Ferroptosis mediated by the IDO1/Kyn/AhR pathway triggers acute thymic involution in sepsis

Abstract Acute thymic involution (ATI) is frequently observed during sepsis, however the underlying mechanisms remain poorly understood. This study demonstrates that ferroptosis plays a crucial role in sepsis-associated ATI. We found that pediatric sepsis patients showed significantly elevated kynurenine (Kyn)/tryptophan (Trp) ratios, indicating increased indoleamine 2,3-dioxygenase 1 (IDO1) activity, along with higher Kyn levels compared to controls. Moreover, Kyn levels were negatively correlated with thymus-to-thorax ratio. Further mechanistic analysis revealed that the enhanced expression of IDO1, induced by inflammatory signals, drives the accumulation of Kyn and subsequent activation of the aryl hydrocarbon receptor (AhR), triggering lipid oxidation-related gene transcription and ferroptosis in thymocytes during sepsis. Treatment with 1-methyltryptophan (IDO1 inhibitor) effectively restore thymic function and improve survival in septic mice. Our findings reveal a novel role for the IDO1/Kyn/AhR pathway in ferroptosis, suggesting that targeting this pathway may offer a promising therapeutic strategy for sepsis.