ↗
l-Carnitine is a ubiquitous quaternary amine, essential for the mitochondrial β-oxidation of long-chain fatty acids, and a dietary supplement widely consumed by athletes due to its purported ergogenic and recovery-enhanc...
l-Carnitine is a ubiquitous quaternary amine, essential for the mitochondrial β-oxidation of long-chain fatty acids, and a dietary supplement widely consumed by athletes due to its purported ergogenic and recovery-enhancing properties. Beyond its metabolic role in muscle tissue, l-Carnitine is highly concentrated in the male reproductive tract, suggesting a critical function in spermatogenesis. In the testis, Sertoli cells (SCs) act as essential "nurse cells," providing structural, nutritional, and immunomodulatory support to developing germ cells. This study elucidates the effects of l-Carnitine on SC viability, proliferation, redox state, and mitochondrial physiology, using an in vitro model (TM4 cell line) exposed to a range of l-Carnitine concentrations (0.005, 0.05, 0.5, and 5 mM) for 24 h. We demonstrate that a concentration mirroring plasma levels in athletes (0.05 mM) significantly enhances SC proliferation and metabolic viability, while selectively upregulating the expression of ATP synthase (Complex V). Conversely, supra-physiological doses (0.5 mM) induce a significant metabolic shift in the SC exometabolome, characterized by a marked reduction in the production of lactate, alanine, and acetate. This suggests a possible disruption of the metabolic support provided to germ cells. At the highest concentration (5 mM), l-Carnitine exhibits overt cytotoxicity, as evidenced by significant lactate dehydrogenase (LDH) leakage. Furthermore, l-Carnitine acts as a potent antioxidant, reducing endogenous reactive oxygen species (ROS) and mitigating oxidative damage to proteins and lipids. These findings provide mechanistic insights into how l-Carnitine use modulates the bioenergetic landscape of the seminiferous epithelium, suggesting that while physiological supplementation may bolster male fertility by improving SC health, excessive concentrations could paradoxically impair germ cell nutrition.
Etanercept suppresses rheumatoid arthritis development via modulating miR-125a-3p.
Wang Y, Yin Z, Wang Z … +4 more , Zhang Q, Song H, Mi X, Zhang N
Toxicol Appl Pharmacol · 2026 Jun · PMID 42309492 · Publisher ↗
Although etanercept is effective in managing inflammatory disorders, its precise anti-inflammatory mechanisms remain unclear. This study explored its therapeutic benefits in rheumatoid arthritis (RA) by focusing on the m...
Although etanercept is effective in managing inflammatory disorders, its precise anti-inflammatory mechanisms remain unclear. This study explored its therapeutic benefits in rheumatoid arthritis (RA) by focusing on the modulation of miR-125a-3p. Viability, apoptosis, and miR-125a-3p expression in MH7A cells, a human rheumatoid arthritis synovial fibroblast cell line, were determined using CCK-8 assay, flow cytometry, and RT-qPCR, respectively. Inflammatory factors, lipid peroxidation levels, apoptosis/ferroptosis-related proteins, and PI3K/AKT/mTOR pathway activation were measured by ELISA and Western blot; bioinformatics analysis was used to predict relevant pathways. Etanercept inhibited MH7A cell viability, promoted apoptosis and ferroptosis, and exerted anti-inflammatory effects, which were abolished by miR-125a-3p inhibitor, partially via the PI3K/AKT/mTOR pathway. miR-125a-3p was downregulated in MH7A cells and RA patients but upregulated following etanercept treatment. This study demonstrates that etanercept has therapeutic potential against RA by modulating miR-125a-3p, providing a promising therapeutic target.
Corynoxine suppresses hepatocellular carcinoma progression by forming the ROS-STAT3 cycle.
Wen C, Wang M, Yu Y … +8 more , Mei J, Ren Y, Ruan Q, Xu J, Qi J, Shentu Y, Li J, Deng J
Toxicol Appl Pharmacol · 2026 Jun · PMID 42303055 · Publisher ↗
Hepatocellular carcinoma (HCC) is a type of highly prevalent malignancy characterized by poor prognosis and high rates of recurrence and metastasis. Corynoxine (Cory), a natural alkaloid extracted from Uncaria rhynchophy...
Hepatocellular carcinoma (HCC) is a type of highly prevalent malignancy characterized by poor prognosis and high rates of recurrence and metastasis. Corynoxine (Cory), a natural alkaloid extracted from Uncaria rhynchophylla, has been identified as an autophagy enhancer. Nevertheless, the biological function of Cory in HCC is yet to be determined. This study aimed to investigate the anti-tumor effects and underlying mechanisms of Cory in HCC using HepG2 and Huh7 cell lines, as well as a xenograft mouse model. Our results demonstrated that Cory significantly suppressed cell growth, migration and invasion, while inducing apoptosis in HCC cells. Mechanistically, Cory promoted intracellular ROS production and inhibited JAK2/STAT3 signaling pathway. The anti-HCC effects of Cory were partially abrogated by the ROS scavenger N-acetyl-L-cysteine (NAC) and the STAT3 activator IL-6, whereas theses effects were potentiated by the STAT3 inhibitor Stattic. Furthermore, NAC pretreatment reversed Cory-mediated STAT3 suppression, IL-6 incubation attenuated Cory-induced ROS production, and Stattic treatment further augmented ROS generation triggered by Cory. These findings suggest the existence of a ROS-STAT3 positive feedback loop activated by Cory in HCC. Consistent with our in vitro observations, in vivo xenograft experiments verified that Cory retarded HCC tumor growth by modulating ROS and STAT3 activity. In summary, this study demonstrates Cory impedes HCC progression via a ROS-STAT3 positive feedback loop, suggesting that Cory may serve as a promising therapeutic candidate for HCC treatment.
Magnesium sulfate attenuates sepsis-induced myocardial injury through macrophage Fxyd2/NF-κB signaling: Integrated evidence from a propensity-matched cohort, single-cell atlas, and mechanistic validation.
Xu D, Zhou Y, Li Y … +3 more , Wu C, Zhou J, Zong G
Toxicol Appl Pharmacol · 2026 Jun · PMID 42303054 · Publisher ↗
BACKGROUND: Sepsis-induced myocardial injury (SIMI) affects approximately 20%-55% of septic patients, with associated mortality ranging from 37% to 70%; however, evidence for magnesium sulfate (MgSO₄) as a targeted SIMI...
BACKGROUND: Sepsis-induced myocardial injury (SIMI) affects approximately 20%-55% of septic patients, with associated mortality ranging from 37% to 70%; however, evidence for magnesium sulfate (MgSO₄) as a targeted SIMI intervention and its molecular basis remain poorly defined. METHODS: We integrated three evidentiary levels. A retrospective cohort of 2219 SIMI patients from the MIMIC-IV database underwent 1:1 propensity score matching (PSM; n = 992) and piecewise Cox regression (Day 10 landmark) to evaluate 28-day mortality. Single-cell RNA sequencing (scRNA-seq) of murine septic cardiac tissue characterized immune dynamics and identified MgSO₄-responsive targets. A macrophage-cardiomyocyte conditioned-medium transfer model, supplemented by Western blotting, RT-qPCR, and pyroptosis assays, validated the Fxyd2/NF-κB axis. RESULTS: MgSO₄ conferred robust survival benefit during the acute phase (Days 0-10; aHR = 0.402, 95% CI: 0.302-0.536, P < 0.001), representing a 59.8% relative risk reduction. The benefit was independent of baseline serum magnesium, indicating a pharmacological rather than nutritional effect. scRNA-seq revealed MgSO₄ enriched reparative macrophage subsets via mineral absorption pathways, identifying Fxyd2 as a key responsive gene. In vitro, MgSO₄ pretreatment remodeled the macrophage secretome-suppressing TNF-α, IL-6, and MCP-1-thereby abrogating paracrine NLRP3-caspase-1-GSDMD pyroptosis in H9c2 cardiomyocytes. Mechanistically, MgSO₄ preserved Fxyd2 expression in LPS-stimulated macrophages, inhibiting NF-κB phosphorylation and downstream pro-inflammatory transcription. CONCLUSIONS: MgSO₄ provides time-dependent cardioprotection in SIMI by reprogramming the macrophage secretome via the Fxyd2/NF-κB axis, repositioning it as a targeted immunomodulatory agent and providing rationale for early administration in future randomized trials.
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