{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:46:36Z","timestamp":1790358396873,"version":"4.1.0"},"reference-count":79,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007950","name":"Tanta University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007950","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Acute kidney injury (AKI) is a serious risk associated with gentamicin. Therefore, the current study investigated whether pretreatment with the antipsychotic trifluoperazine could provide protective effects. Assessment of serum creatinine and blood urea nitrogen, in addition to histopathology analysis, demonstrated that trifluoperazine effectively protected the kidneys from functional and structural abnormalities induced by gentamicin. Several signaling pathways that were modulated by drug treatments were investigated in the kidney and showed that trifluoperazine mitigated gentamicin-triggered oxidative stress evidenced by the preservation of SOD activity, reduction of MDA levels, and inhibition of the transcription of stress-responsive genes,\n                    <jats:italic>Chop<\/jats:italic>\n                    and\n                    <jats:italic>Ho-1<\/jats:italic>\n                    . Moreover, trifluoperazine abrogated the increased protein levels of the p65 subunit of NF-\u03baB and suppressed the transcription of NF-\u03baB target genes,\n                    <jats:italic>IL-1\u03b2, TNF-\u03b1,<\/jats:italic>\n                    and\n                    <jats:italic>Tsp-1<\/jats:italic>\n                    , highlighting the inhibition of the aberrantly activated NF-\u03baB signaling. Further, trifluoperazine attenuated the increased ERK1\/2 phosphorylation by gentamicin. Notably, p62 and LC3B protein levels indicated that trifluoperazine alleviated the impaired autophagy by gentamicin. Additionally, NLRP3 and IL-1\u03b2 protein levels suggested that trifluoperazine mitigated gentamicin-induced NLRP3 inflammasomes activation. Finally, trifluoperazine effectively suppressed apoptosis induction by gentamicin. In conclusion, our study provided the first in vivo preclinical evidence supporting further investigation of the potential of trifluoperazine to mitigate gentamicin-induced AKI.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-47243-w","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T15:51:19Z","timestamp":1776700279000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Amelioration of gentamicin-induced acute kidney injury by trifluoperazine: in vivo mechanistic insights"],"prefix":"10.1038","volume":"16","author":[{"given":"Ahmed E.","family":"Goda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nereen A.","family":"Almosilhy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nageh A.","family":"El-Mahdy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"47243_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics11020182","volume":"11","author":"K Iskandar","year":"2022","unstructured":"Iskandar, K. et al. Antibiotic discovery and resistance: The chase and the race. Antibiotics 11, 182 (2022).","journal-title":"Antibiotics"},{"key":"47243_CR2","doi-asserted-by":"publisher","first-page":"67","DOI":"10.2147\/CPAA.S417298","volume":"15","author":"MY Abbasi","year":"2023","unstructured":"Abbasi, M. Y., Chaijamorn, W., Wiwattanawongsa, K., Charoensareerat, T. & Doungngern, T. Recommendations of gentamicin dose based on different pharmacokinetic\/pharmacodynamic targets for intensive care adult patients: A redefining approach. CPAA 15, 67\u201376 (2023).","journal-title":"CPAA"},{"key":"47243_CR3","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-022-03172-8","volume":"5","author":"SG Mohiuddin","year":"2022","unstructured":"Mohiuddin, S. G., Nguyen, T. V. & Orman, M. A. Pleiotropic actions of phenothiazine drugs are detrimental to Gram-negative bacterial persister cells. Commun. Biol. 5, 217 (2022).","journal-title":"Commun. Biol."},{"key":"47243_CR4","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/s41581-019-0184-x","volume":"15","author":"B Desanti De Oliveira","year":"2019","unstructured":"Desanti De Oliveira, B. et al. Molecular nephrology: types of acute tubular injury. Nat. Rev. Nephrol. 15, 599\u2013612 (2019).","journal-title":"Nat. Rev. Nephrol."},{"key":"47243_CR5","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1093\/cid\/cix186","volume":"64","author":"DSY Ong","year":"2017","unstructured":"Ong, D. S. Y. et al. Short-course adjunctive gentamicin as empirical therapy in patients with severe sepsis and septic shock: A prospective observational cohort study. Clin. Infect. Dis. 64, 1731\u20131736 (2017).","journal-title":"Clin. Infect. Dis."},{"key":"47243_CR6","doi-asserted-by":"publisher","first-page":"7468","DOI":"10.1128\/AAC.03750-14","volume":"58","author":"W Picard","year":"2014","unstructured":"Picard, W. et al. Propensity-based study of aminoglycoside nephrotoxicity in patients with severe sepsis or septic shock. Antimicrob. Agent. Chemother. 58, 7468\u20137474 (2014).","journal-title":"Antimicrob. Agent. Chemother."},{"key":"47243_CR7","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1097\/SHK.0000000000001319","volume":"52","author":"J Cui","year":"2019","unstructured":"Cui, J. et al. N-Acetylcysteine ameliorates gentamicin-induced nephrotoxicity by enhancing autophagy and reducing oxidative damage in miniature pigs. Shock 52, 622\u2013630 (2019).","journal-title":"Shock"},{"key":"47243_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/srep11256","volume":"5","author":"J Cui","year":"2015","unstructured":"Cui, J. et al. Rapamycin protects against gentamicin-induced acute kidney injury via autophagy in mini-pig models. Sci. Rep. 5, 11256 (2015).","journal-title":"Sci. Rep."},{"key":"47243_CR9","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1093\/ndt\/gfl699","volume":"22","author":"S-H Juan","year":"2007","unstructured":"Juan, S.-H. et al. Tetramethylpyrazine protects rat renal tubular cell apoptosis induced by gentamicin. Nephrol. Dial. Transplant. 22, 732\u2013739 (2007).","journal-title":"Nephrol. Dial. Transplant."},{"key":"47243_CR10","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1038\/ki.2010.11","volume":"77","author":"AI Morales","year":"2010","unstructured":"Morales, A. I. et al. Metformin prevents experimental gentamicin-induced nephropathy by a mitochondria-dependent pathway. Kidney Int. 77, 861\u2013869 (2010).","journal-title":"Kidney Int."},{"key":"47243_CR11","doi-asserted-by":"publisher","first-page":"F425","DOI":"10.1152\/ajprenal.1994.266.3.F425","volume":"266","author":"T Nakajima","year":"1994","unstructured":"Nakajima, T., Hishida, A. & Kato, A. Mechanisms for protective effects of free radical scavengers on gentamicin-mediated nephropathy in rats. Am. J. Physiol. Renal Physiol. 266, F425\u2013F431 (1994).","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"47243_CR12","first-page":"388","volume":"16","author":"P Randjelovic","year":"2017","unstructured":"Randjelovic, P., Veljkovic, S., Stojiljkovic, N., Sokolovic, D. & Ilic, I. Gentamicin nephrotoxicity in animals: Current knowledge and future perspectives. Excli J. 16, 388\u2013399 (2017).","journal-title":"Excli J."},{"key":"47243_CR13","doi-asserted-by":"publisher","first-page":"11085","DOI":"10.1073\/pnas.1920154117","volume":"117","author":"K Bhat","year":"2020","unstructured":"Bhat, K. et al. The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma. Proc. Natl. Acad. Sci. U.S.A. 117, 11085\u201311096 (2020).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"47243_CR14","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2018.3885","author":"X Chen","year":"2018","unstructured":"Chen, X., Luo, X. & Cheng, Y. Trifluoperazine prevents FOXO1 nuclear excretion and reverses doxorubicin-resistance in the SHG44\/DOX drug-resistant glioma cell line. Int. J. Mol. Med. https:\/\/doi.org\/10.3892\/ijmm.2018.3885 (2018).","journal-title":"Int. J. Mol. Med."},{"key":"47243_CR15","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2021.183573","volume":"1863","author":"NJ Sylvain","year":"2021","unstructured":"Sylvain, N. J. et al. The effects of trifluoperazine on brain edema, aquaporin-4 expression and metabolic markers during the acute phase of stroke using photothrombotic mouse model. Biochim. Biophys. Acta (BBA) \u2013 Biomembr. 1863, 183573 (2021).","journal-title":"Biochim. Biophys. Acta (BBA) \u2013 Biomembr."},{"key":"47243_CR16","doi-asserted-by":"publisher","first-page":"16982","DOI":"10.1073\/pnas.1004498107","volume":"107","author":"AS Tsvetkov","year":"2010","unstructured":"Tsvetkov, A. S. et al. A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model. Proc. Natl. Acad. Sci. U.S.A. 107, 16982\u201316987 (2010).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"47243_CR17","doi-asserted-by":"publisher","first-page":"797","DOI":"10.7150\/ijms.82677","volume":"20","author":"R Xing","year":"2023","unstructured":"Xing, R. et al. Trifluoperazine reduces apoptosis and inflammatory responses in traumatic brain injury by preventing the accumulation of Aquaporin4 on the surface of brain cells. Int. J. Med. Sci. 20, 797\u2013809 (2023).","journal-title":"Int. J. Med. Sci."},{"key":"47243_CR18","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1164\/rccm.201207-1180OC","volume":"186","author":"C-T Yeh","year":"2012","unstructured":"Yeh, C.-T. et al. Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer. Am. J. Respir. Crit. Care Med. 186, 1180\u20131188 (2012).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"47243_CR19","doi-asserted-by":"publisher","first-page":"15259","DOI":"10.1021\/bi00255a006","volume":"33","author":"WJ Cook","year":"1994","unstructured":"Cook, W. J., Walter, L. J. & Walter, M. R. Drug binding by calmodulin: Crystal structure of a calmodulin-trifluoperazine complex. Biochemistry 33, 15259\u201315265 (1994).","journal-title":"Biochemistry"},{"key":"47243_CR20","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.brainresbull.2005.07.003","volume":"67","author":"CS Lee","year":"2005","unstructured":"Lee, C. S., Han, E. S., Han, Y. S. & Bang, H. Differential effect of calmodulin antagonists on MG132-induced mitochondrial dysfunction and cell death in PC12 cells. Brain Res. Bull. 67, 225\u2013234 (2005).","journal-title":"Brain Res. Bull."},{"key":"47243_CR21","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1007\/s00204-014-1219-5","volume":"88","author":"FD Toledo","year":"2014","unstructured":"Toledo, F. D. et al. The Ca2+-calmodulin-Ca2+\/calmodulin-dependent protein kinase II signaling pathway is involved in oxidative stress-induced mitochondrial permeability transition and apoptosis in isolated rat hepatocytes. Arch Toxicol. 88, 1695\u20131709 (2014).","journal-title":"Arch Toxicol."},{"key":"47243_CR22","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2021.119849","volume":"283","author":"AE Goda","year":"2021","unstructured":"Goda, A. E., Elenany, A. M. & Elsisi, A. E. Novel in vivo potential of trifluoperazine to ameliorate doxorubicin-induced cardiotoxicity involves suppression of NF-\u03baB and apoptosis. Life Sci. 283, 119849 (2021).","journal-title":"Life Sci."},{"key":"47243_CR23","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2021.752771","volume":"15","author":"H-T Huang","year":"2021","unstructured":"Huang, H.-T. et al. Inhibitory effects of Trifluoperazine on peripheral proinflammatory cytokine expression and hypothalamic microglia activation in obese mice induced by chronic feeding with high-fat-diet. Front. Cell. Neurosci. 15, 752771 (2021).","journal-title":"Front. Cell. Neurosci."},{"key":"47243_CR24","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1124\/jpet.107.132167","volume":"325","author":"F Luo","year":"2008","unstructured":"Luo, F. et al. Reversal of chronic inflammatory pain by acute inhibition of Ca2+\/Calmodulin-dependent protein kinase II. J. Pharmacol. Exp. Ther. 325, 267\u2013275 (2008).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"47243_CR25","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.taap.2012.08.001","volume":"264","author":"S Chaudhuri","year":"2012","unstructured":"Chaudhuri, S. et al. Effect of trifluoperazine on toxicity, HIF-1\u03b1 induction and hepatocyte regeneration in acetaminophen toxicity in mice. Toxicol. Appl. Pharmacol. 264, 192\u2013201 (2012).","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"47243_CR26","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1093\/ndt\/15.8.1175","volume":"15","author":"A Erdem","year":"2000","unstructured":"Erdem, A. et al. The protective effect of taurine against gentamicin\u2010induced acute tubular necrosis in rats. Nephrol. Dial. Transplant. 15, 1175\u20131182 (2000).","journal-title":"Nephrol. Dial. Transplant."},{"key":"47243_CR27","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202000926RR","volume":"35","author":"R Zhou","year":"2021","unstructured":"Zhou, R. et al. Nupr1 mediates renal fibrosis via activating fibroblast and promoting epithelial-mesenchymal transition. Faseb. J. 35, e21381 (2021).","journal-title":"Faseb. J."},{"key":"47243_CR28","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1111\/j.1476-5381.2009.00267.x","volume":"157","author":"V Sharma","year":"2009","unstructured":"Sharma, V. & McNeill, J. H. To scale or not to scale: The principles of dose extrapolation. Br. J. Pharmacol. 157, 907\u2013921 (2009).","journal-title":"Br. J. Pharmacol."},{"key":"47243_CR29","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD003545.pub2","author":"LDO Marques","year":"2004","unstructured":"Marques, L. D. O., Soares, B. & Silva De Lima, M. Trifluoperazine for schizophrenia. Cochrane Database Syst. Rev. https:\/\/doi.org\/10.1002\/14651858.CD003545.pub2 (2004).","journal-title":"Cochrane Database Syst. Rev."},{"key":"47243_CR30","doi-asserted-by":"publisher","unstructured":"Bancroft, J. D. & Layton, C. The hematoxylins and eosin. In Bancroft\u2019s Theory and Practice of Histological Techniques 173\u2013186 https:\/\/doi.org\/10.1016\/B978-0-7020-4226-3.00010-X (Elsevier, 2013).","DOI":"10.1016\/B978-0-7020-4226-3.00010-X"},{"key":"47243_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7243\/2055-091X-3-1","volume":"3","author":"U Khalid","year":"2016","unstructured":"Khalid, U. et al. Kidney ischaemia reperfusion injury in the rat: the EGTI scoring system as a valid and reliable tool for histological assessment. J. Histol. Histopathol. 3, 1 (2016).","journal-title":"J. Histol. Histopathol."},{"key":"47243_CR32","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/j.jacc.2010.04.019","volume":"56","author":"SG Drakos","year":"2010","unstructured":"Drakos, S. G. et al. Impact of mechanical unloading on microvasculature and associated central remodeling features of the failing human heart. J. Am. Coll. Cardiol. 56, 382\u2013391 (2010).","journal-title":"J. Am. Coll. Cardiol."},{"key":"47243_CR33","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1186\/1297-9716-44-89","volume":"44","author":"EC Araujo","year":"2013","unstructured":"Araujo, E. C. et al. Heme oxygenase-1 activity is involved in the control of Toxoplasma gondii infection in the lung of BALB\/c and C57BL\/6 and in the small intestine of C57BL\/6 mice. Vet. Res. 44, 89 (2013).","journal-title":"Vet. Res."},{"key":"47243_CR34","doi-asserted-by":"publisher","first-page":"e02106","DOI":"10.1128\/JVI.02106-16","volume":"91","author":"LA Castro-Jorge","year":"2017","unstructured":"Castro-Jorge, L. A. et al. A protective role for interleukin-1 signaling during mouse adenovirus type 1-induced encephalitis. J. Virol. 91, e02106-e2116 (2017).","journal-title":"J. Virol."},{"key":"47243_CR35","doi-asserted-by":"publisher","first-page":"H1344","DOI":"10.1152\/ajpheart.01246.2008","volume":"296","author":"J Sun","year":"2009","unstructured":"Sun, J. et al. Thrombospondin-1 modulates VEGF-A-mediated Akt signaling and capillary survival in the developing retina. Am. J. Physiol. Heart Circ. Physiol. 296, H1344\u2013H1351 (2009).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"47243_CR36","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1311-5","volume":"15","author":"Z Tan","year":"2018","unstructured":"Tan, Z. et al. ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells. J. Neuroinflamm. 15, 275 (2018).","journal-title":"J. Neuroinflamm."},{"key":"47243_CR37","doi-asserted-by":"publisher","first-page":"25395","DOI":"10.1074\/jbc.M302364200","volume":"278","author":"N Yahagi","year":"2003","unstructured":"Yahagi, N. et al. p53 activation in adipocytes of obese mice. J. Biol. Chem. 278, 25395\u201325400 (2003).","journal-title":"J. Biol. Chem."},{"key":"47243_CR38","doi-asserted-by":"publisher","first-page":"E844","DOI":"10.1152\/ajpendo.00029.2011","volume":"301","author":"I Yamakawa","year":"2011","unstructured":"Yamakawa, I. et al. Inactivation of TNF-\u03b1 ameliorates diabetic neuropathy in mice. Am. J. Physiol. Endocrinol. Metab. 301, E844\u2013E852 (2011).","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"47243_CR39","first-page":"879","volume":"10","author":"AP Ponnampalam","year":"2004","unstructured":"Ponnampalam, A. P., Weston, G. C., Trajstman, A. C., Susil, B. & Rogers, P. A. W. Molecular classification of human endometrial cycle stages by transcriptional profiling. MHR: Basic. Sci. Reprod. Med. 10, 879\u2013893 (2004).","journal-title":"MHR: Basic. Sci. Reprod. Med."},{"key":"47243_CR40","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.molonc.2014.08.010","volume":"9","author":"AE Goda","year":"2015","unstructured":"Goda, A. E., Erikson, R. L., Sakai, T., Ahn, J.-S. & Kim, B.-Y. Preclinical evaluation of bortezomib\/dipyridamole novel combination as a potential therapeutic modality for hematologic malignancies. Mol. Oncol. 9, 309\u2013322 (2015).","journal-title":"Mol. Oncol."},{"key":"47243_CR41","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1089\/ars.2013.5768","volume":"23","author":"BL Chen","year":"2015","unstructured":"Chen, B. L. et al. CCAAT-enhancer-binding protein homologous protein deficiency attenuates oxidative stress and renal ischemia-reperfusion injury. Antioxid. Redox Signal. 23, 1233\u20131245 (2015).","journal-title":"Antioxid. Redox Signal."},{"key":"47243_CR42","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1053\/j.ajkd.2016.10.037","volume":"69","author":"S Bolisetty","year":"2017","unstructured":"Bolisetty, S., Zarjou, A. & Agarwal, A. Heme oxygenase 1 as a therapeutic target in acute kidney injury. Am. J. Kidney Dis. 69, 531\u2013545 (2017).","journal-title":"Am. J. Kidney Dis."},{"key":"47243_CR43","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1159\/000531290","volume":"147","author":"H Guo","year":"2023","unstructured":"Guo, H. & Bechtel-Walz, W. The interplay of autophagy and oxidative stress in the kidney: What do we know?. Nephron 147, 627\u2013642 (2023).","journal-title":"Nephron"},{"key":"47243_CR80","doi-asserted-by":"crossref","unstructured":"Yoshii, S. R. & Mizushima, N. Monitoring and measuring autophagy. Int. J. Mol. Sci. 18, 1865 (2017).","DOI":"10.3390\/ijms18091865"},{"key":"47243_CR44","doi-asserted-by":"publisher","first-page":"815","DOI":"10.3389\/fimmu.2019.00815","volume":"10","author":"N Song","year":"2019","unstructured":"Song, N., Thaiss, F. & Guo, L. NF\u03baB and kidney injury. Front. Immunol. 10, 815 (2019).","journal-title":"Front. Immunol."},{"key":"47243_CR45","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.116276","volume":"172","author":"W Chen","year":"2024","unstructured":"Chen, W. et al. Baicalin-2-ethoxyethyl ester alleviates gentamicin-induced acute kidney injury via NF-\u03baB signaling pathway. Biomed. Pharmacother. 172, 116276 (2024).","journal-title":"Biomed. Pharmacother."},{"key":"47243_CR46","doi-asserted-by":"publisher","first-page":"e61","DOI":"10.1159\/000198235","volume":"111","author":"C Hugo","year":"2009","unstructured":"Hugo, C. & Daniel, C. Thrombospondin in renal disease. Nephron. Exp. Nephrol. 111, e61\u2013e66 (2009).","journal-title":"Nephron. Exp. Nephrol."},{"key":"47243_CR47","doi-asserted-by":"publisher","first-page":"3451","DOI":"10.1172\/JCI25461","volume":"115","author":"CV Thakar","year":"2005","unstructured":"Thakar, C. V. Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia. J. Clin. Invest. 115, 3451\u20133459 (2005).","journal-title":"J. Clin. Invest."},{"key":"47243_CR48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2012\/463617","volume":"2012","author":"H Cassidy","year":"2012","unstructured":"Cassidy, H. et al. The role of MAPK in drug-induced kidney injury. J. Signal Transduct. 2012, 1\u201315 (2012).","journal-title":"J. Signal Transduct."},{"key":"47243_CR49","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.606392","volume":"12","author":"AH Albino","year":"2021","unstructured":"Albino, A. H. et al. Renal inflammation and innate immune activation underlie the transition from gentamicin-induced acute kidney injury to renal fibrosis. Front. Physiol. 12, 606392 (2021).","journal-title":"Front. Physiol."},{"key":"47243_CR50","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1111\/1348-0421.12771","volume":"64","author":"K Tsuchiya","year":"2020","unstructured":"Tsuchiya, K. Inflammasome-associated cell death: pyroptosis, apoptosis, and physiological implications. Microbiol. Immunol. 64, 252\u2013269 (2020).","journal-title":"Microbiol. Immunol."},{"key":"47243_CR51","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.2215\/CJN.11290821","volume":"17","author":"MA Perazella","year":"2022","unstructured":"Perazella, M. A. & Rosner, M. H. Drug-induced acute kidney injury. Clin. J. Am. Soc. Nephrol. 17, 1220\u20131233 (2022).","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"47243_CR52","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2019.108863","volume":"315","author":"RS Abdelrahman","year":"2020","unstructured":"Abdelrahman, R. S. & Abdelmageed, M. E. Renoprotective effect of celecoxib against gentamicin-induced nephrotoxicity through suppressing NF\u03baB and caspase-3 signaling pathways in rats. Chem. Biol. Interact. 315, 108863 (2020).","journal-title":"Chem. Biol. Interact."},{"key":"47243_CR53","doi-asserted-by":"publisher","first-page":"4077","DOI":"10.1242\/jcs.00739","volume":"116","author":"S Haupt","year":"2003","unstructured":"Haupt, S., Berger, M., Goldberg, Z. & Haupt, Y. Apoptosis - The p53 network. J. Cell Sci. 116, 4077\u20134085 (2003).","journal-title":"J. Cell Sci."},{"key":"47243_CR54","doi-asserted-by":"publisher","first-page":"3717","DOI":"10.1128\/AAC.00326-16","volume":"60","author":"JA Andersson","year":"2016","unstructured":"Andersson, J. A. et al. New role for FDA-approved drugs in combating antibiotic-resistant bacteria. Antimicrob. Agent. Chemother. 60, 3717\u20133729 (2016).","journal-title":"Antimicrob. Agent. Chemother."},{"key":"47243_CR55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0189950","volume":"13","author":"H Nehme","year":"2018","unstructured":"Nehme, H. et al. Antibacterial activity of antipsychotic agents, their association with lipid nanocapsules and its impact on the properties of the nanocarriers and on antibacterial activity. PLoS ONE 13, e0189950 (2018).","journal-title":"PLoS ONE"},{"key":"47243_CR56","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1007\/s00109-019-01762-4","volume":"97","author":"JH Park","year":"2019","unstructured":"Park, J. H. et al. Repositioning of the antipsychotic drug TFP for sepsis treatment. J. Mol. Med. 97, 647\u2013658 (2019).","journal-title":"J. Mol. Med."},{"key":"47243_CR57","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1189\/jlb.0510286","volume":"90","author":"X Zhang","year":"2011","unstructured":"Zhang, X. et al. Calcium\/calmodulin-dependent protein kinase (CaMK) I\u03b1 mediates the macrophage inflammatory response to sepsis. J. Leukoc. Biol. 90, 249\u2013261 (2011).","journal-title":"J. Leukoc. Biol."},{"key":"47243_CR58","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1152\/physrev.00026.2013","volume":"94","author":"DB Zorov","year":"2014","unstructured":"Zorov, D. B., Juhaszova, M. & Sollott, S. J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol. Rev. 94, 909\u2013950 (2014).","journal-title":"Physiol. Rev."},{"key":"47243_CR59","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1055\/a-1154-8672","volume":"70","author":"A Kiani","year":"2020","unstructured":"Kiani, A., Nik, S. H., Khodadoost, A., Salimi, A. & Pourahmad, J. Trifluoperazine an antipsychotic drug and inhibitor of mitochondrial permeability transition protects cytarabine and ifosfamide-induced neurotoxicity. Drug. Res. (Stuttg.) 70, 265\u2013272 (2020).","journal-title":"Drug. Res. (Stuttg.)"},{"key":"47243_CR60","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2020.101751","volume":"37","author":"S-H Jung","year":"2020","unstructured":"Jung, S.-H. et al. Diclofenac impairs autophagic flux via oxidative stress and lysosomal dysfunction: Implications for hepatotoxicity. Redox Biol. 37, 101751 (2020).","journal-title":"Redox Biol."},{"key":"47243_CR61","doi-asserted-by":"publisher","DOI":"10.3390\/biom10050761","volume":"10","author":"SB Song","year":"2020","unstructured":"Song, S. B. & Hwang, E. S. High levels of ROS impair lysosomal acidity and autophagy flux in glucose-deprived fibroblasts by activating ATM and Erk pathways. Biomolecules 10, 761 (2020).","journal-title":"Biomolecules"},{"key":"47243_CR62","doi-asserted-by":"publisher","first-page":"1700","DOI":"10.1016\/j.neurobiolaging.2014.01.027","volume":"35","author":"M H\u00f6llerhage","year":"2014","unstructured":"H\u00f6llerhage, M. et al. Trifluoperazine rescues human dopaminergic cells from wild-type \u03b1-synuclein-induced toxicity. Neurobiol. Aging 35, 1700\u20131711 (2014).","journal-title":"Neurobiol. Aging"},{"key":"47243_CR63","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2024.122566","volume":"344","author":"AK Saleh","year":"2024","unstructured":"Saleh, A. K., El-Mahdy, N. A., El-Masry, T. A. & El-Kadem, A. H. Trifluoperazine mitigates cyclophosphamide-induced hepatic oxidative stress, inflammation, and apoptosis in mice by modulating the AKT\/mTOR-driven autophagy and Nrf2\/HO-1 signaling cascades. Life Sci. 344, 122566 (2024).","journal-title":"Life Sci."},{"key":"47243_CR64","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2021.174432","volume":"909","author":"E Khaledi","year":"2021","unstructured":"Khaledi, E. et al. Trifluoperazine reduces cuprizone-induced demyelination via targeting Nrf2 and IKB in mice. Eur. J. Pharmacol. 909, 174432 (2021).","journal-title":"Eur. J. Pharmacol."},{"key":"47243_CR65","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27134190","volume":"27","author":"Z Gong","year":"2022","unstructured":"Gong, Z. et al. Phosphorylation of ERK-dependent NF-\u03baB triggers NLRP3 inflammasome mediated by vimentin in EV71-infected glioblastoma cells. Molecules 27, 4190 (2022).","journal-title":"Molecules"},{"key":"47243_CR66","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1111\/imr.12286","volume":"265","author":"EI Elliott","year":"2015","unstructured":"Elliott, E. I. & Sutterwala, F. S. Initiation and perpetuation of NLRP3 inflammasome activation and assembly. Immunol. Rev. 265, 35\u201352 (2015).","journal-title":"Immunol. Rev."},{"key":"47243_CR67","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1038\/nri2725","volume":"10","author":"J Tschopp","year":"2010","unstructured":"Tschopp, J. & Schroder, K. NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production?. Nat. Rev. Immunol. 10, 210\u2013215 (2010).","journal-title":"Nat. Rev. Immunol."},{"key":"47243_CR68","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1038\/ni.1980","volume":"12","author":"K Nakahira","year":"2011","unstructured":"Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222\u2013230 (2011).","journal-title":"Nat. Immunol."},{"key":"47243_CR69","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1038\/nature09663","volume":"469","author":"R Zhou","year":"2011","unstructured":"Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221\u2013225 (2011).","journal-title":"Nature"},{"key":"47243_CR70","doi-asserted-by":"publisher","first-page":"6232","DOI":"10.1002\/jcp.26490","volume":"233","author":"A D\u2019Espessailles","year":"2018","unstructured":"D\u2019Espessailles, A., Mora, Y. A., Fuentes, C. & Cifuentes, M. Calcium-sensing receptor activates the NLRP3 inflammasome in LS14 preadipocytes mediated by ERK1\/2 signaling. J. Cell. Physiol. 233, 6232\u20136240 (2018).","journal-title":"J. Cell. Physiol."},{"key":"47243_CR71","doi-asserted-by":"publisher","first-page":"2172961","DOI":"10.1080\/0886022X.2023.2172961","volume":"45","author":"Z Huang","year":"2023","unstructured":"Huang, Z., Peng, Y., Ke, G., Xiao, Y. & Chen, Y. CaMKII may regulate renal tubular epithelial cell apoptosis through YAP\/NFAT2 in acute kidney injury mice. Ren. Fail. 45, 2172961 (2023).","journal-title":"Ren. Fail."},{"key":"47243_CR72","doi-asserted-by":"publisher","first-page":"F329","DOI":"10.1152\/ajprenal.00358.2017","volume":"314","author":"E-J Park","year":"2018","unstructured":"Park, E.-J. et al. miR-34c-5p and CaMKII are involved in aldosterone-induced fibrosis in kidney collecting duct cells. Am. J. Physiol. Renal Physiol. 314, F329\u2013F342 (2018).","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"47243_CR73","doi-asserted-by":"publisher","first-page":"1778","DOI":"10.1159\/000495681","volume":"51","author":"Y Zhang","year":"2018","unstructured":"Zhang, Y. et al. Hyperglycaemia stress-induced renal injury is caused by extensive mitochondrial fragmentation, attenuated MKP1 signalling, and activated JNK-CaMKII-Fis1 biological axis. Cell. Physiol. Biochem. 51, 1778\u20131798 (2018).","journal-title":"Cell. Physiol. Biochem."},{"key":"47243_CR74","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0130477","volume":"10","author":"E Cipolletta","year":"2015","unstructured":"Cipolletta, E. et al. Targeting the CaMKII\/ERK interaction in the heart prevents cardiac hypertrophy. PLoS ONE 10, e0130477 (2015).","journal-title":"PLoS ONE"},{"key":"47243_CR75","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2022.111758","volume":"209","author":"T Li","year":"2023","unstructured":"Li, T. et al. Pathological implication of CaMKII in NF-\u03baB pathway and SASP during cardiomyocytes senescence. Mech. Ageing Dev. 209, 111758 (2023).","journal-title":"Mech. Ageing Dev."},{"key":"47243_CR76","doi-asserted-by":"publisher","first-page":"H877","DOI":"10.1152\/ajpheart.00223.2019","volume":"317","author":"T Suetomi","year":"2019","unstructured":"Suetomi, T., Miyamoto, S. & Brown, J. H. Inflammation in nonischemic heart disease: initiation by cardiomyocyte CaMKII and NLRP3 inflammasome signaling. Am. J. Physiol. Heart Circ. Physiol. 317, H877\u2013H890 (2019).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"47243_CR77","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1038\/nsb1194-795","volume":"1","author":"M Vandonselaar","year":"1994","unstructured":"Vandonselaar, M., Hickie, R. A., Quail, W. & Delbaere, L. T. J. Trifluoperazine-induced conformational change in Ca2+-calmodulin. Nat. Struct. Mol. Biol. 1, 795\u2013801 (1994).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"47243_CR78","doi-asserted-by":"publisher","first-page":"45101","DOI":"10.1074\/jbc.M305355200","volume":"278","author":"M Illario","year":"2003","unstructured":"Illario, M. et al. Calcium\/Calmodulin-dependent Protein Kinase II binds to Raf-1 and modulates Integrin-stimulated ERK activation. J. Biol. Chem. 278, 45101\u201345108 (2003).","journal-title":"J. Biol. Chem."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-47243-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-47243-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-47243-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T22:25:43Z","timestamp":1781648743000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-47243-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,20]]},"references-count":79,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["47243"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-47243-w","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,20]]},"assertion":[{"value":"15 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12896"}}