The Role of USP13 in Mitigating Hepatic Ischemia-Reperfusion Injury Post-Liver Transplantation

Background Orthotopic liver transplantation (OLT) is one of the crucial approaches for treating severe liver failure and end-stage liver diseases. Post-transplantation, the quality of life of patients undergoes remarkable improvement, and their survival duration is prolonged. Meanwhile, hepatic ischemia-reperfusion injury (HIRI) represents a major clinical issue during the perioperative period and is closely associated with early allograft dysfunction (EAD), acute rejection (AR), and long-term allograft survival. USP13 is a member of the ubiquitin-specific protease (USP) subfamily of deubiquitinases (DUBs) and widely distributed within cells. Recent investigations have revealed that the modification of USP13 by DUBs plays a crucial role in maintaining cellular homeostasis and augmenting antioxidant defenses. Emerging evidence implicates USP13 in the progression of various complications following liver transplantation, particularly ischemia-reperfusion injury (IRI). This study endeavors to elucidate the role of USP13 in hepatic IRI post-liver transplantation. Methods Transcriptome data from patients with ischemia-reperfusion (I/R) injury in various organs were obtained from the Gene Expression Omnibus (GEO) database and analyzed using bioinformatics methods to identify differentially expressed genes (DEGs). Following this, we established both in vitro and in vivo models of IRI to conduct our investigations. Initially, we developed an in vitro hepatocyte oxygen-glucose deprivation/reoxygenation (OGD/R) model using THLE2 cells to examine the impact of I/R on hepatocyte viability and function. Subsequently, after treating the cells with pcDNA followed by OGD/R, we explored the role of USP13 in HIRI. Additionally, we validated the expression of USP13 and its effects on HIRI and hepatic functionality in a rat OLT model. Results In this investigation, we elucidated the inflammatory response and diminished cellular viability following I/R in the OGD/R model of THLE2 cells. Conversely, overexpression of USP13 via pcDNA attenuated the inflammatory response and improved cellular function. Furthermore, siRNA-mediated silencing of USP13 exacerbated the inflammatory response, leading to a significant increase in cell death. Consistent with in vitro findings, the rat OLT model demonstrated a marked reduction in hepatic USP13 expression, correlating with tissue damage and subsequent hepatic dysfunction. Conclusions This study validated the impact of USP13 expression levels on HIRI. These findings provide novel perspectives for devising advanced clinical strategies to enhance the outcome of liver transplant recipients.