Introduction: Sepsis is a systemic inflammatory response that frequently results in multiple organ dysfunction, including significant liver injury. Ubiquitin-specific protease 5 (USP5) has been shown to stabilize thioredoxin-interacting protein (TXNIP), thereby promoting inflammatory signaling in hepatocytes. However, the in vivo relevance of this mechanism in sepsis-related liver injury remains unclear. Methods: A cellular model of sepsis was established using lipopolysaccharide (LPS) to stimulate HepG2 and Huh7 cells. A murine sepsis model was created via cecal ligation and puncture (CLP). The USP5 inhibitor USP5-IN-1 was administered to both LPS-stimulated cells and CLP mice. Protein and mRNA levels of TXNIP and pyroptosis-related markers (NLRP3, ASC, cleaved caspase-1) were assessed using Western blot and qPCR. IL-1β and IL-18 levels were measured by ELISA and qPCR. Cell viability and proliferation were assessed using CCK-8 and Ki-67 immunostaining; apoptosis was evaluated using Annexin V/PI staining and TUNEL assay. Histologic liver injury was assessed via H&E staining. Results: USP5-IN-1 treatment significantly reduced TXNIP expression and downstream NLRP3 inflammasome activation in LPS-induced hepatocytes, without affecting baseline USP5 expression. Levels of IL-1β and IL-18 were also significantly decreased. USP5-IN-1 improved cell viability, reduced apoptosis, and promoted proliferation. In CLP mice, USP5 inhibition alleviated liver injury, reduced serum proinflammatory cytokines, and downregulated TXNIP/NLRP3 pathway activation. Conclusions: USP5 inhibition protects against sepsis-induced liver injury through suppression of the TXNIP/NLRP3 inflammasome pathway. These findings suggest that USP5 may represent a novel therapeutic target for managing hepatic dysfunction in septic patients.
Shi et al. (Sun,) studied this question.