Toxicol. Appl. Pharmacol. [JOURNAL]
Sun
200 papers
Potassium channel tetramerization domain-containing 10 exerts a tumor suppressive function in breast cancer by destabilizing SLC7A11 to induce ferroptosis.
He X, Wang Y, Wang D … +4 more , Wang L, Yu S, Jiang J, Zhou Q
Toxicol Appl Pharmacol · 2026 Mar · PMID 41580159 · Publisher ↗
Potassium channel tetramerization domain-containing 10 (KCTD10) plays a crucial role in the progression of various tumors. However, comprehensive studies on the involvement of KCTD10 in breast cancer are still lacking. T...
Potassium channel tetramerization domain-containing 10 (KCTD10) plays a crucial role in the progression of various tumors. However, comprehensive studies on the involvement of KCTD10 in breast cancer are still lacking. This research aims to elucidate the potential roles and mechanisms of KCTD10 in breast cancer. Reduced KCTD10 expression was observed in breast cancer and was associated with poorer overall survival. Upregulation of KCTD10 resulted in a significant decline in cell growth and proliferation. Notably, KCTD10 overexpression induced ferroptosis, as evidenced by increased cell death, elevated ferrous ion levels, and enhanced lipid peroxidation. The anti-tumor effects mediated by KCTD10 elevation were significantly counteracted by ferroptosis inhibitors, while KCTD10 knockdown resulted in increased resistance to this form of cell death. KCTD10 overexpression reduced the protein levels of SLC7A11, a process reversible by proteasome inhibitors. In KCTD10 knockdown cells, the degradation rate of SLC7A11 protein was significantly decreased. Notably, restoring SLC7A11 expression in KCTD10-overexpressing cells significantly counteracted the tumor-suppressive effects of KCTD10. Tumor-bearing mouse models demonstrated that KCTD10-overexpressing cells exhibited significantly reduced tumor formation capabilities, accompanied by increased ferroptosis levels in tumor tissues. Collectively, KCTD10 exerts a vital anti-cancer role in breast cancer by promoting the ubiquitin-proteasome degradation of SLC7A11, which reduces GSH synthesis, limits the inhibition of lipid peroxidation, and ultimately triggers ferroptosis. By providing new insights into the molecular mechanisms underlying breast cancer pathogenesis, this research identifies KCTD10 as a valuable therapeutic target and suggests that gene therapies aimed at restoring its expression may offer promising avenues for breast cancer treatment.
Sustained cadmium exposure and hyperglycemia additively drives mitochondrial dysfunction in hepatic cells: Implications for MASLD etiopathogenesis.
Kumar R, Chinala A, Palencia Desai S … +5 more , Chen L, Garcia MA, Blossom SJ, Campen MJ, Gullapalli RR
Toxicol Appl Pharmacol · 2026 Mar · PMID 41577143 · Full text
Effects of chronic heavy metal stress on hepatocellular pathophysiology remains ill-understood. Human livers are a long-term accumulative site for many toxic heavy metals (e.g., cadmium and arsenic) whose health effects...
Effects of chronic heavy metal stress on hepatocellular pathophysiology remains ill-understood. Human livers are a long-term accumulative site for many toxic heavy metals (e.g., cadmium and arsenic) whose health effects are unknown. In the current study, we studied the effects of chronic, low-dose exposures of cadmium (CLEC) modulated by normoglycemic (5.6 mM) and diabetes relevant hyperglycemic (15 mM) exposures, focusing on hepatocellular mitochondrial function. Hepatocellular cell lines were exposed to CLEC and glucose for 24 weeks, mimicking a chronic heavy metal exposure paradigm of normal and type II diabetic individuals. CLEC exposures significantly affect the long-term health of mitochondria, including decreased mitochondrial mass, increased superoxide production, and loss of mitochondrial membrane potential (MMP) in a CLEC and glucose-dependent manner. Furthermore, CLEC induced significant chronic oxidative stress revealed by the Seahorse MitoStress assay. In particular, CLEC cells show altered levels of basal and non-mitochondrial respiration, causing dysregulation in mitochondrial oxygen consumption rates (OCRs) of the cells. Lastly, we identify significant impacts of CLEC and glucose exposures on mitochondrial dynamics (fission/fusion), which show enhanced mitochondrial fragmentation and turnover rates. We also identified novel cell compensatory mechanisms that may mask the true extent of chronic Cd exposure induced damage in liver cells. New approach methodologies (NAMs) such as the current toxicology study, establish the insidious, long-term damaging effects of chronic heavy metal pollutant exposures on human hepatocellular function.
EP300 promotes cervical cancer progression through a Wnt/β-catenin-dependent HIF-1α signaling axis.
Zhang Y, Zhang Y, Wang K
Toxicol Appl Pharmacol · 2026 Mar · PMID 41565034 · Publisher ↗
This study aimed to investigate the role of EP300 in cervical cancer progression, focusing on its functional effects related to pyroptosis under Wnt/β-catenin-dependent conditions. In SiHa and HeLa cells, EP300 was silen...
This study aimed to investigate the role of EP300 in cervical cancer progression, focusing on its functional effects related to pyroptosis under Wnt/β-catenin-dependent conditions. In SiHa and HeLa cells, EP300 was silenced using lentiviral-mediated knockdown under hypoxic conditions, and subsequent changes in cell proliferation, inflammatory cytokine secretion, and pyroptosis-related protein expression were evaluated. A subcutaneous HeLa xenograft model was established to examine the in vivo effects. Hypoxia-inducible factor 1-alpha (HIF-1α) expression was also analyzed. The results showed that hypoxia significantly increased the expression levels of EP300, β-catenin, and HIF-1α. EP300 knockdown was associated with decreased Wnt/β-catenin signaling and, under Wnt/β-catenin-dependent conditions, resulted in reduced HIF-1α expression and enhanced pyroptosis-related phenotypes. Activation of Wnt/β-catenin signaling by HLY78 partially reversed these alterations. In vivo, silencing EP300 suppressed tumor growth, decreased Ki67 expression, and increased pyroptosis markers, while activation of the Wnt/β-catenin pathway partially restored proliferation and reduced pyroptosis. Taken together, loss of EP300 function impedes cervical cancer progression by affecting the Wnt/β-catenin signaling axis and inducing concomitant changes in HIF-1α expression. This study provides functional evidence supporting the role of EP300 in the progression of cervical cancer under hypoxic conditions.
Corrigendum to "Pinocembrin protects against cisplatin-induced liver injury via modulation of oxidative stress, TAK-1 inflammation, and apoptosis" [Toxicology and Applied Pharmacology, Volume 502, September 2025, 117433].
Darwish SF, Abdel Mageed SS, Mahmoud AMA … +8 more , El-Demerdash AA, Doghish AS, Azzam RK, Mohamed RE, Farouk EA, Noshy M, Shakweer MM, Elazazy O
Toxicol Appl Pharmacol · 2026 Mar · PMID 41558581 · Publisher ↗
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Nuclear protein 1 defends against acute pancreatitis by mitigating pancreatic acinar cell ferroptosis through the maintenance of cellular iron homeostasis.
Zeng X, Chen W, Dai Q … +5 more , He Y, Fu X, Liu J, Zhong D, Liao Y
Toxicol Appl Pharmacol · 2026 Mar · PMID 41554410 · Publisher ↗
Acute pancreatitis (AP) is a severe inflammatory condition marked by pancreatic acinar cell death, with ferroptosis emerging as a critical factor in its pathogenesis. The nuclear protein 1 (Nupr1) has been identified as...
Acute pancreatitis (AP) is a severe inflammatory condition marked by pancreatic acinar cell death, with ferroptosis emerging as a critical factor in its pathogenesis. The nuclear protein 1 (Nupr1) has been identified as a key regulator of ferroptosis; however, its role in modulating pancreatic acinar cell ferroptosis and its involvement in AP remain unexplored. The objective of this research was to examine whether Nupr1 regulates ferroptosis in pancreatic acinar cells and influences the progression of AP, while elucidating the underlying molecular mechanisms. Nupr1 was significantly upregulated in caerulein-induced AP models. Nupr1 knockdown pancreatic acinar cells exhibited heightened susceptibility to caerulein-induced damage and inflammatory responses, accompanied by elevated levels of ferroptosis. Conversely, overexpression of Nupr1 conferred resistance against caerulein-induced injury, inflammation, and ferroptosis. Inhibition of ferroptosis reversed the sensitivity of Nupr1 knockdown cells to caerulein-induced damage. Further investigations revealed that Nupr1 regulates the expression of lipocalin 2 (Lcn2), thereby maintaining intracellular iron homeostasis. Silencing Lcn2 negated the protective effects of Nupr1 overexpression in pancreatic acinar cells against ferroptosis. In animal models, Nupr1 overexpression significantly attenuated the progression of AP and reduced ferroptotic levels in pancreatic tissues. Collectively, our findings demonstrate that Nupr1 inhibits pancreatic acinar cell ferroptosis by regulating Lcn2-mediated iron homeostasis, thereby mitigating the progression of AP. This research reveals a previously unidentified regulatory mechanism governing acinar cell death in AP and suggests a possible therapeutic target for managing this condition.
Genipin ameliorates cholestatic liver injury in Mdr2 mice: the role of gut microbiota modulation by its dialdehyde intermediates.
Jin J, Zhu L, He C … +4 more , Deng H, Li N, Pan H, Shi F
Toxicol Appl Pharmacol · 2026 Mar · PMID 41548611 · Publisher ↗
Cholestasis causes severe hepatobiliary diseases with poor prognosis and limited therapeutic drugs. Under cholestatic conditions, impairment of the bile acid (BA)-metabolizing function of gut microbiota, along with abnor...
Cholestasis causes severe hepatobiliary diseases with poor prognosis and limited therapeutic drugs. Under cholestatic conditions, impairment of the bile acid (BA)-metabolizing function of gut microbiota, along with abnormal BA profiles, exacerbates disease progression. Interventions targeting the composition and function of gut microbiota represent promising strategies for alleviating cholestatic liver injury. Genipin (GP) is the aglycone of geniposide, the primary bioactive compound in the choleretic herbal medicine Gardenia jasminoides Ellis. The hemiacetal group in GP can generate reactive dialdehyde intermediates that covalently modify intestinal proteins. This study investigates the protective effect of GP against cholestatic liver injury in Mdr2 mice and explores the role of these dialdehyde intermediates in this process. Methylated GP (MGP) was synthesized by methylating the hemiacetal hydroxyl group of GP. The mice received intragastric gavage of GP or MGP at 100 mg/kg for 14 days. GP exhibited significant ameliorative effects on cholestatic liver injury in Mdr2 mice. GP treatment generated dialdehyde intermediates that covalently modified intestinal proteins and restored the gut microbiota composition along with bile salt hydrolase and 7α-dehydroxylase activities, leading to increased levels of intestinal unconjugated BAs and decreased levels of conjugated BAs. These changes activated intestinal farnesoid X receptor (FXR)-FGF15-hepatic CYP7A1 pathway. The ameliorative effect of GP on cholestasis was abolished by co-administration of a specific intestinal FXR inhibitor. In contrast, MGP did not exhibit these beneficial effects. In conclusion, the gut microbiota modulation by dialdehyde intermediates generated from GP contributes to its amelioration of cholestatic liver injury in Mdr2 mice.
Pharmacological inhibition of USP7 attenuates deltamethrin-induced neuronal ferroptosis via GPX4 stabilization.
Wu M, Chen Y, Ma P … +8 more , Pan W, Deng Y, Wei L, Lu G, Aschner M, Jiang Y, Zhou J, Huang X
Toxicol Appl Pharmacol · 2026 Mar · PMID 41539346 · Publisher ↗
Recent studies suggest a significant association between deltamethrin (DM) exposure and an elevated risk of neurodegenerative diseases, yet the underlying molecular mechanisms remain poorly understood. The role of Ubiqui...
Recent studies suggest a significant association between deltamethrin (DM) exposure and an elevated risk of neurodegenerative diseases, yet the underlying molecular mechanisms remain poorly understood. The role of Ubiquitin-specific protease 7 (USP7), a key deubiquitinating enzyme regulating protein homeostasis, in DM-induced neurotoxicity is particularly elusive. Here, we combined in vitro HT22 mouse hippocampal neuronal cells and in vivo male C57BL/6 J mice, which received daily oral gavage of DM at 4.5, 9.0, and 18.0 mg/kg for 30 consecutive days, to investigate the molecular mechanisms underlying DM-induced neurotoxicity. DM exposure significantly induced ferroptosis which was characterized by lipid peroxidation, disruption of iron homeostasis, mitochondrial damage and GPX4 degradation in HT22 cells and in the hippocampus, and was accompanied by impaired spatial learning and memory and neuronal hyperexcitability in mice. Consistently, DM decreased GSH and SOD levels, increased MDA and Fe, and reduced GPX4, supporting ferroptosis-associated oxidative injury in both models. Mechanistically, DM treatment markedly increased USP7 expression and enhanced GPX4 ubiquitination, thereby promoting its degradation. Increased USP7 levels subsequently induced the ubiquitination of GPX4. Critically, inhibition of USP7 reversed DM-induced GPX4 degradation, lipid peroxidation, iron dysregulation, and mitochondrial damage, thereby stabilizing GPX4 and mitigating neuronal ferroptosis. In conclusion, our findings identify that the upregulation of USP7 is a key mechanism in DM-induced neurotoxicity. USP7 promotes GPX4 degradation via ubiquitination, and inhibition of USP7 preserves GPX4 stability, thereby protecting neurons from ferroptosis and highlighting USP7 as a promising therapeutic target for preventing and treating DM-induced neurotoxicity.
GKB7I-53: A novel anti-metastatic agent for colorectal cancer.
Yang MH, Le D, Dang T … +4 more , Truong V, Ha IJ, Lee M, Ahn KS
Toxicol Appl Pharmacol · 2026 Feb · PMID 41534640 · Publisher ↗
Metastasis driven by epithelial-mesenchymal transition (EMT) remains a critical challenge in colorectal cancer treatment. This study investigated GKB7I-53, a saponin compound isolated through feature-based molecular netw...
Metastasis driven by epithelial-mesenchymal transition (EMT) remains a critical challenge in colorectal cancer treatment. This study investigated GKB7I-53, a saponin compound isolated through feature-based molecular networking, as a potential therapeutic agent targeting EMT pathways. GKB7I-53 demonstrated minimal cytotoxicity (>90% cell viability at 50 μM) while effectively inhibiting metastatic processes. The compound downregulated mesenchymal markers (CXCR4, CXCR7) and upregulated epithelial markers (E-cadherin, occludin), suppressing EMT progression. In CXCL12-stimulated cells, GKB7I-53 significantly reduced cell migration and invasion while decreasing MMP-2/9 activity, key enzymes facilitating metastatic spread. Mechanistically, GKB7I-53 suppressed MnSOD-induced STAT3 activation, thereby blocking the JAK/STAT3 signaling pathway crucial for metastasis. Molecular docking studies confirmed strong binding affinity to target proteins involved in EMT and cancer progression. These findings suggest that GKB7I-53 may serve as a potential lead compound with anti-metastatic properties in colorectal cancer. Rather than inducing general cytotoxicity, GKB7I-53 selectively modulates EMT-related pathways, indicating a mechanistic basis for its anti-metastatic effects. However, further in vivo validation and preclinical studies are required to determine its therapeutic relevance.
Paclitaxel impairs mitochondrial dynamics in human sensory-like neuron cells.
Schiess MC, Silva GSA, Hösch NG … +8 more , Troitiño VC, de Souza MM, DeOcesano-Pereira C, Glaser T, Ulrich H, Chudzinski-Tavassi AM, Bufalo MC, Zambelli VO
Toxicol Appl Pharmacol · 2026 Mar · PMID 41534639 · Publisher ↗
Taxanes are considered first-line chemotherapeutic agents to treat solid cancer. Paclitaxel (PTX) is a commonly used taxane and although effective, it induces peripheral chronic neuropathy in around 60-70% of patients. S...
Taxanes are considered first-line chemotherapeutic agents to treat solid cancer. Paclitaxel (PTX) is a commonly used taxane and although effective, it induces peripheral chronic neuropathy in around 60-70% of patients. Studies have demonstrated a correlation between impairment in bioenergetic metabolism and the development of neuropathies. However, the correlation between mitochondrial fusion-fission processes in sensory neurons and the development of neurodegeneration and pain remains poorly understood. Considering that neurons have a high metabolic demand and numerous mitochondria, and that chemotherapy-induced neuropathy is often accompanied by mitochondrial dysfunction, we investigated the role of mitochondrial plasticity in sensory-like neuron cells incubated with paclitaxel. Our findings indicate that neurotoxic concentrations of paclitaxel induce mitochondrial fragmentation by downregulating fusion proteins, such as mitofusin-1 and - 2 (MFN1 and MFN2), and upregulating fission proteins, such as dynamin-related protein 1 (Drp1). Also, paclitaxel increases superoxide release, impairs neuritogenesis, and activates pro-nociceptive signaling, measured by activating transcription factor 3 (ATF-3) expression, substance P release, and prostaglandin E2 (PGE2) - induced calcium influx. Of note, blocking excessive fission with P110, a pharmacological inhibitor of Drp1, PTX-induced cytotoxicity was prevented in sensory neuron-like cells. Together, our data suggest that impairment in mitochondrial dynamics of sensory neurons contributes to paclitaxel neurotoxicity and, consequently, to nociception. Therefore, preventing mitochondrial fission may be a strategy to prevent PTX-induced neurotoxicity, opening a new perspective to understanding the mechanisms involved in the development of PTX-induced neuropathy.
GSDMD inhibitor GI-Y1 alleviates doxorubicin-induced cardiotoxicity via the inhibition of mitochondrial dysfunction.
Zhang Y, Zheng R, Xie M … +10 more , Chen Y, Xia B, Yang Z, Li Z, Li Y, Luo L, Huang W, Dai S, Ye B, Zhang W
Toxicol Appl Pharmacol · 2026 Feb · PMID 41525956 · Publisher ↗
OBJECTIVE: This study aimed to explore GI-Y1's (a GSDMD inhibitor) protective effect against doxorubicin (Dox)-induced cardiotoxicity (DIC) and clarify its molecular mechanisms. METHODS: In vivo, wild-type and Gsdmd/ mic...
OBJECTIVE: This study aimed to explore GI-Y1's (a GSDMD inhibitor) protective effect against doxorubicin (Dox)-induced cardiotoxicity (DIC) and clarify its molecular mechanisms. METHODS: In vivo, wild-type and Gsdmd/ mice received Dox (5 mg/kg/week for 4 weeks) and GI-Y1 (10 or 20 mg/kg/day). AAV9-mediated GSDMD overexpression verified target specificity. Cardiac function was assessed by echocardiography; myocardial injury via H&E staining, TUNEL assay, and serum biomarkers (CK-MB, LDH, cTnT). In vitro, HL-1 cardiomyocytes were treated with Dox (0.5 μg/mL) and GI-Y1 (10 or 20 μM). Pyroptosis markers (GSDMD cleavage, IL-1β secretion, LDH release) and mitochondrial function were measured using Western blot, ELISA, JC-1 staining, and TEM. RESULTS: GI-Y1 improved survival and cardiac function in Dox-treated mice. It reduced serum cardiac injury biomarkers and alleviated myocardial histological damage. In vivo and in vitro, GI-Y1 inhibited Dox-induced cardiomyocyte pyroptosis, shown by reduced GSDMD cleavage, less IL-1β secretion, and decreased cell death. Mechanistically, GI-Y1 bound GSDMD, impairing its lipid-binding and pore-forming abilities. It also relieved Dox-induced mitochondrial dysfunction by reducing mitochondrial GSDMD-N, restoring MMP, boosting ATP, and inhibiting mtDNA release. CONCLUSION: GI-Y1 alleviates DIC by directly targeting GSDMD, inhibiting pyroptosis and mitochondrial damage. This study highlights GI-Y1 as a promising therapy for chemotherapy-related cardiac injury and a valuable tool to study pyroptosis in cardiovascular diseases.
Norcantharidin inhibits the EZH2-mediated JAK2/STAT3 signaling pathway to inhibit the proliferation of non-small cell lung cancer.
Wu S, Zhang W
Toxicol Appl Pharmacol · 2026 Feb · PMID 41520926 · Publisher ↗
OBJECTIVE: The purpose of this study was firstly to investigate the anti-tumor effects of NCTD on NSCLC cell proliferation, apoptosis, migration, and invasion. Secondly, it aimed to explore whether these effects were ass...
OBJECTIVE: The purpose of this study was firstly to investigate the anti-tumor effects of NCTD on NSCLC cell proliferation, apoptosis, migration, and invasion. Secondly, it aimed to explore whether these effects were associated with the modulation of the EZH2/JAK2/STAT3 signaling axis. METHODS: This study employed a series of in vitro experiments, including CCK-8, Edu staining, colony formation, flow cytometry, and Transwell assays, to evaluate the effects of NCTD on the proliferation, apoptosis, migration, and invasion of NSCLC cells. The in vivo anti-tumor efficacy was evaluated using an A549 xenograft mouse model. Underlying mechanisms were explored via western blot and genetic perturbation (knockdown and overexpression) of EZH2. RESULTS: The results of the in vitro experiments demonstrated that NCTD significantly inhibited NSCLC cell proliferation, colony formation, migration, and invasion, while promoting apoptosis. Furthermore, NCTD effectively suppressed tumor growth in the xenograft mouse model. The molecular mechanism study revealed that NCTD treatment was associated with downregulation of EZH2 and concomitant suppression of JAK2/STAT3 phosphorylation and activation of the JAK2/STAT3 signaling pathway. Genetic knockdown of EZH2 mimicked the anti-tumor effects of NCTD, whereas overexpression of EZH2 partially reversed its efficacy. CONCLUSION: The anti-tumor activity of NCTD is associated with the downregulation of EZH2 protein expression and concomitant inhibition of the JAK2/STAT3 signaling pathway. These findings provide novel insights into the molecular mechanisms underlying NCTD's anti-tumor activity.
Synergistic assault of DEHP and MPs: Unmasking the ER stress-triggered autophagic injury male fertility.
Guo J, Feng X, Zhou Y … +2 more , You T, Xu H
Toxicol Appl Pharmacol · 2026 Feb · PMID 41519275 · Publisher ↗
As an emerging category of environmental pollutants, microplastics (MPs) garner significant attention due to their exceptionally high exposure risk. Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer in the plas...
As an emerging category of environmental pollutants, microplastics (MPs) garner significant attention due to their exceptionally high exposure risk. Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer in the plastics industry, shares a similar trajectory of escalating risk as plastic pollution intensifies. MPs and DEHP are widely present in environments accessible to humans, exerting significant adverse effects on human health. The reproductive toxicity of both MPs and DEHP has been reported. However, their combined toxicity, particularly the damage to the male reproductive system, remains unclear. Here, we employed the C57BL/6 J mouse model for our experiments. The mice were continuously exposed to 10 mg/L MPs and 500 μg/L DEHP through free drinking water for two months to investigate the effects of these two pollutants on mouse testes. Our study found that mice co-exposed to MPs and DEHP experienced severe impairment of male reproductive system, manifested as disruption of testicular structure, decline in sperm quality, and dysregulation of sex hormone synthesis. Furthermore, the co-exposure to DEHP and MPs activated endoplasmic reticulum stress via the PERK-eIF2α-ATF4 pathway, and also induced excessive autophagy, contributing to reproductive damage. In summary, our findings highlight the significant risks of co-exposure to DEHP and MPs and provide new insights into their combined reproductive toxicity in male mammals.
Akkermansia muciniphila enhances the antitumour efficacy of αPD-1 therapy in gastric cancer by remodelling the tumour immune microenvironment.
Yang Z, Liang L, Li X … +6 more , Peng X, Qian X, Huang Z, Wang X, Hu Q, Fu X
Toxicol Appl Pharmacol · 2026 Feb · PMID 41519274 · Publisher ↗
There is growing advocacy for employing probiotics as adjuncts to potentiate immune checkpoint blockade (ICB) in cancer therapy. In this study, we investigated whether the probiotic Akkermansia muciniphila (A. muciniphil...
There is growing advocacy for employing probiotics as adjuncts to potentiate immune checkpoint blockade (ICB) in cancer therapy. In this study, we investigated whether the probiotic Akkermansia muciniphila (A. muciniphila) could enhance the antitumour responses to anti-PD-1 (αPD-1) in gastric cancer (GC) by reshaping the tumour microenvironment (TME). A subcutaneous GC model was established in male strain 615 mice by inoculating 1 × 10 Mouse Forestomach Carcinoma (MFC) cells on Day 10. A. muciniphila was given by daily oral gavage (1 × 10 CFU per mouse) from Day 0 to Day 31, and the αPD-1 antibody was administered intraperitoneally (100 μg per mouse) every 3 days from Day 16 to Day 31. Tumour volume was recorded every 3 days, and tumours were collected on Day 31 for histology, flow cytometry, enzyme-linked immunosorbent assay (ELISA), 16S rRNA sequencing and statistical analyses. Combined treatment with A. muciniphila and αPD-1 significantly inhibited subcutaneous tumour growth (P < 0.0001) and promoted tumour cell apoptosis (P < 0.0001). A. muciniphila increased the therapeutic effectiveness of αPD-1 treatment by driving CD8 T-cell accumulation within the TME (P < 0.0001). Supplementation with A. muciniphila reshaped the leading constituents of the gut microbiota and was associated with a significant fall in the relative abundance of Escherichia coli (E. coli) (P = 0.0170). By driving CD8 T-cell infiltration and activation and reshaping the intestinal microbiota, A. muciniphila augmented the efficacy of αPD-1 therapy against gastric tumours.
Sinapic acid attenuates colistin-driven nephrotoxicity by targeting the miRNA-21/SIRT1/NF-κB pathway and facilitating tubular repair and inflammation in a rat model.
Öz MA, Şimşek H, Özdemir S … +5 more , Kandemir Ö, Küçükler S, Mutlu H, Yazıcı R, Kandemir FM
Toxicol Appl Pharmacol · 2026 Feb · PMID 41519273 · Publisher ↗
The present study aimed to investigate the nephrotoxic effects of colistin (CS) in a rat model and to elucidate the potential renoprotective mechanisms of sinapic acid (SA) at biochemical, molecular, and metabolic levels...
The present study aimed to investigate the nephrotoxic effects of colistin (CS) in a rat model and to elucidate the potential renoprotective mechanisms of sinapic acid (SA) at biochemical, molecular, and metabolic levels. Colistin administration induced pronounced renal dysfunction, as evidenced by significant elevations in serum creatinine (Scr) and blood urea nitrogen (BUN), along with marked increases in kidney injury biomarkers, including KIM-1, NGAL, FABP, IL-18, MCP-1, and YKL-40. Metabolic disruption was further confirmed by reduced ATP levels and increased lactate dehydrogenase (LDH) and triacylglycerol (TAG) concentrations, indicating mitochondrial dysfunction and cytotoxicity. Serum proteomic profiling using proximity extension assay identified significant alterations in 22 of 43 proteins, with IL-1β, IL-2, CXCL2, CSF-1, CCL22, and IFN-α2 showing marked upregulation following CS exposure. These inflammatory and immune-related proteins were significantly attenuated by SA co-treatment. Molecular analyses revealed that CS activated the miR-21/NF-κB/CD68 axis while suppressing SIRT1 expression, reflecting enhanced inflammation and macrophage infiltration. Sinapic acid effectively normalized these molecular disturbances. Furthermore, CS significantly upregulated renal mRNA expression of Cst3, Timp2, Igfbp7, Hgf, IL9, and Dkk3-genes associated with renal stress, fibrosis, and inflammation-whereas SA treatment markedly reduced their expression. Collectively, these findings demonstrate that sinapic acid exerts renoprotective effects primarily through modulation of inflammatory signaling pathways, suppression of miR-21/NF-κB-mediated responses, restoration of SIRT1 activity, and improvement of metabolic homeostasis. The study confirms the therapeutic potential of SA against colistin-induced nephrotoxicity.
Nicotinamide N-oxide alleviates sepsis-induced hepatic inflammation, oxidative stress, and mitochondrial damage depends on SIRT3/AKT signaling pathway.
Liu S, Shi P, Jin Y … +7 more , Fan L, Ni Q, Mao J, Shao Z, Du X, Chen H, Fu M
Toxicol Appl Pharmacol · 2026 Feb · PMID 41506539 · Publisher ↗
Sepsis frequently gives rise to acute hepatic injury, representing a prevalent and critical pathological manifestation associated with high morbidity and mortality, yet effective therapeutic strategies remain limited. In...
Sepsis frequently gives rise to acute hepatic injury, representing a prevalent and critical pathological manifestation associated with high morbidity and mortality, yet effective therapeutic strategies remain limited. In this study, sepsis-induced acute liver injury was modeled in mice using cecum ligation and puncture (CLP) surgery. The therapeutic potential and underlying mechanisms of Nicotinamide nitrogen oxide (NAMO) were evaluated via intraperitoneal injection at doses of 40, 80, and 160 mg/kg. Histological analysis revealed that increasing doses of NAMO led to more orderly hepatocyte arrangement and significantly reduced vacuolar degeneration and inflammatory cell infiltration. NAMO treatment significantly downregulated the mRNA expression of pro-inflammatory cytokines (iNOS, IL-1β, TNF-α, and IL-6) and upregulated the anti-inflammatory cytokine IL-10. Additionally, NAMO enhanced the activity of antioxidant enzymes (CAT, GSH, and T-AOC), while reducing levels of lipid peroxidation markers (MDA) and reactive oxygen species (ROS) in both liver tissues and hepatocytes. Furthermore, NAMO restored the protein expression of mitochondrial regulatory factors NRF1 and PGC-1α and preserved intracellular ATP levels, indicating improved mitochondrial function. Mechanistic investigations showed that NAMO exerted its protective effects by modulating mitochondrial homeostasis and oxidative stress through the SIRT3/AKT signaling pathway being blocked. In conclusion, by minimizing oxidative stress and inflammation, keeping mitochondrial integrity, and managing the SIRT3/AKT pathway, NAMO shields with sepsis-induced acute liver injury. The results indicate that NAMO holds significant potential as a therapeutic agent for managing hepatic impairment associated with sepsis.
Effects of prenatal DINP exposure induced hepatic steatosis and underlying mechanism.
Jin Y, Zhao J, Wang X … +3 more , Li D, Wu M, Li B
Toxicol Appl Pharmacol · 2026 Feb · PMID 41490809 · Publisher ↗
Prenatal exposure to diisononyl phthalate (DINP) exerts sex-specific effects on offspring liver lipid metabolism, yet the underlying mechanisms remain insufficiently defined. In this study, pregnant mice were administere...
Prenatal exposure to diisononyl phthalate (DINP) exerts sex-specific effects on offspring liver lipid metabolism, yet the underlying mechanisms remain insufficiently defined. In this study, pregnant mice were administered DINP throughout gestation, and offspring were evaluated through growth assessment, liver histopathology, lipid profiling, hepatic gene expression, and fecal metabolomics to investigate potential gut-liver axis involvement. Maternal weight and food intake were unaffected, whereas offspring exhibited growth retardation and developmental delay. Male offspring showed elevated serum and hepatic triglycerides and total cholesterol, accompanied by marked hepatic steatosis, while females displayed milder lipid deposition. Mechanistic analyses indicated that males exhibited impaired fatty acid oxidation, with upregulation of fatty acid binding protein (FABP) and perilipin 2 (PLIN2) and downregulation of peroxisome proliferator-activated receptor alpha (PPARα). In contrast, females maintained fatty acid β-oxidation through increased carnitine palmitoyltransferase-1a (CPT-1A) expression and lipid regulation mediated by peroxisome proliferator-activated receptor gamma (PPARγ). Fecal metabolomics revealed alterations in α-linolenic acid metabolism and ubiquinone biosynthesis in males, suggesting disrupted fatty acid utilization and mitochondrial function contributing to hepatic lipid accumulation. Female offspring primarily showed alterations in glycerophospholipid metabolism, which may facilitate membrane remodeling and lipid redistribution, thereby mitigating steatosis. In summary, prenatal DINPexposure induces hepatic steatosis through sex-specific disruptions of the gut-liver metabolic axis. Males are more susceptible to lipid accumulation, whereas females exhibit compensatory adaptations that preserve metabolic balance. These findings provide mechanistic insight into the sex-dependent metabolic consequences of early-life DINP exposure and support a more comprehensive evaluation of its safety profile.
Pre-treatment with sevoflurane alleviates hypoxia-reoxygenation-induced cardiomyocyte damage through PAX8-AS1-targeted miR-145-5p.
Xu Y, Di X, Cai Y … +1 more , Hu S
Toxicol Appl Pharmacol · 2026 Mar · PMID 41485502 · Publisher ↗
OBJECTIVE: To explore the regulatory role of the lncRNA PAX8-AS1/miR-145-5p axis in the mitigation of hypoxia-induced damage to oxygenated myocardial cells by sevoflurane (Sev). METHODS: A hypoxic-reoxygenation (HR) in v...
OBJECTIVE: To explore the regulatory role of the lncRNA PAX8-AS1/miR-145-5p axis in the mitigation of hypoxia-induced damage to oxygenated myocardial cells by sevoflurane (Sev). METHODS: A hypoxic-reoxygenation (HR) in vitro model was established by subjecting cells to 4 h of hypoxia followed by 24 h of aeration. An in vivo MI/RI model was established via ischemia-reperfusion. Gene expression was detected using RT-qPCR. Cell proliferation and apoptosis was assessed using CCK8 and flow cytometry. Expression of myocardial injury markers, inflammatory factors, and oxidative stress markers was measured via ELISA. The targeted relationship between genes was validated using dual luciferase reporter assays and RNA immunoprecipitation. RESULTS: Sev can resist the upregulation of PAX8-AS1 and downregulation of miR-145-5p in HR cardiomyocytes or MI/RI myocardial tissue. PAX8-AS1 overexpression attenuates Sev-induced suppression of cardiomyocyte proliferation and apoptosis inhibition following injury Sev pre-treatment reduced the expression of myocardial cell damage markers, inflammatory factors, and oxidative stress markers, but these markers increased after PAX8-AS1 overexpression and decreased after miR-145-5p analogue transfection. CONCLUSION: Sev can alleviate HR-induced myocardial cell injury by inhibiting PAX8-AS1 and promoting miR-145-5p expression.
Salidroside derivative SHPL-49 accelerates cutaneous wound healing in diabetic mice by modulating macrophage-mediated TGF-β1/Smad2/3 signaling pathway.
Wang F, Ma Z, Latif A … +5 more , Zhan C, Cui C, Zhang P, Cui Q, Zhang J
Toxicol Appl Pharmacol · 2026 Feb · PMID 41485501 · Publisher ↗
Impaired wound healing represents a major complication of diabetes, yet effective therapeutic options remain limited. Our research group has developed a salidroside derivative, SHPL-49, which exhibits antioxidant, anti-i...
Impaired wound healing represents a major complication of diabetes, yet effective therapeutic options remain limited. Our research group has developed a salidroside derivative, SHPL-49, which exhibits antioxidant, anti-inflammatory, and pro-angiogenic properties. We hypothesized that SHPL-49 may promote diabetic wound healing through the modulation of macrophage-mediated immune responses and fibroblast activity. In vivo studies revealed that SHPL-49 significantly accelerated wound closure in diabetic mice, with enhanced granulation tissue formation and extracellular matrix (ECM) deposition. Mechanistically, SHPL-49 induced M2 polarization of wound-associated macrophages, which subsequently secreted TGF-β1 to activate the TGF-β1/Smad2/3 pathway in fibroblasts. In vitro experiments further confirmed that SHPL-49 directly promoted M2 polarization in RAW 264.7 macrophages, as evidenced by increased CD206 expression and TGF-β1 secretion. The conditioned medium from SHPL-49-activated macrophages promoted Smad2/3 phosphorylation in L929 fibroblasts, thereby stimulating their proliferation, migration, and upregulating the expression of collagen I/III, α-SMA, and TGFβRI. Collectively, our findings suggest that SHPL-49 is a promising therapeutic candidate for diabetic wound healing, functioning through a macrophage-to-fibroblast signaling axis: it polarizes macrophages toward an M2 phenotype, which subsequently release TGF-β1 to enhance fibroblast function via the Smad2/3 signaling pathway. This study establishes a theoretical foundation for the future exploration and development of novel therapeutic indications for SHPL-49.
Histone deacetylase SIRT2 regulates the development and metastasis of tongue cancer via FZD1-mediated Wnt/β-catenin pathway.
Lu Z, Lin M
Toxicol Appl Pharmacol · 2026 Mar · PMID 41485500 · Publisher ↗
In this research, we mainly focus on the mechanism of histone deacetylase sirtuin 2 (SIRT2) affecting the growth and metastasis of tongue cancer using in vitro and in vivo experiments. Human tongue cancer cells SCC-25, S...
In this research, we mainly focus on the mechanism of histone deacetylase sirtuin 2 (SIRT2) affecting the growth and metastasis of tongue cancer using in vitro and in vivo experiments. Human tongue cancer cells SCC-25, SCC-9, CAL-27, CAL-33 and human oral epithelial cells were cultured for cell line selection. In vitro, SCC-25 cells were manipulated with pcDNA3.1-SIRT2, pcDNA3.1-FZD1, pcDNA3.1-NC, or/and Wnt/β-catenin pathway inhibitor (MSAB) or activator (SKL2001), while CAL-33 cells were treated with siRNA-SIRT2, siRNA-NC or MSAB. The levels of H3K27ac, β-catenin (nuclear, cytoplasmic and total protein), and Wnt1/3a/7a were detected using WB. Based on data from the ENCODE database, the enrichment level of H3K27ac in the FZD1 promoter region was examined by ChIP experiment. Finally, an orthotopic xenograft tumor model in nude mice was constructed for in vivo validation. Re-expression of SIRT2 impaired the proliferative, invasive, and migratory behaviors of tongue cancer cells, while strengthening their apoptosis. Furthermore, SIRT2 decreased H3K27 acetylation, resulting in increased cytoplasmic β-catenin and decreased expression of FZD1, Wnt1/3a/7a, and nuclear β-catenin. FZD1 overexpression or the Wnt/β-catenin pathway activation partially compromised the inhibitory impacts of SIRT2 on the aforementioned behaviors of human tongue cancer cells. The in vivo validation suggested that SIRT2 played a regulatory role in FZD1 expression and Wnt/β-catenin pathway, thereby hindering the growth and metastasis of the orthotopic tongue cancer xenograft model. SIRT2 inhibits the transcriptional expression of FZD1 through H3K27 deacetylation to block the Wnt/β-catenin pathway, consequently suppressing the growth and metastasis of tongue cancer.
Aloperine mitigates cigarette smoke-induced inflammation and pyroptosis by inhibiting the BRD4/NLRP3/GSDMD pathway in chronic obstructive pulmonary disease.
Li X, Wang Z, Zhang T … +5 more , Zeng X, Li X, Liu K, Huang P, Liu X
Toxicol Appl Pharmacol · 2026 Feb · PMID 41485499 · Publisher ↗
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and progressive airflow limitation, primarily caused by cigarette smoke (CS) exposure. Current pharmacological interventions...
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and progressive airflow limitation, primarily caused by cigarette smoke (CS) exposure. Current pharmacological interventions for COPD merely slow disease progression, which further underscores the urgent need for innovative therapeutics. Aloperine has demonstrated potent anti-inflammatory properties, yet its therapeutic potential in COPD remains unclear. In this study, we investigated the effects and mechanisms of aloperine using a CS-induced COPD mouse model and a cigarette smoke extract (CSE)-stimulated alveolar macrophage (AM; MH-S cell) model. Aloperine treatment significantly improved pulmonary function and alleviated emphysema in COPD mice. Furthermore, it suppressed CSE-induced alveolar macrophage pyroptosis and inflammatory responses both in vivo and in vitro. Mechanistically, the bromodomain-containing protein 4 (BRD4) inhibitor-JQ1-attenuated CSE-induced pyroptosis; however, this effect was partially reversed by the NLRP3 activator- nigericin. Comprehensive analyses, including results from molecular docking, molecular dynamics simulations, surface plasmon resonance, and in vivo and in vitro experiments, supported that aloperine interacts with BRD4 and attenuates NLRP3-mediated pyroptosis. Collectively, our findings indicate that aloperine alleviates CS-induced airway inflammation and pyroptosis potentially by modulating the BRD4/NLRP3/GSDMD signaling, positioning it as a promising therapeutic candidate for COPD.
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