Abstract: Background　Leukocyte cell-derived chemotaxin 2 (LECT2), secreted by hepatocytes, participates in the regulation of inflammatory responses and may play a pivotal role in sepsis-associated liver injury. Objective　To investigate the function and molecular mechanisms of LECT2 in sepsis-associated liver injury and to evaluate the protective effects of LECT2 gene knockout. Methods An in vitro model of septic hepatocellular injury was established by stimulating THLE-2 cells with lipopolysaccharide (LPS). Cells were randomly assigned to four groups: untreated control (Control), exogenous LECT2 supplementation (LECT2), LPS stimulation (LPS), and LPS with exogenous LECT2 (LPS+LECT2). The effects of LECT2 on cell viability, apoptosis, cell death, and levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in supernatants were assessed. In vivo, a murine sepsis model was generated using cecal ligation and puncture (CLP). Mice were randomly divided into six groups (n=6 per group): wild-type (WT) mice, LECT2 knockout (LECT2 KO) mice, WT mice receiving tail vein injection of AAV8 control vector (WT+ AAV8-vehicle), WT mice injected with AAV8 carrying full-length LECT2 plasmid (WT+AAV8-LECT2 overexpression), WT mice injected with 100 μL PBS as vehicle control (WT+PBS), and WT mice injected with 100 μL recombinant LECT2 protein (WT+ rLECT2). CLP-induced sepsis models and corresponding sham operations were performed in all groups. Liver histopathological changes were evaluated by H&E staining, expression levels of inflammatory cytokines including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor- α (TNF-α) were measured, and serum concentrations of ALT and AST were determined. Results　In vitro, compared with the LPS group, the LPS+LECT2 group showed further reduced THLE-2 cell viability (P＜0.01), aggravated cellular injury, and a further increase in ALT concentration in the culture supernatant (P＜0.05). In vivo, hepatic and serum LECT2 expression in sepsis model groups was markedly downregulated compared to sham groups (both P＜0.01). The liver histopathological injury score in the LECT2 KO group was lower than in the WT group (P＜0.01). Hepatic expression of IL-1β and TNF-α in the LECT2 KO group was lower than in the WT group (P＜0.05 and P＜0.001, respectively). Serum levels of ALT and AST in the LECT2 KO group were also significantly lower than in the WT group (both P＜0.01). Conclusion　LECT2 gene knockout attenuates sepsis-associated liver injury, suppresses inflammatory cytokine release, and improves liver histopathological structure and function.