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However, little is known about their mechanisms. Using an<jats:italic>in\u00a0vitro<\/jats:italic>model of cytotoxicity induced by geneticin (G418), we explored the potential signalling mechanisms involved. Incubation of cells with G418 resulted in cell death, as indicated by the change in cell morphology, loss of cell viability and activation of caspase\u20103. Before the onset of cell injury, G418 induced reactive oxygen species (<jats:styled-content style=\"fixed-case\">ROS<\/jats:styled-content>) generation, activated oxidative sensitive kinase P38 and caused a shift of connexin 43 (Cx43) from non\u2010phosphorylated form to hyperphosphorylated form. These changes were largely prevented by antioxidants, suggesting an implication of oxidative stress. Downregulation of Cx43 with inhibitors or si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>suppressed the expression of thioredoxin\u2010interacting protein (<jats:styled-content style=\"fixed-case\">TXNIP<\/jats:styled-content>), activated Akt and protected cells against the toxicity of G418. Further analysis revealed that inhibition of<jats:styled-content style=\"fixed-case\">TXNIP<\/jats:styled-content>with si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>activated Akt and reproduced the protective effect of Cx43\u2010inhibiting agents, whereas suppression of Akt sensitized cells to the toxicity of G418. Furthermore, interference of<jats:styled-content style=\"fixed-case\">TXNIP<\/jats:styled-content>\/Akt also affected puromycin\u2010 and adriamycin\u2010induced cell injury. Our study thus characterized<jats:styled-content style=\"fixed-case\">TXNIP<\/jats:styled-content>as a presently unrecognized molecule implicated in the regulatory actions of Cx43 on oxidative drug injury. Targeting Cx43\/<jats:styled-content style=\"fixed-case\">TXNIP<\/jats:styled-content>\/Akt signalling cascade might be a promising approach to modulate cell response to drugs.<\/jats:p>","DOI":"10.1111\/jcmm.12641","type":"journal-article","created":{"date-parts":[[2015,7,8]],"date-time":"2015-07-08T08:28:53Z","timestamp":1436344133000},"page":"2469-2480","source":"Crossref","is-referenced-by-count":20,"title":["A novel<scp>TXNIP<\/scp>\u2010based mechanism for Cx43\u2010mediated regulation of oxidative drug injury"],"prefix":"10.1111","volume":"19","author":[{"given":"Kun","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Molecular Signaling Interdisciplinary Graduate School of Medicine and Engineering University of Yamanashi Chuo Yamanashi Japan"},{"name":"Department of Nephrology Affiliated Hospital of Nanjing University of Chinese Medicine Nanjing Jiangsu 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