Irisin is associated with survival in sepsis and attenuates macrophage pro-inflammatory responses with involvement of AMPK signaling

Background: Sepsis is a leading cause of morbidity and mortality, yet effective targeted therapies remain limited. We evaluated the prognostic significance of irisin, a myokine, in sepsis cohort and examined its immunomodulatory effects on macrophages using a translational approach. Methods: Patients were enrolled in a prospectively collected sepsis registry and biobank. Multivariable Cox proportional hazards model was conducted to assess independent association between irisin and 30-day mortality. Mechanistic studies used macrophages ex vivo and a murine cecal ligation and puncture (CLP) model. Results: Higher serum irisin was independently associated with lower 30-day mortality (adjusted hazard ratio 0.955, 95% confidence interval 0.913–0.999, p=0.044) in patients with sepsis (N=655). Irisin showed modest discrimination for 30-day mortality (AUROC 0.609), with no statistically significant difference from lactate (AUROC 0.652; p=0.145). In vitro , irisin suppressed LPS-induced pro-inflammatory cytokine production, preserved AMPK phosphorylation, attenuated IκBα degradation, and reduced pro-inflammatory markers in macrophages. Several of these cellular effects were attenuated following AMPKα1 depletion. In vivo , irisin improved 7-day survival after CLP (75% vs. 36%, p<0.05) and reduced systemic inflammatory cytokines at 24 hours. Conclusions: Higher serum irisin was independently associated with lower 30-day mortality in patients with sepsis, although its standalone discriminatory performance was modest. Experimental findings further showed that irisin improved survival and attenuated macrophage inflammatory responses, with AMPK signaling contributing to several cellular effects. These findings support further evaluation of irisin as part of integrated prognostic assessment and investigation of irisin-related signaling in sepsis.