Indoleamine 2,3-dioxygenase 1 as a Metabolic Switch in Sepsis-Induced Immunosuppression: Transcriptomic Validation and Therapeutic Inhibition by Novel Quinoline Derivatives

Sepsis is a life-threatening condition driven by a dysregulated immune response, remains a leading cause of ICU mortality due to its complex, heterogeneous pathophysiology. This study employed a systems biology approach to analyze human transcriptomic data (GSE128303), identifying phase-specific molecular signatures to bridge the gap between initial hyperinflammation and subsequent immunosuppression. Analysis revealed 2,805 differentially expressed genes (DEGs) in the early phase (6 h) and 1,355 in the late phase (24 h). While pro-inflammatory markers like IL1B persisted, the late phase was uniquely characterized by the activation of the Kynurenine Pathway (KP), specifically the rate-limiting enzyme Indoleamine 2,3-dioxygenase 1 (IDO1). We identified Oncostatin M (OSM), acting through JAK-STAT signaling, as a key activator of the KP. This metabolic shift was synchronized with significant disruptions in zinc homeostasis and elevated metallothionein expression, collectively driving the transition toward immune paralysis. To explore therapeutic interventions, molecular docking and simulation analyses were performed on IDO1 using 19 novel quinoline derivatives. The ligand 2b exhibited superior binding affinity (docking score: -19.07), with simulations confirming a stable protein-ligand complex. These findings establish the OSM-IDO1 axis as a pivotal immune-metabolic hub connecting inflammation and immune exhaustion. Targeting this pathway with quinoline-based inhibitors represents a promising strategy to restore immune equilibrium and improve clinical outcomes in critically ill patients, though further experimental validation is warranted.