A Novel IDO1/NE Dual Inhibitor, IMM‐H018 Prevents the Primary and Secondary Sepsis and Ameliorates the Kidney Injury Through Inhibiting the Cytokine Storm and Microthrombosis, and Reversing Immunosuppression

ABSTRACT Sepsis is characterized by the simultaneous presence of hyperinflammation, immunosuppression, and coagulation abnormalities, making single‐target therapies insufficient. In this study, we explored a strategy that concurrently suppresses neutrophil‐mediated inflammation and reverses immune dysfunction. Combined treatment with the neutrophil elastase (NE) inhibitor Sivelestat and the indoleamine 2,3‐dioxygenase‐1 (IDO1) inhibitor Epacadostat showed superior efficacy to either monotherapy in LPS‐ and CLP‐induced septic mice. Based on this concept, a novel dual IDO1/NE inhibitor, IMM‐H018, was designed and synthesized. IMM‐H018 effectively inhibited both IDO1 and NE activities in vitro and in vivo and significantly improved survival in CLP‐induced sepsis. In low‐dose LPS models, IMM‐H018 reduced systemic inflammation and restored immune function in peripheral blood, thymus, and spleen, outperforming the combination therapy. Furthermore, IMM‐H018 alleviated sepsis‐associated acute kidney injury by improving renal perfusion and reducing microthrombosis through inhibition of the IDO1‐Kyn‐AhR‐TF pathway. In a two‐hit sepsis model, IMM‐H018 prevented secondary infection, enhanced bacterial clearance through improved phagocytosis, protected against renal damage, and delayed progression from acute kidney injury to chronic kidney dysfunction. These findings identify IMM‐H018 as a promising therapeutic candidate for sepsis and sepsis‐associated kidney injury.