Nesfatin-1 Reduces Cholic Acid-Induced Intrahepatic Cholestasis of Pregnancy by Regulating the General Control Nonderepressible 2/Eukaryotic Initiation Factor 2α Pathway

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that significantly impacts pregnancy outcomes, with oxidative stress (OS) playing a crucial role in its pathogenesis. The animal model was constructed using 8–10-week-old CD-1 mice, which were administered cholic acid (CA) orally from gestational day (GD) 12–GD17 to induce placental injury. Nesfatin-1 (NF-1) was administered intraperitoneally to assess its protective effects. Our study found that NF-1 effectively attenuated placental dysfunction by reducing glucocorticoid (GC) production and boosting 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression, a key enzyme for GC inactivation. Furthermore, NF-1 reduced OS markers such as malondialdehyde (MDA) and reactive oxygen species (ROS) in both placental tissue and HTR8/SVneo cells. The protective effects of NF-1 were correlated with the suppression of the general control nonderepressible 2 (GCN2)/eukaryotic initiation factor 2α (eIF2α) signaling pathway, which became activated under OS conditions. Notably, halofuginone, a GCN2 agonist, abolished the beneficial effects of NF-1, further confirming the involvement of the GCN2/eIF2α pathway. These results suggest that NF-1 may serve as a potential therapeutic agent for managing ICP and related stress-induced pregnancy complications by modulating GC metabolism and mitigating OS.