Elovanoid-N34 is a homeostatic switch that modulates TXNRD1 for cell survival

Abstract The thioredoxin (TRX) system is an NADP/FAD redox-triggered effector that sustains oxidative stress homeostatic environment, bioenergetics, and detoxifying drug networks. The bioactive lipid Elovanoid (ELV)-N34, derived from omega-3 fatty acid precursors, elicits pro-homeostatic activity via pathways that enhance cell survival and modulate inflammation and senescence gene programming under damaging conditions that encompass redox changes. Limited proteolysis (LiP) screening identified TXNRD1 variants 2, 3, or 5, the reductase of the TXR system, as an intracellular target of ELV-N34. The silencing of TXNRD1 confirmed that the target of ELV-N34 was variant 3. The lipid mediator induces changes in the structure of TXNRD1 that modify the FAD interface domain leading to the modulation of its activity. The addition of ELV-N34 decreased TXNRD1 activity of the membrane subfraction as well as of the cytosol, suggesting possible localizations for the targeted reductase. These results show for the first time that the lipid mediator ELV-N34 directly modulates TXNRD1 activity, undeleting its protective role in several pathological conditions when uncompensated oxidative stress (UOS) evolves.