FNDC4 modulates macrophage responses and suppresses NF-κB in sepsis-induced lung injury

Regulation of pulmonary macrophages and their related functions is crucial for preventing further deterioration in many diseases. Fibronectin III domain-containing 4 (FNDC4) is a secreted factor with high homology to the exercise-related myokine irisin (FNDC5) and has been reported to be significantly upregulated in multiple mouse models of inflammation and under human inflammatory conditions. Here, we investigated the role and mechanisms of FNDC4 in regulating pulmonary macrophage function and the NF-κB pathway in sepsis. Plasma samples and clinical data from sepsis patients and healthy volunteers were collected to quantify FNDC4 levels and analyze their association with sepsis severity. In vivo, septic rat models with different disease severities were established to evaluate the effects of FNDC4 on lung injury. In vitro, LPS-stimulated mouse macrophages (RAW264.7) were preincubated with varying concentrations of FNDC4 to explore its functional effects and underlying mechanisms. Clinically, plasma FNDC4 levels were lower in sepsis patients than in healthy controls and were positively correlated with sepsis severity. In animal experiments, FNDC4 administration effectively alleviated sepsis-induced lung injury. In cell-based assays, FNDC4 preserved the proliferation and migration of LPS-stimulated RAW264.7 cells and reduced their apoptosis rate, while also inhibiting phosphorylation-dependent activation within the NF-κB pathway. Collectively, these findings suggest that FNDC4 may reflect sepsis severity and that exogenous FNDC4 can mitigate sepsis-related lung damage in vivo, potentially through modulation of the NF-κB signaling pathway, indicating its potential therapeutic value in sepsis. • Plasma FNDC4 levels vary in sepsis and reflect disease severity. • Recombinant FNDC4 improves survival and lung injury in septic rats. • FNDC4 reduces apoptosis and inflammatory cytokines in RAW264.7 cells. • FNDC4 shifts macrophages from M1-like to M2-like phenotypes in septic lungs. • FNDC4 inhibits NF-κB activation in sepsis-associated lung injury.