Kynurenine importation by SLC7A11 propagates anti-ferroptotic signaling

IDO1 oxidizes tryptophan (TRP) to generate kynurenine (KYN), the substrate for 1-carbon and NAD metabolism, and is implicated in pro-cancer pathophysiology and infection biology. However, the mechanistic relationships between IDO1 in amino acid depletion versus product generation have remained a longstanding mystery. We found an unrecognized link between IDO1 and cell survival mediated by KYN that serves as the source for molecules that inhibit ferroptotic cell death. We show that this effect requires KYN export from IDO1-expressing cells, which is then available for non-IDO1-expressing cells via SLC7A11, the central transporter involved in ferroptosis suppression. Whether inside the “producer” IDO1+ cell or the “receiver” cell, KYN is converted into downstream metabolites, suppressing ferroptosis by ROS scavenging and activating an NRF2-dependent, AHR-independent cell-protective pathway, including SLC7A11, propagating anti-ferroptotic signaling. IDO1, therefore, controls a multi-pronged protection pathway from ferroptotic cell death, underscoring the need to re-evaluate the use of IDO1 inhibitors in cancer treatment. [Display omitted] •IDO1 generates metabolites that suppress ferroptosis•Kynurenine-derived metabolites activate three anti-ferroptotic pathways•Exported kynurenine is imported by SLC7A11•Kynurenine activates transient cysteine starvation IDO1 metabolizes tryptophan to kynurenine, which is closely tied to the pro-tumor effects of myeloid cells and tumor cells that hijack IDO1 expression. By tracing tryptophan consumption by IDO1, Fiore et al. show that kynurenine is the source of molecules that suppress redox cell death by three distinct molecular pathways.