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In this study, we explored a strategy that concurrently suppresses neutrophil\u2010mediated inflammation and reverses immune dysfunction. Combined treatment with the neutrophil elastase (NE) inhibitor Sivelestat and the indoleamine 2,3\u2010dioxygenase\u20101 (IDO1) inhibitor Epacadostat showed superior efficacy to either monotherapy in LPS\u2010 and CLP\u2010induced septic mice. Based on this concept, a novel dual IDO1\/NE inhibitor, IMM\u2010H018, was designed and synthesized. IMM\u2010H018 effectively inhibited both IDO1 and NE activities in vitro and in vivo and significantly improved survival in CLP\u2010induced sepsis. In low\u2010dose LPS models, IMM\u2010H018 reduced systemic inflammation and restored immune function in peripheral blood, thymus, and spleen, outperforming the combination therapy. Furthermore, IMM\u2010H018 alleviated sepsis\u2010associated acute kidney injury by improving renal perfusion and reducing microthrombosis through inhibition of the IDO1\u2010Kyn\u2010AhR\u2010TF pathway. In a two\u2010hit sepsis model, IMM\u2010H018 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\u2010H018 as a promising therapeutic candidate for sepsis and sepsis\u2010associated kidney injury.<\/jats:p>","DOI":"10.1002\/advs.76504","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:55:49Z","timestamp":1784559349000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel IDO1\/NE Dual Inhibitor, IMM\u2010H018 Prevents the Primary and Secondary Sepsis and Ameliorates the Kidney Injury Through Inhibiting the Cytokine Storm and Microthrombosis, and Reversing Immunosuppression"],"prefix":"10.1002","volume":"13","author":[{"given":"Yi","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences &amp; Peking Union Medical College  Beijing P. R. 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