RETN exacerbates sepsis by GBP5/NLRP3 signaling pathway-mediated pyroptosis of macrophage.

Current therapeutic options remain insufficient for sepsis, driving the search for alternative treatment approaches. Accumulating evidence suggests that resistin (RETN) serves as a crucial factor in sepsis initiation and development. Nevertheless, the specific pathways through which RETN influences sepsis pathophysiology have yet to be elucidated. Single-cell sequencing analysis reveals RETN is primarily expressed in monocytes/macrophages. RETN in macrophages is markedly upregulated in septic patients, exhibiting a marked positive correlation with pro-inflammatory cytokines and disease severity. Bioinformatics analysis and in vitro experiments reveal that knockdown of RETN alleviated macrophage pyroptosis. RNA-Seq analysis and in vitro experiments revealed that the overexpression of RETN markedly upregulates the expression of GBP5 and NLRP3. Further in vivo experiments revealed that RETN knockdown markedly downregulates GBP5 expression, inhibits NLRP3 activation, and mitigates macrophage pyroptosis. This consequently reduces organ (lung, spleen, and heart) damage and improves survival in sepsis. Finally, knocking down GBP5 can reverse the promoting effect of overexpressed RETN on macrophage pyroptosis, organ damage and sepsis lethality. This investigation initially demonstrates that the RETN/GBP5/NLRP3 signaling axis regulates macrophage pyroptosis to aggravate sepsis, providing new potential targets and theoretical support for the research on the pathogenic mechanism of sepsis and clinical treatment.