Toxicol. Appl. Pharmacol. [JOURNAL]
Sun
200 papers
Damage response and postnatal compensatory repair in the male offspring mouse reproductive system following gestational cadmium exposure.
Zhu J, Tan A, Lu Y … +8 more , Guo H, Ye L, Huang Z, Ma Y, Zou H, Li J, Ju H, Liu Z
Toxicol Appl Pharmacol · 2026 Aug · PMID 42208908 · Publisher ↗
Cadmium (Cd), an environmental toxicant, is known to cause significant damage to reproductive systems in human and animals. However, the detrimental effects of maternal Cd exposure during gestation on male offspring and...
Cadmium (Cd), an environmental toxicant, is known to cause significant damage to reproductive systems in human and animals. However, the detrimental effects of maternal Cd exposure during gestation on male offspring and the underlying mechanisms remain unknown. In this study, pregnant mice were exposed to Cd (32 mg/l) in drinking water throughout gestation to investigate the mechanisms underlying testicular and sperm injury and repair in male offspring. Results showed that maternal Cd exposure caused growth inhibition in male offspring at birth, accompanied by testicular DNA damage and upregulation of Rad51, a key protein involved in homologous recombination repair. After delivery, when Cd was removed, the male offspring exhibited compensatory growth and development. At 7 weeks of age, despite abnormally enlarged seminiferous tubules, spermatogonial stem cell meiosis arrest, and reduced total sperm motility, DNA damage levels, DNA repair capacity, and the motility function of surviving sperm were all at normal levels. Compared with controls, the offspring at 7 weeks of age showed no alterations in global 5-methylcytosine (5-mC) of sperm, whereas DNA methylation of Line1 were decreased. Meanwhile, DNA methylation of imprinted genes H19 and Peg3, which regulate sperm quality and post-fertilization embryonic development, remained normal. Cd exposure during gestation led to transcriptomic abnormalities in the testes of newborn male offspring, but these abnormalities were gradually repaired during postnatal growth and development. These findings indicate that although gestational Cd exposure impairs reproductive function of male offspring, postnatal growth and development, coupled with DNA repair mechanisms, can partially restore their reproductive potential.
Carnosic acid alleviates cisplatin-induced acute kidney injury by enhancing prohibitin 2-dependent mitophagy.
Chen Y, Xu C, Chen Y … +2 more , Liu Q, Yin W
Toxicol Appl Pharmacol · 2026 Aug · PMID 42203181 · Publisher ↗
Cisplatin is an effective chemotherapeutic agent, but its clinical use is limited by nephrotoxicity characterized by renal tubular epithelial injury. In this study, we found that carnosic acid (CA), a natural phenolic di...
Cisplatin is an effective chemotherapeutic agent, but its clinical use is limited by nephrotoxicity characterized by renal tubular epithelial injury. In this study, we found that carnosic acid (CA), a natural phenolic diterpene derived from rosemary and sage, significantly alleviated cisplatin-induced renal dysfunction and tubular epithelial damage. Mechanistically, CA suppressed mitochondria-dependent apoptosis and reduced mitochondrial damage by activating mitophagy. Further analysis revealed that CA upregulated prohibitin 2 (PHB2), a key mitophagy receptor involved in mitochondrial quality control. Importantly, inhibition or silencing of PHB2 abolished CA-induced mitophagy and cytoprotective effects. These findings indicate that CA protects against cisplatin-induced acute kidney injury by maintaining mitochondrial homeostasis through PHB2-dependent mitophagy, suggesting its potential as a therapeutic strategy for preventing cisplatin-associated nephrotoxicity.
Sulforaphane attenuates oxidative stress and vascular remodeling in indium lung disease rats via mediating the NF-κB and Nrf2 pathways.
Wan P, Cao F, Li G … +5 more , Hao X, Mu Y, Sun J, Xue L, Liu N
Toxicol Appl Pharmacol · 2026 Aug · PMID 42203180 · Publisher ↗
Indium lung disease is characterized by interstitial pneumonia, pulmonary alveolar proteinosis (PAP), pulmonary fibrosis, and lung cancer. However, this is insofar irreversible. The disease is believed to be caused by in...
Indium lung disease is characterized by interstitial pneumonia, pulmonary alveolar proteinosis (PAP), pulmonary fibrosis, and lung cancer. However, this is insofar irreversible. The disease is believed to be caused by inhalation of indium and its compounds. We constructed a rat model of indium lung disease to explore the possible role of the NF-κB/Nrf2 pathway in indium‑tin oxide nanoparticle (Nano-ITO)-induced pulmonary injury and to reveal the regulatory mechanism. To integrate computational network toxicology and molecular docking with a rat model to identify core molecular targets and pathways underpinning ITO toxicity, and evaluate whether modulation of the NF-κB/Nrf2 axis by sulforaphane or all-trans retinoic acid mitigates Nano-ITO-induced lung injury. Toxicity prediction, target mining and integration with oxidative stress and vascular remodeling gene sets identified intersection targets that were analyzed by PPI, GO/KEGG/Reactome enrichment and topological analysis to select core nodes. Molecular docking probed interactions between ITO components and proteins in NF-κB/Nrf2 pathways. Next, we evaluated the NF-κB/Nrf2 signaling pathway to elucidate the molecular mechanism of sulforaphane in regulating inflammation, oxidative stress, vascular remodeling, vascular hyperplasia, PAP, cholesterol accumulation, and interstitial fibrosis in indium lung disease induced by Nano-ITO. Findings show that the NF-κB/Nrf2 signaling pathway is involved in Nano-ITO-induced vascular remodeling, cholesterol crystal formation, alveolar protein deposition, collagen hyperplasia, and interstitial fibrosis in rats. Sulforaphane can effectively attenuate Nano-ITO-induced inflammation, oxidative stress and vascular remodeling, as manifested by decreased expression of CD31, α-SMA, Collagen I, SP-A, SP-D, and inflammatory cytokine, via activating Nrf2 and inhibiting the NF-κB signaling pathway.
Emodin alleviates renal fibrosis by targeting the ALKBH1/mC axis to sustain TRPV4 expression and inhibit TGF-β1/Smad2/3 signaling.
Liu Y, Sun X, Sun W … +1 more , Li R
Toxicol Appl Pharmacol · 2026 May · PMID 42203179 · Publisher ↗
Renal fibrosis is the hallmark pathological outcome of chronic kidney disease (CKD), and effective anti-fibrotic therapies remain scarce. This study investigates the renoprotective effects and underlying mechanisms of em...
Renal fibrosis is the hallmark pathological outcome of chronic kidney disease (CKD), and effective anti-fibrotic therapies remain scarce. This study investigates the renoprotective effects and underlying mechanisms of emodin. A rat model of renal fibrosis was established using doxorubicin hydrochloride (DXR, 4 mg/kg), and NRK-52E cells were treated with angiotensin II (Ang II, 1 μM) to induce renal fibrosis in vitro. The regulatory effects of emodin (oral gavage of 40 mg/kg/day for 4 weeks in vivo and 100 μmol/L in vitro) on renal dysfunction, fibrosis, oxidative stress, and pyroptosis were evaluated. Additionally, the role of emodin in mediating the 5-methylcytosine (mC) modification of transient receptor potential vanilloid 4 (TRPV4) was investigated in vitro. The interaction between emodin and the mC regulatory protein AlkB homolog 1 (ALKBH1), as well as the association between ALKBH1 and TRPV4 mRNA, were detected. Emodin significantly ameliorated renal dysfunction and attenuated fibrosis in DXR-induced rats. Emodin also restored TRPV4 expression, which was downregulated in the fibrotic models. Conversely, TRPV4 knockdown partially reversed the protective effects of emodin, leading to exacerbated activation of the transforming growth factor-β1 (TGF-β1)/Smad2/3 pathway, along with enhanced fibrosis and pyroptosis. Mechanistically, Ang II elevated global mC RNA modification and upregulated the demethylase ALKBH1; these effects were reversed by emodin. Furthermore, ALKBH1 overexpression promoted the destabilization of TRPV4 mRNA via site-specific mC demethylation. Emodin alleviates renal fibrosis by preserving TRPV4 expression through targeting the ALKBH1-dependent mC demethylation axis. Targeting the ALKBH1-mC-TRPV4 axis may represent a promising therapeutic strategy for renal fibrosis.
Thymoquinone is effective in thioacetamide-induced liver damage via the RIP1/RIP3/MLKL axis.
Karabulut D, Çetin A, Sayan M … +5 more , Önal E, Değer N, Karagöz H, Tufanoğlu N, Gülmez H
Toxicol Appl Pharmacol · 2026 Aug · PMID 42184866 · Publisher ↗
Impaired regenerative capacity following liver damage affects tissue functionality and forms the basis of diseases such as fibrosis, cirrhosis, and carcinoma. This study aimed to induce thioacetamide (TAA)-induced liver...
Impaired regenerative capacity following liver damage affects tissue functionality and forms the basis of diseases such as fibrosis, cirrhosis, and carcinoma. This study aimed to induce thioacetamide (TAA)-induced liver damage and to investigate the effect of thymoquinone (THQ) through receptor-interacting kinases (RIP/RIPK) and various other mechanisms. Study design: Control, TAA (2 doses 300 mg/kg), TAA + THQ10 (2 doses 300 mg/kg TAA + 10 mg/kg THQ), TAA + THQ20 (2 doses 300 mg/kg TAA + 20 mg/kg THQ), TAA + THQ40 (2 doses 300 mg/kg TAA + 40 mg/kg THQ). Histologically, hepatocyte degeneration, inflammatory cell infiltration, necrosis, glycogen accumulation, and collagen density were semi-quantitatively scored. α-SMA, TNF-α, RIP1, RIP3 and MLKL expression levels were determined. AST, ALT, and GGT levels in blood serum, and TGF-ß1, MMP-7, MMP-9, MMP-13, and TIMP1 levels in liver tissue homogenate were examined using ELISA. TAA increased liver AST, ALT, and GGT levels, α-SMA and TNF-α gene and protein expression, necroptosis markers RIP3 and MLKL, in addition to histopathological necrosis, and TGF-β1 and MMP-7 levels. While it was shown that THQ doses (20 and 40 mg/kg) may have therapeutic effects on these parameters, the effect of TAA on liver damage, specifically necrotic tissue damage, was demonstrated in this study not through histopathological evidence, but through increased necroptosis markers RIP3 and MLKL. It has been suggested that TAA may achieve this effect through the presence of increased TNF-α and TGF-β1, and the resulting oxidative stress, which alters MMPs in the tissue. New findings indicate that THQ, at doses of 20 and 40 mg/kg, can exhibit therapeutic effects in tissue.
Polyethylene terephthalate microplastics activate AKT1 signaling and induce neurotoxic responses in SH-SY5Y cells.
Hou P, Li X, Yan Y … +5 more , Lu Q, Wang J, Yuan M, Wang X, Wang X
Toxicol Appl Pharmacol · 2026 Aug · PMID 42167701 · Publisher ↗
Microplastic exposure has emerged as a growing environmental health concern, with increasing evidence suggesting potential effects on the nervous system. However, the molecular basis by which polyethylene terephthalate (...
Microplastic exposure has emerged as a growing environmental health concern, with increasing evidence suggesting potential effects on the nervous system. However, the molecular basis by which polyethylene terephthalate (PET) contributes to Alzheimer's disease (AD)-related neurotoxicity remains unclear. This study examined whether PET induces neuronal injury by activating the AKT1 signaling pathway. Network toxicology integrating PubChem, STITCH, SwissTargetPrediction, OMIM, TTD, and GeneCards was used to identify PET-associated targets relevant to AD. Core targets were analyzed with Cytoscape, followed by GO and KEGG enrichment using R and clusterProfiler. Molecular docking and molecular dynamics simulations characterized the interaction between PET and AKT1. For in vitro validation, SH-SY5Y cells were treated with 100 μg/mL PET for 24 h or 48 h to detect cytotoxicity and molecular alterations. Four experimental groups were set in this study: Control, PET, PET + MK2206 (1 μM) and MK2206 (1 μM) single treatment groups. PET exposure reduced cell viability, increased intracellular reactive oxygen species (ROS) levels, and enhanced AKT phosphorylation at Ser473, while MK2206 attenuated these effects. These research results show that PET microplastics can induce neurotoxic reactions by activating the AKT1 pathway.
Carbon-chain length dictates per- and polyfluorinated substance potency as inhibitors of human and rat 11β-hydroxysteroid dehydrogenase 1.
Zhao C, Yu Z, Wang M … +5 more , Ying Y, Tang Y, Li H, Ge RS, Liang J
Toxicol Appl Pharmacol · 2026 Aug · PMID 42162928 · Publisher ↗
Per- and polyfluorinated substances (PFAS) are synthetic, long-lasting contaminants that persist in the environment. However, it is still unknown whether these chemicals can inhibit the activity of 11β-hydroxysteroid deh...
Per- and polyfluorinated substances (PFAS) are synthetic, long-lasting contaminants that persist in the environment. However, it is still unknown whether these chemicals can inhibit the activity of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in humans and rats to disrupt glucocorticoid metabolism. Eighteen PFAS (11 carboxylic acids and 7 sulfonic acids) were used to analyze their inhibition on human and rat 11β-HSD1 activity. Eight of the eleven PFAS carboxylic acids (from C7 to C14) gradually inhibited human 11β-HSD1 with the increase of carbon-chain length (inhibitory potency was C4-C6 < C7 < C8 < C9 < C10 < C11 < C12 < C13 < C14). The IC values of perfluoroheptanoic acid (C7) and perfluorotetradecanoic acid (C14) were 100.4 and 10.33 μM, respectively. Perfluorooctanesulfonic acid (PFOS, C8) from 7 sulfonic acids can significantly inhibit human 11β-HSD1. The carbon-chain length, carbon atom number, fluorine atom number, molecular weight, rotatable bonds, boiling point, and melting point, pKa, apolar desolvation, and polar desolvation, and LogP were negatively correlated with IC values to inhibit human 11β-HSD1 (the higher the number, the lower the IC value, thus, stronger inhibition). On the contrary, LogS, Gibbs free energy, and lowest binding energy were positively correlated with IC values. All these chemicals bind to steroid binding site of human 11β-HSD1 as competitive or mixed inhibitors. Only perfluorononanoic acid (C9, IC = 128.2 μM) and perfluorodecanoic acid (C10, 68.21 μM) markedly inhibited rat 11β-HSD1. In conclusion, PFAS show structure-dependent inhibition on human 11β-HSD1 and they increase inhibitory potency with the increase in carbon-chain length, and rat enzyme is less sensitive to the inhibition of these chemicals.
Hyperoside exposure impairs cardiac development in zebrafish embryos: Evidence from phenotyping, transcriptomics, and antioxidant rescue.
Zhou Z, Yang Y, Li G … +7 more , Guo H, Zhang X, Guo X, Lv S, Zhou H, Bei L, Wu D
Toxicol Appl Pharmacol · 2026 Aug · PMID 42162927 · Publisher ↗
Hyperoside, a common flavonoid glycoside, was evaluated for developmental toxicity in zebrafish embryos (6-96 hpf). Hyperoside reduced hatchability and survival (96-h LC50 170.9 μM; LC10 118.3 μM) and caused prominent ca...
Hyperoside, a common flavonoid glycoside, was evaluated for developmental toxicity in zebrafish embryos (6-96 hpf). Hyperoside reduced hatchability and survival (96-h LC50 170.9 μM; LC10 118.3 μM) and caused prominent cardiac defects, including tachycardia, pericardial edema, and atrioventricular malformation, along with altered expression of cardiac markers (nppa, vmhc, sox9b, and gata4). Transcriptomic and phenotypic assays indicated the activation of oxidative stress and apoptosis pathways. Hyperoside increased ROS and MDA, decreased antioxidant enzyme activities (SOD and CAT), and induced apoptosis in the cardiac region (AO staining; baxa/caspase-3/p53 upregulated, bcl2a downregulated). Co-treatment with N-acetyl-L-cysteine (NAC) reduced ROS, attenuated apoptosis, and rescued cardiotoxicity, supporting ROS-driven injury as a key mechanism.
Molecular disruption of neuroinflammatory and metabolic pathways mediates triclosan-induced depressive-like behavior in zebrafish.
Wang D, Liu J, Zhou R … +7 more , Han B, Chen C, Meng W, Qin L, Sun L, Tan B, Huang C
Toxicol Appl Pharmacol · 2026 Aug · PMID 42162926 · Publisher ↗
Triclosan (TCS), a widely used antimicrobial agent and known endocrine disruptor, is commonly found in the environment and living organisms, but its neurobehavioral toxicity mechanisms remain unclear. This study integrat...
Triclosan (TCS), a widely used antimicrobial agent and known endocrine disruptor, is commonly found in the environment and living organisms, but its neurobehavioral toxicity mechanisms remain unclear. This study integrated computational toxicology with zebrafish experiments to evaluate TCS-induced neurotoxicity. Network toxicology and molecular docking predicted that TCS interacts with neuropsychiatric-related genes including MTOR, TNF, LEP, and NPY, which was verified by RT-qPCR showing upregulation of these genes in zebrafish larvae. In 5-dpf zebrafish larvae, TCS (300 μg/L) caused morphological abnormalities, elevated ROS levels, increased neutrophil and macrophage infiltration (Tg(mpx:EGFP) and Tg(mpeg1:mCherry)), and reduced cerebrovascular branching and vessel diameter (Tg(fli1a:EGFP)). In adult zebrafish (28-day exposure), TCS induced behavioral changes in males, including reduced social interaction (SI), decreased exploration in novel tank test (NTT), shorter center duration in open field test (OFT), and light-dark box test (LDB), accompanied by brain histopathological alterations (granule cell loss, pyknosis, and lighter Nissl staining). Fluoxetine Hydrochloride (FLX) co-treatment partially attenuated these behavioral and histological changes. Females showed similar but weaker trends. These findings indicate that TCS induces neurodevelopmental and behavioral changes in zebrafish via neuroinflammation, oxidative stress, and vascular damage. The observed effects included but were not limited to depressive-like phenotypes and might involve broader neurotoxic mechanisms. This study provided multi-level experimental evidence for TCS neurobehavioral toxicity and highlighted the need for future investigations using lower, more environmentally relevant concentrations and longer exposure designs.
Combined acylated catalpol diglycoside and Lactobacillus therapy restores the miR-146a-TRAF6-SIRT1/AMPK signaling axis in experimental colitis.
El-Baz AM, Goda RM, Baraka HN … +14 more , Saad AS, Amer AE, Abdelhamid AM, Salama MM, Anwer HM, Ali S, Marei AM, El-Kott AF, Negm S, AlShehri MA, Ghanim AMH, Ashmawy SA, Saleh MM, Saber S
Toxicol Appl Pharmacol · 2026 Aug · PMID 42155683 · Publisher ↗
Inflammatory bowel disease is characterized by altered innate immunity, oxidative stress, and gut microbiota imbalance. This study explored the association between miR-146a expression and the TRAF6-NF-κB-SIRT1-AMPK axis...
Inflammatory bowel disease is characterized by altered innate immunity, oxidative stress, and gut microbiota imbalance. This study explored the association between miR-146a expression and the TRAF6-NF-κB-SIRT1-AMPK axis and assessed the therapeutic potential of an acylated catalpol diglycoside (CAT) and a Lactobacillus preparation containing Lactobacillus delbrueckii and Lactobacillus fermentum (LB) in dextran sodium sulfate (DSS)-induced colitis. Colonic injury, oxidative stress, inflammatory mediators, selected gut microbial markers, and molecular signaling were evaluated using histopathology, immunohistochemistry, ELISA, qPCR, and Western blotting. DSS induced marked colonic damage, inflammatory cytokine elevation, oxidative stress, alterations in selected gut microbial taxa, NF-κB activation, SIRT1/AMPK suppression, and miR-146a downregulation. CAT or LB alone partially improved inflammatory and oxidative stress parameters, although changes in miR-146a, SIRT1, and AMPK activation did not reach statistical significance. In contrast, combined CAT+LB treatment was associated with the greatest recovery of miR-146a expression, SIRT1 levels, AMPK activation, and overall colonic protection. Correlation, regression, and mediation analyses supported an inferred upstream network-associated position for miR-146a in relation to TRAF6-NF-κB activity and SIRT1/AMPK signaling. DSS-normalized synergy modeling indicated non-additive network-level effects on miR-146a restoration, TRAF6 suppression, NF-κB attenuation, and SIRT1/AMPK recovery. Collectively, these findings support miR-146a as a putative network-associated regulatory node and suggest that CAT+LB promotes coordinated immune-metabolic recovery in acute DSS-induced colitis.
Nitroxoline attenuates sepsis-associated pancreatic injury through inhibiting NLRP3-inflammasome mediated pyroptosis.
Gong T, Zeng X, Li C … +1 more , Liu P
Toxicol Appl Pharmacol · 2026 Aug · PMID 42144162 · Publisher ↗
OBJECTIVE: Pancreatic injury constitutes a prevalent and clinically critical complication in the setting of sepsis, typified by both an increased occurrence and a substantial mortality risk. This study investigated the m...
OBJECTIVE: Pancreatic injury constitutes a prevalent and clinically critical complication in the setting of sepsis, typified by both an increased occurrence and a substantial mortality risk. This study investigated the mechanism by which nitroxoline (NTX), a novel NLRP3 inflammasome inhibitor, alleviates pancreatic injury in septic mice through modulating classical pyroptosis pathways. MATERIALS AND METHODS: Sepsis-associated pancreatic injury (SPI) was induced in experimental animals by performing cecal ligation and puncture procedures. For in vitro mechanistic studies, primary pancreatic acinar cells and macrophages were harvested from pancreatic tissues and maintained in culture. Histopathological alterations indicative of pancreatic injury were evaluated through HE staining. Pyroptosis in pancreatic cells and macrophages was identified using Hoechst33342/PI dual staining. IHC analysis was employed to detect Caspase-1 expression in pancreatic tissue sections, whereas IF staining was utilized to measure Caspase-1 levels in isolated pancreatic acinar cells. ELISA was conducted to quantify the serum levels of inflammatory cytokines including TNF-α, IL-6, IL-1β and IL-18. Western blotting was performed to examine the protein abundance of NLRP3, Caspase-1 p20 and GSDMD-N. RESULTS: NTX treatment relieved pancreatic tissue lesions in SPI-model mice, accompanied by a significant decrease in injury scores and the extent of necrotic regions. The protective effect conferred by high-dose NTX was superior to that achieved in the group receiving VX-765. Within the SPI group, NTX prominently downregulated the expression of NLRP3, Caspase-1 p20 and GSDMD-N, and high-dose NTX displayed a more favorable inhibitory action in comparison to VX-765. Exposure to gradient concentrations of NTX substantially ameliorated LPS-induced pyroptotic events and decreased the ratio of pyroptotic pancreatic acinar cells. Following LPS challenge, the levels of pyroptosis activation-related proteins NLRP3, Caspase-1 p20 and GSDMD-N were markedly increased in pancreatic acinar cells, and these increases were abrogated upon NTX administration. Additionally, NTX significantly diminished pyroptosis in macrophages and the expression of pyroptosis-associated proteins in the SPI model. CONCLUSION: The protective efficacy of NTX in the context of SPI was achieved via the regulation of pathological pyroptotic activation in both pancreatic acinar cells and macrophages, with the NLRP3-Caspase-1-GSDMD pyroptotic pathway serving as the key underlying molecular mechanism.
Arylacetamide deacetylase attenuates hepatic lipid accumulation under ER stress conditions by regulating iron-dependent oxidative stress.
Nagaoka M, Watanabe M, Fujino C … +2 more , Nakajima M, Fukami T
Toxicol Appl Pharmacol · 2026 Aug · PMID 42142810 · Publisher ↗
Arylacetamide deacetylase (AADAC) is a drug-metabolizing enzyme that catalyzes the hydrolysis of clinical drugs containing an acetyl moiety. Recent in vitro studies have suggested that AADAC also reduces intracellular li...
Arylacetamide deacetylase (AADAC) is a drug-metabolizing enzyme that catalyzes the hydrolysis of clinical drugs containing an acetyl moiety. Recent in vitro studies have suggested that AADAC also reduces intracellular lipid accumulation; however, the underlying mechanism remains unclear. AADAC has been reported to decrease hepatic ferrous iron (Fe) levels, which are known to promote activation of the unfolded protein response. Excess unfolded protein response activation can lead to endoplasmic reticulum (ER) stress and subsequent hepatic steatosis. The aim of this study was to elucidate the role of AADAC in lipid metabolism under ER stress using Aadac knockout (KO) mice. ER stress was induced by intraperitoneal administration of tunicamycin (1.0 mg/kg) to wild-type (WT) mice and Aadac KO mice. Compared with WT mice, Aadac KO mice exhibited increased hepatic iron levels and oxidative stress, accompanied by elevated expression of ER stress-related genes, indicating that Aadac deficiency exacerbates iron-associated ER stress. Consistently, hepatic lipid accumulation was significantly greater in Aadac KO mice than in WT mice. Notably, pre-administration of the iron chelator deferoxamine (200 mg/kg, i.p.) attenuated ER stress and reduced hepatic lipid accumulation in Aadac KO mice to levels comparable to those in WT mice. Collectively, these findings demonstrate that AADAC protects the liver against lipid accumulation under ER stress conditions by regulating iron-dependent oxidative stress.
Irisin alleviates ferroptosis in LPS-induced acute kidney injury via regulating FGL2.
Yin S, Wang Y, Huang D … +2 more , Quan Z, Tao R
Toxicol Appl Pharmacol · 2026 Aug · PMID 42134514 · Publisher ↗
Sepsis-associated acute kidney injury (SA-AKI) is significantly associated with high morbidity and mortality rates. Emerging evidence has suggested that ferroptosis plays a key role in AKI. It has been also reported that...
Sepsis-associated acute kidney injury (SA-AKI) is significantly associated with high morbidity and mortality rates. Emerging evidence has suggested that ferroptosis plays a key role in AKI. It has been also reported that irisin exerts anti-inflammatory, anti-oxidative and anti-apoptotic properties. However, its protective effect, particularly via regulating ferroptosis, in AKI remains unclear. Therefore, the present study aimed to investigate the potential of irisin to restrain ferroptosis and relieve SA-AKI via activating fibrinogen-like 2 (FGL2). For the in vivo experiments, a lipopolysaccharide (LPS)-induced AKI model was established in wildtype and FGL2 mice. The effects of irisin in vitro were assessed in LPS-induced HK-2 cells. The results demonstrated that irisin could alleviate AKI, and attenuate ferroptosis and mitochondrial dysfunction in LPS-induced mice. However, these effects were partly abolished in FGL2 mice. Additionally, the results revealed that irisin inhibited reactive oxygen species accumulation and malondialdehyde levels, while increasing superoxide dismutase activity and glutathione levels in HK2 cells. However, the protective effects of irisin on LPS-induced HK-2 cells were abrogated following FGL2 silencing. In conclusion, irisin could protect against SA-AKI via conferring resistance to ferroptosis through activating FGL2. These findings indicated that irisin could represent a potential therapeutic approach for the treatment of SA-AKI.
Indole-3-Carbinol (I3C) suppression of IgG2b-triggered signaling in innate cells involves early suppression of p-Akt.
Deb A, Miceli A, Kaplan BLF
Toxicol Appl Pharmacol · 2026 Aug · PMID 42134513 · Publisher ↗
Immunoglobulin G (IgG) plays a crucial role in immune defence mechanisms, yet IgG antibodies can contribute to the pathology of autoimmune diseases like multiple sclerosis (MS). Our prior work demonstrated that the aryl...
Immunoglobulin G (IgG) plays a crucial role in immune defence mechanisms, yet IgG antibodies can contribute to the pathology of autoimmune diseases like multiple sclerosis (MS). Our prior work demonstrated that the aryl hydrocarbon receptor (AHR) ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppressed antibody production in the animal model of MS. However, relatively little is known about other downstream cellular effects of compromised antibody production. In this study, we investigated how AHR ligand suppression of IgG antibodies has the potential to impact Fcγ receptor (FcγR) signaling in innate immune cells. Our findings revealed that although TCDD suppressed IgG1, IgG2a, and IgG2b antibody production in vivo, streptavidin (Strept)-biotinylated IgG1 (Biotin IgG1) immune complex-triggered innate cell activation was modestly affected by several AHR ligands in vitro in mouse splenocytes (SPLC) and RAW 264.7 macrophages. To address the role of other IgG isotypes, we noted that IgG2a complexes failed to stimulate SPLC or RAW 264.7 cells, but it stimulated BV2 microglia cells. In contrast, IgG2b robustly activated SPLC, RAW 264.7, and BV2 cells. IgG2b-triggered IL-6 and TNF-α cytokine secretion was significantly suppressed by the dietary AHR ligand indole-3-carbinol (I3C) in both female splenocytes (SPLC) and RAW 264.7 cells. To further understand the underlying molecular mechanism behind the cellular effect of I3C, we analyzed Akt signaling, which is commonly activated in response to FcγR activation. We found that Strept-Biotin IgG2b stimulation increased phosphorylation of Akt, and I3C transiently inhibited IgG2b-induced Akt phosphorylation. Collectively, these findings show that I3C could be a potential nontoxic anti-inflammatory therapeutic strategy through inhibition of antibody-triggered signaling and Akt activation, which could be beneficial in MS.
Puerarin inhibits SiO-induced pulmonary epithelial-mesenchymal transition via suppressing NF-κB activation: Insights from network pharmacology and experiment validation.
Wen S, Wang K, Wang Q … +1 more , Liu Z
Toxicol Appl Pharmacol · 2026 Aug · PMID 42134512 · Publisher ↗
Silicosis is a progressive and irreversible occupational pulmonary fibrotic disease for which no clinically available agents can effectively reverse established fibrosis. Puerarin (PUE), a natural isoflavonoid, has previ...
Silicosis is a progressive and irreversible occupational pulmonary fibrotic disease for which no clinically available agents can effectively reverse established fibrosis. Puerarin (PUE), a natural isoflavonoid, has previously been demonstrated to exert protective effects against silicosis; however, its underlying protective mechanisms remain poorly understood. In the present study, we integrated network pharmacology, molecular docking, molecular dynamics simulations, and in vitro experiments to elucidate the therapeutic targets and mechanisms of PUE against SiO₂-induced pulmonary fibrosis. Network pharmacological analysis identified 227 potential targets of PUE for silicosis treatment. The IL-17 signaling pathway emerged as the most significantly enriched pathway, with core targets including IL6, TNF, AKT1, IL1B, ALB, EGFR, CASP3, MMP9, NF-κB1, and MAPK3. Molecular docking revealed that PUE exhibited the lowest binding energy with NF-κB1, and molecular dynamics simulations further confirmed a stable binding affinity between PUE and NF-κB1. In the SiO₂-induced BEAS-2B cell model, PUE treatment markedly inhibited NF-κB p65 phosphorylation, downregulated the expression of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, and reversed epithelial-mesenchymal transition (EMT). Collectively, this study provides experimental evidence that the anti-fibrotic effect of PUE may be mediated by binding to NF-κB1, thereby inhibiting NF-κB signaling activation, attenuating SiO₂-induced EMT, and suppressing inflammatory responses. These findings lay a theoretical foundation for the further development of PUE as a potential therapeutic agent for silicosis.
Gut microbiome-related tryptophan metabolites modulate drug transporters, with prominent effects on OAT1 and OAT3.
Kang MJ, Lee KR, Kim MJ … +2 more , Jeong HC, Chae YJ
Toxicol Appl Pharmacol · 2026 Aug · PMID 42134511 · Publisher ↗
The gut microbiome plays a key role in tryptophan metabolism by directly generating indole derivatives and indirectly modulating the host-driven kynurenine pathway via microbial metabolites. In this study, we examined th...
The gut microbiome plays a key role in tryptophan metabolism by directly generating indole derivatives and indirectly modulating the host-driven kynurenine pathway via microbial metabolites. In this study, we examined the effects of 12 gut microbiome-related tryptophan metabolites on major drug transporters. In vitro assays using transporter-overexpressing cell lines revealed that indole-3-acrylic acid (IA), indole-3-propionic acid (IPA), kynurenic acid (KA), xanthurenic acid (XA), and 3-hydroxyanthranilic acid (HAA) inhibited organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) activity by up to 83.7%, with half-maximal inhibitory concentration (IC) values ranging from 5.41 to 121 μM for OAT1 and 0.31 to 9.50 μM for OAT3. Molecular docking analysis provided qualitative support for potential interactions with OAT1. In vivo pharmacokinetic studies in rats showed that the coadministration of these metabolites significantly increased systemic exposure of furosemide, a representative OAT1/OAT3 substrate, by 1.3- to 2.9-fold and was accompanied by changes in renal excretion. In contrast, most metabolites showed minimal effects on other transporters such as organic anion transporting polypeptide 1B1/1B3 (OATP1B1/OATP1B3), organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), multidrug resistance protein 1 (MDR1), and breast cancer resistance protein (BCRP). These findings provide mechanistic in vitro evidence that selected gut microbiome-related tryptophan metabolites interact with OAT1/OAT3 and proof-of-concept rat pharmacokinetic data showing altered furosemide disposition after metabolite coadministration. Further studies are required to determine whether these transporter-related effects are clinically relevant in humans.
Harnessing plant-derived bioactive compounds as LOX-1 inhibitors in Helicobacter pylori-driven gastric inflammation.
Njini NG, Singh S, Shrivastava H … +6 more , Vulli D, Kale SS, Yamthe LRT, Fossi CT, Bhandari V, Jha HC
Toxicol Appl Pharmacol · 2026 Jul · PMID 42128233 · Publisher ↗
Helicobacter pylori persistence and rising antibiotic resistance have intensified interest in host-directed adjunctive strategies. Recent studies identify LOX-1 as a gastric epithelial receptor for H. pylori catalase and...
Helicobacter pylori persistence and rising antibiotic resistance have intensified interest in host-directed adjunctive strategies. Recent studies identify LOX-1 as a gastric epithelial receptor for H. pylori catalase and support its role in bacterial adhesion, making it a plausible host-directed target. In the current study, BI-0115, a structurally defined selective LOX-1 inhibitor, was used for functional validation in gastric epithelial cells infected with two clinical H. pylori isolates. Since LOX-1 is linked to inflammatory signalling pathways, we investigated the phosphorylation of p38-MAPK, ERK1/2, JNK, and NF-κB. BI-0115 treatments reduced LOX-1-associated inflammatory cascades by inhibiting LOX-1, phosphorylated p38-MAPK, ERK 1/2, JNK, and NF-κB, while elevating E-cadherin and ZO-1 expression. Also, bioactive compounds from selected medicinal plants with known anti-oxidant, anti-inflammatory and gastroprotective properties were computationally screened against LOX-1. Docking and molecular dynamics matrix prioritized epigallocatechin (MO-24) and alpha-copaene (PN-230), comparable to the reference molecule (BI-0115). Collectively, these findings suggest LOX-1 as a plausible therapeutic target for ligand discovery in mitigating H. pylori induced pathology.
Paroxetine attenuates doxorubicin-induced cardiotoxicity: Integrated network pharmacology, molecular modeling, and in vivo evidence consistent with modulation of GRK2/iNOS-related pathways.
Nabil M, Abdel-Ghany R, Abo-Dya NE … +2 more , Barakat W, Elbatreek MH
Toxicol Appl Pharmacol · 2026 Aug · PMID 42128232 · Publisher ↗
Doxorubicin is a potent chemotherapeutic agent whose clinical utility is compromised by dose-dependent, irreversible cardiotoxicity. Given the limitations of current cardioprotective strategies regarding efficacy and saf...
Doxorubicin is a potent chemotherapeutic agent whose clinical utility is compromised by dose-dependent, irreversible cardiotoxicity. Given the limitations of current cardioprotective strategies regarding efficacy and safety, repurposing approved medications presents a feasible therapeutic option. This study investigated the cardioprotective potential of paroxetine (PARX), a selective serotonin reuptake inhibitor, against doxorubicin-induced cardiotoxicity (DIC). We employed a multi-disciplinary approach combining network pharmacology, molecular docking, and 300 ns molecular dynamics simulation to identify biologically plausible PARX-associated targets. These in silico predictions were further examined in a murine model of acute DIC (single 15 mg/kg DOX i.p.), where mice received PARX pretreatment (20 mg/kg p.o.) for five days. Network pharmacology identified AKT1 and iNOS as key intersecting targets, while GRK2 was included based on supporting evidence from the literature. Computational modeling suggested that PARX maintains favorable in silico interaction within the ATP-binding region of GRK2 and engages the heme-propionate region of iNOS with a more favorable predicted interaction profile for iNOS. In vivo, PARX pretreatment attenuated biochemical and histopathological markers of cardiac injury, evidenced by reduced serum CK-MB and LDH activities and lower cardiac Troponin and NT-proBNP levels. Mechanistically, PARX reversed the doxorubicin-induced suppression of AKT1 expression, downregulated GRK2 and iNOS overexpression, and mitigated oxidative stress by restoring SOD/CAT activity. Furthermore, PARX alleviated inflammation (reduced NF-κB) and attenuated maladaptive autophagy (reduced LC3-II and Beclin-1). Histological and morphometric analyses confirmed that PARX effectively prevented cardiomyocyte necrosis and interstitial fibrosis. In conclusion, PARX ameliorates DIC via modulation of GRK2/iNOS-related pathways, restoration of AKT1 signaling, and suppression of oxidative stress and maladaptive autophagy. These findings strongly support the cardioprotective potential of PARX and warrant its further investigation during doxorubicin chemotherapy.
Novel GLP-1RA-like effects of Bafetinib: a preliminary study integrated in vitro screening and in vivo validation.
Zheng X, Xu Q, Wei Y … +4 more , Chen F, Li G, Yu S, Ge J
Toxicol Appl Pharmacol · 2026 Jul · PMID 42128231 · Publisher ↗
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are first-line treatments for type 2 diabetes mellitus and obesity. Nevertheless, their clinical application is constrained by the adimistration route of subcutaneous...
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are first-line treatments for type 2 diabetes mellitus and obesity. Nevertheless, their clinical application is constrained by the adimistration route of subcutaneous injection and the safety concerns including gastrointestinal side effects.Aiming to screen novel compounds with potent GLP-1RA-like activityand good safety, and can be given orally, we performed structure-based virtual screening of a library, subsequent surface plasmon resonance and molecular docking analyses in this study. The results showed that Bafetinib stood our from the library with high high binding affinity to GLP-1R and great thermal stability. Moreover, results of the in vitro study, demonstrated that Bafetinib could upregulated the expression of GLP-1R in cultured Min6 and HT22 cells, together with increased levels of intracellular cAMP, PKA, and phosphorylated CREB·In C57BL/6 mice, consecutive 7 days' administration of Bafetinib resulted in a loss of body weight and postprandial blood glucose, but not fasting glucose, similar to the effect of Exendin-4, which is a reagent of GLP-1RA. Histopathological assessment further indicated no significant toxicity in major organs. Overall, these results clarify that Bafetinib can bind and activate GLP-1R, and exert GLP-1RA-like activity orally and safetly in mice.
Sodium danshensu mitigates myocardial ischemia-reperfusion injury by attenuating ferroptosis through Nrf2/SLC7A11/GPX4 pathway.
Liu P, Luo Y, Zhang Y … +4 more , Dong Y, Qiu Z, Chen T, Zhang C
Toxicol Appl Pharmacol · 2026 Aug · PMID 42119709 · Publisher ↗
Myocardial ischemia-reperfusion injury (MI/RI) frequently occurs in individuals experiencing acute myocardial infarction (AMI) after undergoing reperfusion therapy. The process of ferroptosis is intricately linked to MI/...
Myocardial ischemia-reperfusion injury (MI/RI) frequently occurs in individuals experiencing acute myocardial infarction (AMI) after undergoing reperfusion therapy. The process of ferroptosis is intricately linked to MI/RI, and the nuclear factor erythroid 2-related factor 2 (Nrf2) is crucial in either promoting or impeding ferroptosis. Sodium danshensu (SDSS), a water-soluble substance obtained from the Traditional Chinese Medicine known as Danshen, exhibits significant impacts on oxidative stress and inflammation. However, the specific molecular mechanisms by which it addresses MI/RI are not fully understood. This study aims to investigate the therapeutic effects and underlying mechanisms of SDSS in mitigating MI/RI. Using both in vivo and in vitro models, we evaluated the impact of SDSS on ferroptosis and its associated regulators. Myocardial injury was assessed via echocardiography, Masson's trichrome, and H&E staining. Mitochondrial function was examined through transmission electron microscopy and JC-1 staining. Expression levels of ferroptosis-related markers, including Nrf2, GPX4, and SLC7A11, were measured using Western blotting, immunohistochemistry, and immunofluorescence. The findings indicated that SDSS provided significant cardiac protection and reduced MI/RI by inhibiting ferroptosis through modulation of the Nrf2 pathway, which in turn diminished oxidative stress and restored mitochondrial function in both in vivo and in vitro settings. Mechanistically, SDSS not only enhanced the levels of Nrf2 but also promoted its translocation into the nucleus, which in turn initiated the subsequent antioxidant defense processes. In summary, this research highlights that SDSS alleviates MI/RI by targeting the Nrf2/SLC7A11/GPX4 signaling pathway, indicating its potential as a therapeutic agent for ferroptosis inhibition.
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