靶向DNAJC9的共价抑制剂用于脓毒症治疗：一个可成药的炎症靶点

Abstract

Sepsis is a leading cause of mortality among patients in intensive care units (ICUs), with no specific treatments for sepsis available in clinical practice. In this study, we report the discovery of compound A12 , a tanshinone derivative featuring a covalent warhead, which demonstrates potent anti-inflammatory effects both in vitro and in vivo . In a lipopolysaccharide-induced mouse model of endotoxemia and acute systemic inflammation, A12 significantly reduces levels of TNF- α , IL-6, and IL-12. Distinct from current anti-inflammatory small molecules, A12 presents a unique mechanism, covalently binding to DNAJC9, thereby modulating the HSP complex and inhibiting the downstream inflammatory response. This work represents the first application of covalent drug design principles to the structural modification of the natural product tanshinone, and reveals the previously unrecognized role of DNAJC9 in inflammatory diseases, offering a novel therapeutic target for management of sepsis-associated acute systemic inflammation.