Isorhapontigenin alleviates sepsis-induced acute lung injury by targeting the RAF1-ERK1/2-CXCL10 axis to inhibit CXCR3+ neutrophil recruitment.

Abstract

Sepsis is a life-threatening organ dysfunction syndrome resulting from a dysregulated host response to infection and is characterized by persistent hyperinflammation followed by immunosuppression. Isorhapontigenin (ISO), a natural stilbene derivative found in Chinese herbs and grapes, possesses potent antioxidant and anti-inflammatory properties; however, its potential therapeutic role in sepsis remains unclear. In this study, we investigated the protective effects of ISO against sepsis-induced multi-organ injury and the underlying molecular mechanisms. Using a murine model of sepsis, we observed that ISO administration considerably suppressed the expression of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the tissues. Furthermore, ISO treatment markedly improved survival rates and attenuated pathological damage in the liver and lung. Transcriptomic profiling revealed that ISO confers protection by modulating inflammatory cascades and inhibiting chemokine-mediated immune cell migration. Notably, C-X-C motif chemokine ligand 10 (CXCL10) was identified as a key hub gene. Mechanistically, ISO directly binds to RAF proto-oncogene serine/threonine-protein kinase (RAF1) and inhibits the RAF1-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, thereby downregulating CXCL10 expression and preventing excessive infiltration of C-X-C motif chemokine receptor 3-positive (CXCR3+) neutrophils into pulmonary tissue. In conclusion, our findings demonstrate that ISO mitigates sepsis-induced lung injury via the RAF1/ERK1/2/CXCL10 axis, providing a potential mechanistic basis for further investigation of ISO as a therapeutic candidate for sepsis.