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Ferroptosis Mediated by the IDO1/Kyn/AhR Pathway Triggers Acute Thymic Involution in Sepsis

ABSTRACT: Sepsis triggers a systemic inflammatory response that leads to immune dysregulation and widespread organ damage. Acute thymic involution (ATI), a hallmark of sepsis, is characterized by decreased T cell production and weakened immune responses. The mechanism of ATI is not fully understood. In this study, we demonstrate that ferroptosis, an iron-dependent form of regulated cell death, plays a pivotal role in ATI during sepsis. Using a polymicrobial sepsis model, we observed significant ferroptosis-associated thymic damage, which was marked by lipid peroxidation, mitochondrial dysfunction, and a reduction in thymic size and cellularity. Treatment with 1-methyltryptophan (1-MT), an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), effectively reversed these phenotypes, restoring thymic structure and function, and significantly improved survival outcomes in septic mice. Further mechanistic analysis revealed that IDO1 upregulation led to the accumulation of kynurenine, which activates the aryl hydrocarbon receptor (AhR), thereby driving ferroptosis in thymocytes. Our findings uncover a novel role for the IDO1/Kyn/AhR pathway in ferroptosis and suggest that targeting this pathway could be a promising therapeutic strategy for restoring thymic function and improving outcomes in sepsis.

ORGANISM(S): Mus musculus

PROVIDER: GSE280678 | GEO | 2025/07/30

REPOSITORIES: GEO

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Ferroptosis Mediated by the IDO1/Kyn/AhR Pathway Triggers Acute Thymic Involution in Sepsis

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