Kynurenine importation by SLC7A11 propagates anti-ferroptotic signaling
IDO1 oxidizes tryptophan (TRP) to generate kynurenine (KYN), the substrate for 1-carbon metabolism and NAD biosynthesis 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 long-standing 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 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, which further propagates anti-ferroptotic signaling. IDO1 therefore controls a multi-pronged protection pathway from ferroptotic cell death, underscoring the need to re-focus the clinical use of IDO1 inhibitors in cancer.