Itaconate regulates PANoptosis in splenocytes to alleviate sepsis-induced multiple organ dysfunction syndrome.

Sepsis is a life-threatening condition triggered by infection and frequently progresses to multiple organ dysfunction syndrome (MODS). Its complex pathophysiology poses significant challenges for effective treatment. Itaconic acid, a key metabolic intermediate, has been recognized for its anti-inflammatory and immunomodulatory properties. Notably, elevated levels of extracellular circulating histones have been detected in the bloodstream of septic patients, and animal models further confirm that circulating histones play a critical role in driving multi-organ injury. This study was developed to investigate the therapeutic potential of itaconate in sepsis-induced MODS and elucidates its underlying molecular mechanisms. Using a sepsis mouse model, the spleen was identified as the primary source of circulating histones in sepsis. Itaconate intervention in septic mice effectively suppressed splenic cell PANoptosis and reduced histone release by modulating iNOS expression, thereby improving survival rates and alleviating multi-organ damage. In parallel, cellular experiments using primary splenic cells further confirmed that itaconate mitigates PANoptosis and decreases circulating histone production through a similar pathway. These findings suggest that itaconate represents a promising therapeutic strategy for sepsis and its complications. Moreover, this study highlights the critical role of splenocyte PANoptosis in histone release, establishing itaconate as a potential candidate for histone-targeted therapy in sepsis.