Interleukin‐39 is a Prognostic Biomarker and Therapy Target for Sepsis

Sepsis remains a global health crisis with high mortality, due to a paucity of reliable diagnostic markers for accurate risk stratification and precision management. Interleukin-39 (IL-39), a novel immunomodulatory cytokine, plays an important role in regulating the pathophysiology of immunity, metabolism, and et al. Here, we observed significantly elevated serum IL-39 levels in septic patients at admission compared with non-sepsis ICU patients and healthy controls across two independent cohorts. Furthermore, circulating IL-39 concentrations could predict 28-days survival in patients with sepsis. Single-cell sequencing demonstrated that elevated IL-39 was derived from macrophages during sepsis. Meanwhile, supplementation of IL-39, via either recombinant protein (rmIL-39) administration or macrophage-specific AAV-mediated overexpression, profoundly aggravates multiple organ dysfunction and damage in septic mice. Consistently, macrophage IL-39 deficiency, via either macrophage-conditional knockout or macrophage-specific AAV-mediated silence, protects against sepsis. Mechanistically, IL-39 engages GP130 to trigger MAPK/P38 signaling, driving pro-inflammatory cytokine production. Consequently, macrophage-specific GP130 deletion abrogates IL-39-induced sepsis aggravation. Finally, pharmaceutical inhibition of IL-39 with neutralizing antibodies can protect against sepsis. Together, these results highlight the dual clinical utility of IL-39, as both a robust biomarker with independent prognostic value for sepsis patient stratification and a promising therapeutic strategy for sepsis.