Integrated proteomic and metabolomic analysis reveals lipid metabolic dysregulation and ferroptosis as potential drivers of placental dysfunction in intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse fetal outcomes, while current biomarkers such as total bile acid remain suboptimal. This study aimed to identify novel biomarkers and clarify metabolic pathways underlying ICP through integrated metabolomic and proteomic analyses. Placental profiles were obtained from ICP model rats and healthy controls, with differential metabolites and proteins validated in human placental and serum samples. Multiomics integration revealed prominent dysregulation of lipid metabolism, particularly fatty acid degradation and biosynthesis, highlighting lipids as central players in ICP. Palmitic acid and acyl-CoA synthetase long chain family member 1 (ACSL1) were central to these pathways, markedly elevated in ICP, and showed high diagnostic value (area under the curve 0.794 and 0.825), with combined detection reaching 0.894. Both markers also stratified patients by disease severity, suggesting their potential use for disease monitoring and risk classification. Moreover, ferroptosis was implicated in ICP pathophysiology, supported by validations in both patient placental tissues and taurocholic acid (TCA)-treated trophoblast cells, showing reduced glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) together with increased six-transmembrane epithelial antigen of prostate 3 (STEAP3), transferrin receptor protein 1 (CD71), and acyl-CoA synthetase long-chain family member 4 (ACSL4). In summary, palmitic acid and ACSL1 represent promising biomarkers for ICP diagnosis and classification, while ferroptosis contributes to ICP-related placental dysfunction. These findings provide comprehensive evidence linking altered lipid metabolism and ferroptosis to ICP, offering new insights for clinical diagnosis and potential therapeutic strategies.