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The animal model was constructed using 8\u201310\u2010week\u2010old CD\u20101 mice, which were administered cholic acid (CA) orally from gestational day (GD) 12\u2013GD17 to induce placental injury. Nesfatin\u20101 (NF\u20101) was administered intraperitoneally to assess its protective effects. Our study found that NF\u20101 effectively attenuated placental dysfunction by reducing glucocorticoid (GC) production and boosting 11\u03b2\u2010hydroxysteroid dehydrogenase type 2 (11\u03b2\u2010HSD2) expression, a key enzyme for GC inactivation. Furthermore, NF\u20101 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\u20101 were correlated with the suppression of the general control nonderepressible 2 (GCN2)\/eukaryotic initiation factor 2\u03b1 (eIF2\u03b1) signaling pathway, which became activated under OS conditions. Notably, halofuginone, a GCN2 agonist, abolished the beneficial effects of NF\u20101, further confirming the involvement of the GCN2\/eIF2\u03b1 pathway. These results suggest that NF\u20101 may serve as a potential therapeutic agent for managing ICP and related stress\u2010induced pregnancy complications by modulating GC metabolism and mitigating OS.<\/jats:p>","DOI":"10.1111\/cbdd.70147","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T01:35:57Z","timestamp":1750988157000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nesfatin\u20101 Reduces Cholic Acid\u2010Induced Intrahepatic Cholestasis of Pregnancy by Regulating the General Control Nonderepressible 2\/Eukaryotic Initiation Factor 2\u03b1 Pathway"],"prefix":"10.1111","volume":"105","author":[{"given":"Yong","family":"Liang","sequence":"first","affiliation":[{"name":"Department of Obstetrics The First Affiliated Hospital of Guizhou University of Chinese Medicine  Guiyang 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