doi:10.3390/jpm12050747engSalido, EduardoTimson, David J.Betancor-Fernández, IsabelPalomino-Morales, RogelioAnoz-Carbonell, ErnestoPacheco-García, Juan LuisMedina, MilagrosPey, Ángel L.Targeting HIF-1a Function in Cancer through the Chaperone Action of NQO1: Implications of Genetic Diversity of NQO1ART-2022-129152HIF-1a is a master regulator of oxygen homeostasis involved in different stages of cancer development. Thus, HIF-1a inhibition represents an interesting target for anti-cancer therapy. It was recently shown that the HIF-1a interaction with NQO1 inhibits proteasomal degradation of the former, thus suggesting that targeting the stability and/or function of NQO1 could lead to the destabilization of HIF-1a as a therapeutic approach. Since the molecular interactions of NQO1 with HIF-1a are beginning to be unraveled, in this review we discuss: (1) Structure–function relationships of HIF-1a; (2) our current knowledge on the intracellular functions and stability of NQO1; (3) the pharmacological modulation of NQO1 by small ligands regarding function and stability; (4) the potential effects of genetic variability of NQO1 in HIF-1a levels and function; (5) the molecular determinants of NQO1 as a chaperone of many different proteins including cancer-associated factors such as HIF-1a, p53 and p73a. This knowledge is then further discussed in the context of potentially targeting the intracellular stability of HIF-1a by acting on its chaperone, NQO1. This could result in novel anti-cancer therapies, always considering that the substantial genetic variability in NQO1 would likely result in different phenotypic responses among individuals.2022http://zaguan.unizar.es/record/15105510.3390/jpm12050747http://zaguan.unizar.es/record/151055oai:zaguan.unizar.es:151055info:eu-repo/grantAgreement/ES/AEI/PID2019-110900GB-I00info:eu-repo/grantAgreement/ES/DGA-FEDER/E35-20RJournal of Personalized Medicine 12, 5 (2022), [28 pp.]byhttps://creativecommons.org/licenses/by/4.0/deed.esinfo:eu-repo/semantics/openAccess