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We conclude that iASPP integrates the NF-κBp65 and p53 signaling pathways and thereby regulates cell fate in response to TIS, leading to chemotherapy resistance. These findings suggest that iASPP inhibition might be a strategy that could help restore senescence in cancer cells and improve outcomes of chemotherapy-based therapies. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Globular protein sequences encode not only functional structures (the native state) but also protein foldability, i.e.