Toxicology and applied pharmacology最新文献

{"title":"Corrigendum to 'Carnosic acid prevents COL1A2 transcription through the reduction of Smad3 acetylation via the AMPKα1/SIRT1 pathway' [Toxicology and Applied Pharmacology 339 (2018) 172-180].","authors":"Yan Zhao, Xue Shi, Chunchun Ding, Dongcheng Feng, Yang Li, Yan Hu, Li Wang, Dongyan Gao, Xiaofeng Tian, Jihong Yao","doi":"10.1016/j.taap.2026.117808","DOIUrl":"10.1016/j.taap.2026.117808","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117808"},"PeriodicalIF":3.4,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147616795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ginsenoside Rb1 attenuates hyperoxia-induced lung injury in neonatal rats by inhibiting ferroptosis via the system Xc^- pathway.","authors":"Huidan Lian, Haiyu Zhou, Jie Dong, Junyi Qian, Yue Cheng, Jinyu Lou, Xinqi Zheng, Wei Lin, Danyun Jia","doi":"10.1016/j.taap.2026.117855","DOIUrl":"https://doi.org/10.1016/j.taap.2026.117855","url":null,"abstract":"<p><strong>Background: </strong>Hyperoxia-induced lung injury (HALI) is a common and severe complication in neonatal intensive care units, and there is currently no effective therapy available. Ferroptosis, a newly recognized form of iron-dependent regulated cell death, has recently been implicated in the pathogenesis of this disease. Ginsenosides are bioactive components extracted from ginseng. Among them, ginsenoside Rb1 (GsRb1) belongs to the protopanaxadiol-type saponins, and its molecular structure is C₅₄H₉₂O₂₃. This study aimed to investigate the protective effects and underlying mechanisms of GsRb1 in neonatal rats with hyperoxia-induced lung injury.</p><p><strong>Methods: </strong>A neonatal rat model of hyperoxia-induced lung injury and an in vitro alveolar epithelial cell model of hyperoxic damage were established. Histopathological changes, inflammatory cytokines, oxidative stress, and key ferroptosis-related proteins like the solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression were assessed using hematoxylin-eosin staining, enzyme-linked immunosorbent assay, Western blotting, transmission electron microscopy, and immunofluorescence. The ferroptosis inhibitor, liproxstatin-1(Lip-1), and the system Xc^- inhibitor, erastin, were used for mechanistic validation.</p><p><strong>Results: </strong>GsRb1 significantly alleviated hyperoxia-induced alveolar structural disruption, pulmonary edema, and elevated levels of inflammatory cytokines (interleukin (IL)-1β, IL-6, and tumor necrosis factor-α(TNF-α)). Moreover, GsRb1 reversed the characteristic features of hyperoxia-induced ferroptosis, including decreased intracellular ferrous and malondialdehyde levels, improved mitochondrial morphology, and regulation of ferroptosis-associated proteins (upregulating SLC7A11, GPX4, and Ferritin heavy chain 1 (FTH1) while downregulating Transferrin receptor protein (TFR). The protective effects of GsRb1 were comparable to those of the classical ferroptosis inhibitor Lip-1. Molecular docking analysis revealed that GsRb1 could directly and stably bind to the active pocket of the SLC7A11. Furthermore, GsRb1 reversed erastin-induced pulmonary injury and ferroptosis, confirming that its protective effects depend on system Xc^- pathway activation.</p><p><strong>Conclusion: </strong>GsRb1 exerts protective effects against hyperoxia-induced lung injury in neonatal rats by targeting SLC7A11 to activate the system Xc^- pathway, thereby inhibiting ferroptosis in alveolar epithelial cells.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117855"},"PeriodicalIF":3.4,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of TGF-β/ALK5/SMAD signaling alleviates behavioral and neurochemical deficits in tramadol withdrawal.","authors":"Shahid Nazir Wani, Amarjot Kaur Grewal, Ojashvi Sharma, Amit Kumar, Varinder Singh, Heena Khan, Thakur Gurjeet Singh, Tanveer Singh, Sheikh F Ahmad, Haneen A Al-Mazroua","doi":"10.1016/j.taap.2026.117849","DOIUrl":"10.1016/j.taap.2026.117849","url":null,"abstract":"<p><p>Opioid withdrawal state poses profound neurobiological and clinical complications characterized by neuroinflammation, oxidative stress, and neurotransmitter imbalance. Tramadol, a widely used synthetic opioid, induces a distinct withdrawal syndrome with poorly understood mechanisms, limiting targeted therapeutic options. The current investigation evaluated the neuroprotective potential of SRI-011381 hydrochloride, a selective TGF-β receptor agonist, against neurobehavioral and biochemical changes in mice induced by tramadol withdrawal. Male albino mice were administered tramadol (50 mg/kg, s.c.) twice daily for 56 days to induce dependence; on day 57, only the morning dose was administrated followed by administration of naloxone (5 mg/kg) by intraperitoneal (i.p) route to precipitate the withdrawal symptoms. Behavioral parameters, including jumping frequency, withdrawal severity score (WSS), and hyperalgesia, were assessed. Biochemical evaluations measured oxidative stress (TBARS, GSH), inflammatory mediators (IL-1β, IL-6, TNF-α, NF-κB), and neurotransmitters (glutamate, serotonin, dopamine). Treatment with SRI-011381 hydrochloride (15 and 30 mg/kg, i.p.) significantly mitigated behavioral signs of withdrawal and restored biochemical homeostasis by enhancing antioxidant defenses, reducing lipid peroxidation, normalizing neurotransmitter levels, and attenuating inflammatory mediators. Co-administration of the SMAD4 inhibitor galnusertib (150 mg/kg, i.p.) reversed these effects, confirming the involvement of a SMAD-dependent mechanism. The standard drug clonidine (0.1 mg/kg, i.p.) exhibited comparable protective effects. These findings suggest that pharmacological activation of the TGF-β/ALK5/SMAD signaling pathway by SRI-011381 hydrochloride effectively ameliorates the neurobehavioral and biochemical disturbances associated with opioid withdrawal, highlighting this pathway as a potential therapeutic target for the treatment of opioid dependence and withdrawal syndromes.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117849"},"PeriodicalIF":3.4,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An innovative label-free approach for investigating epithelial-mesenchymal transition: pharmacological characterization of TGF-β1 effects in A549 cells.","authors":"Francine Medjiofack Djeujo, Marco Solimano Negrini, Pietro Ferri, Andrea Mion, Francesca Ruscitti, Vanessa Pitozzi, Davide Malfacini, Marcello Trevisani, Gessica Marchini, Girolamo Calò","doi":"10.1016/j.taap.2026.117853","DOIUrl":"https://doi.org/10.1016/j.taap.2026.117853","url":null,"abstract":"<p><p>Epithelial-mesenchymal transition (EMT) is a fundamental biological process involved in normal functions such as embryonic development and tissue repair, as well as in pathological conditions including cancer progression, metastasis, and fibrosis. TGF-β1 is a key inducer of EMT, activating pathways that alter cell morphology and gene expression (e.g., downregulation of E-cadherin, upregulation of α-smooth muscle actin (α-SMA)). EMT contributes to fibrotic tissue remodeling in idiopathic pulmonary fibrosis (IPF), a chronic and progressive lung disease characterized by excessive scarring of lung tissue. To achieve a comprehensive evaluation of EMT in respiratory epithelial cells (A549), we employed the standard Operetta CLS platform to assess morphological changes and protein expression of key biomarkers (E-cadherin, α-SMA), alongside an advanced approach that monitored cellular dynamics using the xCELLigence Real-Time Cell Analysis (RTCA) system and quantified biomarker gene expression via RT-qPCR. In Operetta experiments, TGF-β1 reduced cell roundness and E-cadherin protein levels, while it increased cell length and α-SMA protein levels. In xCELLigence RTCA experiments, TGF-β1 reduced the cellular index and E-cadherin gene expression while increasing α-SMA expression. SB-525334 blocked all effects of TGF-β1, whereas nintedanib was more effective in counteracting the stimulatory effects of TGF-β1 on cell length and α-SMA. Interestingly, nintedanib, per se, evoked small but consistent effects opposite to those of TGF-β1. In conclusion, integrating these experimental approaches provides a powerful platform for detailed investigation of EMT mechanisms and for the identification of novel drug candidates that counteract EMT.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117853"},"PeriodicalIF":3.4,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Onalespib enhances antitumor immunity through coordinated catalytic and chaperone-dependent regulation of tryptophan metabolism.","authors":"Linhan Yang, Ruiyang Zhang, Lingyu Li, Minghui Ji, Ruiying Xi, Fei Wang, Yuwen Sheng","doi":"10.1016/j.taap.2026.117854","DOIUrl":"https://doi.org/10.1016/j.taap.2026.117854","url":null,"abstract":"<p><p>Tryptophan metabolism via the kynurenine (Kyn) pathway represents a central mechanism of tumor immune tolerance. Although HSP90 inhibitors have been extensively investigated as anticancer agents, their role in metabolic immune regulation remains incompletely unknown. Here, we identify the HSP90 inhibitor onalespib as a potent suppressor of IDO1-dependent tryptophan metabolism in breast cancer. Mechanistically, onalespib suppresses the tryptophan-kynurenine pathway through coordinated catalytic modulation of IDO1 and interference with HSP90 chaperone-associated regulation of IDO1, accompanied by attenuation of IFN-γ-induced JAK-STAT and NF-κB signaling programs. In vivo, onalespib remodels the tumor immune microenvironment, promotes CD8⁺ effector T-cell infiltration, and enhances the antitumor efficacy of cisplatin without compromising tolerability. Collectively, these findings define a functional HSP90-IDO1 regulatory axis and provide a mechanistic rationale for combination strategies targeting metabolic immune tolerance.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117854"},"PeriodicalIF":3.4,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RAD23A promotes multiple myeloma cell survival through DNA damage response, proteostasis and enhanced metabolic activity.","authors":"Hongxiu Liu, Yihua Wang, Xunru Liu, Ni Yang, Senxin Wang, Jie Zhao, Yaqi Shi, Huichao Wang, Yanping Ma","doi":"10.1016/j.taap.2026.117852","DOIUrl":"https://doi.org/10.1016/j.taap.2026.117852","url":null,"abstract":"<p><p>Multiple myeloma (MM) remains incurable and is characterized by the abnormal proliferation of malignant plasma cells in the bone marrow. RAD23A is a multifunctional protein involved in the ubiquitin-proteasome system (UPS) and DNA damage repair; however, its role in MM remains unclear. Here, we analyzed RAD23A expression and its prognostic relevance across multiple MM cohorts. The biological functions of RAD23A in MM cells were predicted using bulk RNA-seq and single-cell RNA-seq data. Experimental validation was performed in H929 and RPMI8226 MM cell lines. Flow cytometry was used to assess cell cycle progression and apoptosis. Oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and glucose uptake assays were performed to evaluate mitochondrial respiration, glycolytic activity, and glucose uptake, respectively, and RNA sequencing was conducted to further verify the role of RAD23A in MM. Our results showed that RAD23A is upregulated in MM and that high RAD23A expression is associated with greater disease burden and more advanced disease stage. Bioinformatics analyses revealed that RAD23A high MM cells exhibited elevated metabolic activity and increased protein transport. RAD23A knockdown suppressed MM cell growth both in vitro and in vivo, induced DNA damage and endoplasmic reticulum stress, and caused G2/M cell cycle arrest and apoptosis. Moreover, RAD23A knockdown enhanced the sensitivity of MM cells to bortezomib (BTZ) and impaired mitochondrial respiration, glycolytic activity, and glucose uptake. These findings suggest that RAD23A may serve as a multifunctional regulator and potential therapeutic target in MM.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117852"},"PeriodicalIF":3.4,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient pulmonary-targeted therapy and mechanistic insights of a novel glutathione dry powder inhaler in a model of radiation-induced lung injury.","authors":"Yupeng Zhi, Yandong Yang, Bo Wu, Zibin Chen, Hongzhao Huang, Qianqian Wang, Jinsheng Hong, Yingying Xu, Chun Chen","doi":"10.1016/j.taap.2026.117841","DOIUrl":"https://doi.org/10.1016/j.taap.2026.117841","url":null,"abstract":"<p><p>Radiation-induced lung injury (RILI) remains a serious complication of thoracic radiotherapy, with limited treatment options. While reduced glutathione (GSH) has therapeutic potential, its efficacy is hindered by poor pulmonary bioavailability via systemic administration. This study developed a novel glutathione dry powder inhaler (GSH-DPI) through rational formulation optimization. The optimized GSH-DPI exhibited excellent aerosol performance, with a fine particle fraction of 84.48% and sustained release in simulated lung fluid. In a murine RILI model, GSH-DPI (50 mg/kg, intrapulmonary administration) demonstrated superior efficacy in alleviating histopathological damage, restoring immune homeostasis, and reducing oxidative stress and pro-inflammatory cytokine expression compared to equimolar liquid GSH or high-dose oral administration. Mechanistically, analyses of single-cell RNA sequencing data revealed that RILI involves substantial alveolar type II epithelial cell (AT2) loss, compensatory oxidative stress (Nrf2/HO-1 activation), and progressive pyroptosis. GSH-DPI improved the survival of AT2 cells, simultaneously enhancing Nrf2 response and suppressing GSDMD-N-mediated pyroptosis, thereby interrupting the \"oxidative stress-pyroptosis-inflammation\" vicious cycle. This study highlights GSH-DPI as a promising pulmonary-targeted strategy for RILI, leveraging dual antioxidative and antipyroptotic mechanisms.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"512 ","pages":"117841"},"PeriodicalIF":3.4,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diacerein protects against thioacetamide-induced acute liver injury via modulating HMGB1/TLR4/MyD88/NF-κB signaling pathway.","authors":"Radwa M El Redeny, Mahmoud M Samaha, Dalia H El-Kashef","doi":"10.1016/j.taap.2026.117848","DOIUrl":"10.1016/j.taap.2026.117848","url":null,"abstract":"<p><p>Acute liver injury (ALI) is a serious disease which happens suddenly in people with or without previous liver disease. In this experiment, thioacetamide (TAA) was utilized to induce ALI. The experimental design was conducted using forty-eight adult male Sprague-Dawley rats, which were randomly divided into six groups (n = 8 per group). The control group received no treatment, Dia 100 group received diacerein (100 mg/kg, orally) only once daily for six consecutive days, TAA group received a single intraperitoneal injection of TAA at a dose of 500 mg/kg. For the treatment groups, rats were pretreated orally for six days prior to TAA administration; NAC + TAA group received N-acetylcysteine (50 mg/kg), followed by a single intraperitoneal injection of TAA (500 mg/kg) on day 6. Dia 50 + TAA group received diacerein (50 mg/kg) and Dia 100 + TAA group received diacerein (100 mg/kg) for six consecutive days, followed by TAA injection on day 6. Twenty-four hours after TAA administration, all rats were euthanized. Blood samples were collected for serum separation, and liver tissues were harvested for the assessment of biochemical parameters. Pretreatment with diacerein conferred hepatoprotective effects as evidenced by considerable (p ≤ 0.05) decrease in liver enzymes; ALT, AST, ALP, GGT concomitant with profound (p ≤ 0.05) elevation in serum level of albumin besides improvement in hepatic architecture when compared to TAA group. Diacerein also showed antioxidant properties as evidenced by the significant (p ≤ 0.05) decline in MDA content and substantial (p ≤ 0.05) increment in GSH level. Moreover, diacerein markedly (p ≤ 0.05) reduced inflammation by down-regulating HMGB1/TLR4/MYD88/NF-κB signaling pathway. Collectively, diacerein might be a potential therapeutic candidate for treatment of ALI pending further clinical studies to confirm this notion.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117848"},"PeriodicalIF":3.4,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147821186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tetramethylpyrazine promotes spinal cord injury repair by modulating macrophage M1/M2 polarization via inhibition of the IL-6/JAK2/STAT3 pathway.","authors":"Huizhong Bai, Luyao Huo, Ruiqin Yu, Bowen Deng, Jiashu Yue, Yu Jiang, Yimin Zhou, Yi Zhao, Xiaohong Mu","doi":"10.1016/j.taap.2026.117839","DOIUrl":"10.1016/j.taap.2026.117839","url":null,"abstract":"<p><p>Spinal cord injury (SCI) induces a detrimental secondary inflammatory cascade driven largely by pro-inflammatory M1 macrophages, which impedes neural repair. Tetramethylpyrazine (TMP), a bioactive alkaloid from Ligusticum chuanxiong, has shown promise in modulating neuroinflammation. In this study, Sprague-Dawley rats subjected to thoracic contusion SCI received daily intraperitoneal TMP at 60 mg/kg or 80 mg/kg for 7 days. TMP treatment significantly improved hindlimb motor function, as evidenced by higher Basso-Beattie-Bresnahan (BBB) locomotor scores from day 7 through day 28 post-injury and increased motor evoked potential (MEP) amplitudes at day 28, confirming enhanced motor pathway conduction. Histological analyses (HE and Nissl staining) revealed reductions in lesion cavitation, preservation of neuronal architecture, and attenuated glial scar formation in TMP-treated groups. Immunofluorescence demonstrated increased NeuN, MAP2, and NF200 and decreased GFAP expression, while double staining for iNOS/CCR2 and Arg1/CCR2 indicated a shift from M1 to M2 macrophage polarization. ELISA showed significant reductions in IL-6 and TNF-α and elevation of IL-10, and both WB and RT-qPCR confirmed TMP-mediated suppression of IL-6/JAK2/STAT3 phosphorylation and gene transcription. In vitro, TMP reversed LPS-induced M1/M2 polarization imbalance in RAW 264.7 cells, meanwhile suppressing IL-6/JAK2/STAT3 phosphorylation and gene transcription, reduced pro-inflammatory cytokine release in TMP groups. Furthermore, rescue experiments demonstrated that co-treatment with recombinant IL-6 reversed TMP-mediated suppression of JAK2/STAT3 phosphorylation and M1-to-M2 polarization shift, confirming the IL-6/JAK2/STAT3 pathway as a direct mechanistic target of TMP. These results indicate that TMP fosters histopathological and functional recovery after SCI by reshaping macrophage polarization via inhibition of the IL-6/JAK2/STAT3 pathway, highlighting its potential as an anti-inflammatory neuroprotective therapy.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117839"},"PeriodicalIF":3.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147821159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-clinical pharmacology, pharmacokinetics, and safety evaluation of TAX2, a first-in-class peptide targeting the TSP-1/CD47 matricellular axis.","authors":"Aubéri Henry, Marion Etiennot, Mariem Ghoula, Sonia Poli, Stéphane Dedieu, Albin Jeanne, Aurélie Moniot","doi":"10.1016/j.taap.2026.117835","DOIUrl":"https://doi.org/10.1016/j.taap.2026.117835","url":null,"abstract":"<p><p>Thrombospondin-1 (TSP-1) is a matricellular glycoprotein involved in the regulation of angiogenesis, immune responses, and extracellular matrix remodeling within the tumor microenvironment. Its overexpression and interaction with receptor CD47 have been associated with tumor progression and resistance to therapy. In contrast to CD47/SIRPα blockade, which is constrained by hematological and immunotoxic adverse effects, selective inhibition of the TSP-1/CD47 interaction axis may represent a mechanistically distinct and potentially safer therapeutic approach. TAX2, a 12-amino-acid cyclic peptide, was designed as an orthosteric antagonist of this interaction. Its non-clinical profile was characterized through cross-species binding assays, receptor selectivity profiling, pharmacokinetic and biodistribution analyses in rodents and dogs, in vitro off-target and cytokine release assays, and GLP-compliant toxicology studies. Human pharmacokinetics were predicted using multiple species allometric scaling. TAX2 demonstrated binding to TSP-1 from human, rodent, and canine origin, without measurable interference with CD47/SIRPα signaling under the conditions tested. The peptide exhibited rapid plasma clearance (1-4 h), dose-proportional exposure, and detectable signal in TSP-1-rich tissues and tumor-associated regions in biodistribution studies. No relevant off-target activity or unexpected immunostimulatory effects were observed. TAX2 was well tolerated at doses up to 400 mg/kg in rats and 100 mg/kg in dogs, with no hematological or systemic toxicity, and exposures exceeding the projected clinical range. Overall, these findings establish a translational non-clinical framework for TAX2 as a first-in-class TSP-1/CD47 antagonist with cross-species-reactivity and a favorable pharmacokinetic and safety profile².</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117835"},"PeriodicalIF":3.4,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147821172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}