FTY720 alleviates D-GalN/LPS-induced acute liver failure by regulating the JNK/MAPK pathway

Acute liver failure (ALF) poses a considerable health and economic burden worldwide and has limited treatment options. Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive phospholipid that participates in various cellular processes by through S1P receptors (S1PRs). Previous studies have showed that the hepatic S1P levels were increased. Notably, deletion or inhibition of sphingosine kinase 1 (SphK1), the key enzyme responsible for S1P biosynthesis, could alleviate D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced ALF in mice. However, the role of the S1P receptor modulator FTY720 in ALF remains unclear. In this study, we investigated the effects of FTY720 on D-GalN/LPS-induced ALF model. Our results demonstrated that FTY720 pretreatment significantly alleviated liver injury, decreased the serum levels of alanine aminotransferase and aspartate aminotransferase, and mitigated histopathological damage in ALF model mice. Mechanistically, FTY720 could inhibit the inflammatory response and reduced apoptosis. The protective effect of FTY720 was mediated by c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) signalling. A pharmacological JNK activator (anisomycin) partially counteracted these protective effects. FTY720, targeting S1PRs, is expected to be an effective therapeutic strategy for ALF.