IDO1-mediated AhR activation up-regulates pentose phosphate pathway via NRF2 to inhibit ferroptosis in lung cancer

Ferroptosis is a type of cell death marked by iron-dependent lipid peroxide accumulation. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the catabolism of tryptophan through kynurenine pathway, participates in the development of multiple tumor types. However, the role of IDO1 in tumor ferroptosis is unclear. In this study, we identified IDO1 as a key regulator of ferroptosis in lung cancer. With Erastin-treated lung cancer cells, we found that IDO1 inhibited ferroptosis, reduced the generation of lipid peroxide and ROS. Mechanistically, IDO1 promoted the expression of nuclear factor erythroid 2-related factor 2 (NRF2) through activating aryl hydrocarbon receptor (AhR) pathway. IDO1 up-regulated the expression of solute carrier family 7 member 11 (SLC7A11) and the activity of pentose phosphate pathway (PPP) via AhR-NRF2 axis, promoted the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), thereby inhibiting ferroptosis. Moreover, combined treatment with IDO1 inhibitor and Erastin inhibited tumor growth, down-regulated SLC7A11 expression and PPP activity, promoted tumor ferroptosis in lung cancer-bearing mice. In conclusion, this study revealed the function of IDO1 in lung cancer ferroptosis and provided a new strategy for lung cancer therapy.