RIPK1 Drives JAK1-STAT3 Signaling to Promote CXCL1-Mediated Neutrophil Recruitment in Sepsis-Induced Lung Injury

Sepsis-induced lung injury, characterized by unregulated inflammation and impaired alveolar epithelial integrity, significantly contributes to sepsis-related mortality. Although receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is critical in regulating necroptosis and inflammation, its precise contribution to sepsis-induced lung injury remains poorly understood. In this study, selective activation of RIPK1 in type II alveolar epithelial cells (AECs) is observed during sepsis. CXCL1 is identified as a critical downstream target of RIPK1 through integrative transcriptomic and proteomic analyses. Mechanistically, RIPK1 interacts with JAK1 to induce STAT3 phosphorylation, facilitate its nuclear translocation, and promote its binding to the Cxcl1 promoter, thereby upregulating its expression and driving excessive neutrophil recruitment. Genetic or pharmacological inhibition of RIPK1 attenuated CXCL1 production, neutrophil infiltration, and alveolar damage, improving survival in septic mice. Compound 62, a selective RIPK1 inhibitor, has demonstrated efficacy in attenuating systemic inflammatory cascades, preserving epithelial barrier integrity, and improving survival rates in mice. These findings establish RIPK1 as a therapeutic target in sepsis-induced lung injury and redefine alveolar epithelial cells as positive contributors to inflammatory amplification. This work advances precision strategies to mitigate sepsis-induced lung injury, addressing a critical unmet need in critical care medicine.