FTY720 attenuates APAP‑induced liver injury via the JAK2/STAT3 signaling pathway

Abstract

As the current clinical treatment of acetaminophen (APAP)-induced liver injury (AILI) has its limitations, new and effective treatment methods are required. Fingolimod (FTY720) is an immunosuppressive drug developed in recent years that has been shown to have a protective effect against ischemia/reperfusion liver injury. However, the role of FTY720 in AILI remains unclear. The aim of the present study was to determine whether FTY720 has a protective effect on AILI. AILI was induced using intraperitoneal injection of 300 mg/kg APAP in male C57BL/6J mice. Following APAP challenge, the mice were administered 5 mg/kg FTY720 for 30 min. Protein expression levels were measured using western blot analysis. Cell viability was examined using Cell Counting Kit-8 assays. mRNA levels were measured using reverse transcription-quantitative PCR. Inflammation levels were evaluated using immunohistochemistry. Cell death and reactive oxygen species levels were examined using immunofluorescence. Furthermore, laser scanning intravital microscopy was used to directly observe immune cell recruitment. APAP treatment increased the serum levels of alanine transaminase and aspartate transaminase at the 6- and 12-h time-points, suggesting liver tissue damage. However, FTY720 attenuated the liver injury induced by APAP by reducing the recruitment of immune cells and the release of pro-inflammatory cytokines and chemokines. FTY720 activated JAK2/STAT3 signaling and regulated the expression of BAX, BCL-2 and p65 to inhibit apoptosis and inflammation. In addition, compared with APAP treatment, the viability of primary hepatocytes treated with APAP and FTY720 was increased. Inhibition of JAK2/STAT3 signaling attenuated the protective, antioxidant effects of FTY720. In conclusion, FTY720 reduced liver injury by regulating the JAK2/STAT3 signaling pathway. This compound was capable of inhibiting oxidative stress to reduce hepatocyte death and the infiltration of neutrophils in the liver.

FTY720-P, a Biased S1PR Ligand, Increases Mitochondrial Function through STAT3 Activation in Cardiac Cells

“…In this regard, our results indicate that FTY720-P promotes mitochondrial respiration without an effect on aerobic glycolysis. In addition, we also observed a significant decrease in mitochondrial superoxide generation upon FTY720-P treatment ( Figure 1 h), being the latter in agreement with the antioxidant effect of FTY720 observed in the heart, brain, and liver [ 7 , 35 , 53 ].…”

“…Several reports have demonstrated that FTY720-P reduces STAT3-P (T705) and represses the inflammatory response in pathological mouse models [ 34 , 35 ]. Remarkably, FTY720-P induced the phosphorylation of JAK2 (Y1007/1008) and STAT3 (Y705) (pSTAT3) ( Figure 5 a,b).…”

“…Recent evidence suggests that STAT3 signaling also modulates S1P signaling. First, JAK2-STAT3 signal inhibitor decreases the FTY720-dependent protective effects in white matter (WM) ischemic injury and acetaminophen-induced liver injury mouse models [ 34 , 35 ]. In contrast, FTY720 suppresses STAT3 activation in a chronic colitis disease model and B-cell lymphoma cells lines [ 36 , 37 ].…”

Self-assembled FGF21 nanoparticles alleviate drug-induced acute liver injury

“…Sustained injury to and necrosis of hepatocytes lead to the activation and aggregation of large amounts of proinflammatory mediators ( Chowdhury et al, 2020 ). Upon activation of inflammation-related signaling pathways, proinflammatory cytokines cause hepatocyte apoptosis and inflammatory responses, which lead to abnormal liver function ( Bai et al, 2021 ; He et al, 2022 ).…”

The research development of STAT3 in hepatic ischemia-reperfusion injury

“…Fingolimod (FTY720) is an inhibitor of the Sphingosine-1-phosphate (S1P) receptor with diverse anti-inflammatory effects ( 86 ). Xiangmin He demonstrated that Fingolimod (FTY720) could activate the JAK2/STAT3 pathway, thereby inhibiting hepatic IRI induced by acetaminophen (APAP) ( 87 ). Relevant studies have confirmed that STAT3 in hepatocytes can promote liver regeneration after hepatectomy.…”