Igalan Attenuates Sepsis-Induced Inflammation through Covalent Targeting of the NLRP3 Inflammasome Pathway

Abstract

Macrophages play a critical role in sepsis, a life-threatening systemic inflammatory syndrome that necessitates urgent therapeutic intervention. Unfortunately, no approved drugs currently target this specific pathological mechanism. In this study, we identify Igalan, a natural compound that selectively disrupts macrophage-mediated inflammatory cascades in macrophages. Mechanistic studies demonstrate that Igalan alleviates oxidative stress and maintains mitochondrial integrity. Crucially, we reveal that Igalan covalently modifies the NLRP3 (NLR family pyrin domain containing 3) NACHT domain, thereby irreversibly suppressing inflammasome activation and subsequent pro-inflammatory signaling. In vivo studies demonstrate potent therapeutic effects of Igalan, mitigating systemic inflammation in LPS-challenged zebrafish and providing protection against pulmonary injury and intestinal barrier dysfunction in murine sepsis models. Collectively, our work establishes Igalan as a covalent NLRP3 inhibitor with translational potential for sepsis treatment.