Secretory LGALS3BP exacerbates sepsis-associated liver dysfunction by activating inflammasome-mediated pyroptosis.

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection, leading to multiorgan dysfunction. Inflammasome activation and pyroptosis are key mechanisms driving sepsis-associated organ dysfunction. However, it remains unclear whether circulating biomarkers actively contribute to disease progression. Although galectin-3-binding protein (LGALS3BP) has been proposed as a diagnostic and prognostic marker of sepsis, its functional role in sepsis-associated organ dysfunction remains undefined. In this study, the dynamics and function of LGALS3BP in sepsis were investigated using cecal ligation and puncture (CLP) and lipopolysaccharide (LPS)-induced mouse models. Plasma LGALS3BP levels were markedly elevated during sepsis and were accompanied by increased LGALS3BP expression in multiple organs, particularly in the liver. Hepatocyte-specific LGALS3BP overexpression exacerbated sepsis-associated liver injury, as evidenced by elevated serum alanine aminotransferase and aspartate aminotransferase levels, increased hepatocyte death, and reduced survival. Transcriptomic profiling of septic livers revealed that LGALS3BP overexpression markedly enriched cytokine signaling, inflammatory response gene sets, and the pyroptosis pathway, indicating dysregulated immune responses and an injury-driven transcriptional program during sepsis. RNA sequencing and in vitro experiments using primary hepatocytes treated with recombinant LGALS3BP, which mimics secreted LGALS3BP, demonstrated that recombinant LGALS3BP increased pyroptosis-associated gene signatures but was not sufficient to induce pyroptotic cell death. Instead, recombinant LGALS3BP promoted pyroptotic cell death only in the presence of septic stimuli. Mechanistically, under septic conditions, secretory LGALS3BP activated the TLR2-IRF3-NF-κB signaling axis, leading to NLRP3 inflammasome activation, cleavage of caspase-1 and gasdermin D, and increased IL-1β and IL-18 release, thereby promoting pyroptotic cell death. Importantly, antibody-mediated neutralization of secretory LGALS3BP suppressed TLR2-IRF3-NF-κB signaling and concomitantly attenuated inflammasome activation and pyroptosis in hepatocytes. Collectively, these findings identify LGALS3BP as a key pathogenic driver of sepsis-associated liver dysfunction through pyroptosis-mediated hepatocyte injury. Therapeutic targeting of LGALS3BP may therefore represent a promising strategy to mitigate sepsis-related liver failure beyond its proposed role as a circulating biomarker.