Six‐Transmembrane Epithelial Antigen of the Prostate 3 Deficiency in Hepatocytes Protects the Liver Against Ischemia‐Reperfusion Injury by Suppressing Transforming Growth Factor‐β‐Activated Kinase 1

Abstract

Background and Aims Hepatic ischemia‐reperfusion (I/R) injury remains a major challenge affecting the morbidity and mortality of liver transplantation. Effective strategies to improve liver function after hepatic I/R injury are limited. Six‐transmembrane epithelial antigen of the prostate 3 (Steap3), a key regulator of iron uptake, was reported to be involved in immunity and apoptotic processes in various cell types. However, the role of Steap3 in hepatic I/R‐induced liver damage remains largely unclear. Approach and Results In the present study, we found that Steap3 expression was significantly up‐regulated in liver tissue from mice subjected to hepatic I/R surgery and primary hepatocytes challenged with hypoxia/reoxygenation insult. Subsequently, global Steap3 knockout (Steap3‐KO) mice, hepatocyte‐specific Steap3 transgenic (Steap3‐HTG) mice, and their corresponding controls were subjected to partial hepatic warm I/R injury. Hepatic histology, the inflammatory response, and apoptosis were monitored to assess liver damage. The molecular mechanisms of Steap3 function were explored in vivo and in vitro. The results demonstrated that, compared with control mice, Steap3‐KO mice exhibited alleviated liver damage after hepatic I/R injury, as shown by smaller necrotic areas, lower serum transaminase levels, decreased apoptosis rates, and reduced inflammatory cell infiltration, whereas Steap3‐HTG mice had the opposite phenotype. Further molecular experiments showed that Steap3 deficiency could inhibit transforming growth factor‐β–activated kinase 1 (TAK1) activation and downstream c‐Jun N‐terminal kinase (JNK) and p38 signaling during hepatic I/R injury. Conclusions Steap3 is a mediator of hepatic I/R injury that functions by regulating inflammatory responses as well as apoptosis through TAK1‐dependent activation of the JNK/p38 pathways. Targeting hepatocytes, Steap3 may be a promising approach to protect the liver against I/R injury.

The protective effects of fibroblast growth factor 10 against hepatic ischemia-reperfusion injury in mice

“…Furthermore, the MAPK signaling pathway has also been reported to have an important role in the control of hepatic IRI [ 25 , 30 ]. Among the MAPK family members, MAPK/ERK kinase (MEK) and extracellular-signal-regulated kinase (ERK) are known downstream targets of FGF10 [ 10 , 12 ].…”

“…Cellular apoptosis directly contributes to liver damage during hepatic IRI [ 18 , 25 , 30 ]. Recent studies demonstrated that FGF10 can inhibit neuronal apoptosis during cerebral IRI [ 31 ], suggesting a possible role for FGF10 in the regulation of apoptosis after liver IRI.…”

Protective role of microRNA-9-5p in oxygen glucose deprivation/reperfusion-induced injury in liver sinusoidal endothelial cell

“…given the essential role of LSECs in the maintenance of liver functioning, insight into the biological role of miR-9-5p in LSCEs is worthwhile. The conventional mouse model of liver I/R injury involves clamping the portal vein, bile duct and hepatic artery with microvascular clips to interrupt the blood supply, followed by reperfusion [22,23]. The method, however, makes it di cult to elucidate cell type-speci c role of the factor studied.…”

Maresin 1 Protects the Liver Against Ischemia/Reperfusion Injury via the ALXR/Akt Signaling Pathway

“…In addition to in ammation, recent evidence indicated that apoptosis is another essential contributor to hepatic I/R injury (Guo et al 2020). Apoptosis can also be enhanced by reperfusion-induced in ammatory responses (Jassem et al 2019).…”

“…Liver ischemia-reperfusion (I/R) injury is a crucial contributor to liver damage and dysfunction after liver transplantation, partial hepatectomy, and hemorrhagic shock (Chen et al 2020). Although great efforts have been made to explore therapeutic strategies to alleviate acute liver I/R injury, no pharmacologic intervention has been documented to be effective in preventing or treating this condition in clinical practice (van Golen et al 2013).…”