Multi-omics characterization of autophagy-related molecular features in Intrahepatic cholestasis of pregnancy

Abstract Introduction: Despite the increasing body of evidence that autophagy implicate in Intrahepatic cholestasis of pregnancy (ICP), we are still far from a mechanistic understanding of the autophagy in ICP pathogenesis. Methods: In this study, we performed untargeted lipidomics, scRNA-seq, and RNA-seq data to systematically demonstrate the lipid alterations, cells and gene expression closely related to autophagy in placenta. These results were also verified by tissue, cell, and animal experiments. Results: We confirmed that autophagy plaed a pivotal role in ICP, autophagy-related lipids including PE (38:2e) and PE (54:5) had a good diagnostic value. Autophagy genes were mainly concentrated in villous cytotrophoblast (VCT), extravillous trophoblast (EVT), and macrophage. VCT was found increased while EVT decreased in ICP. In the subcluster analysis of VCT, VCT-EVT, the precursor cells of EVT, was significantly reduced. In the subcluster analysis of EVT, EVT2 cells with epithelial migration and regulatory functions were significantly reduced. Furthermore, autophagy gene TNFSF10 was decreased in ICP, while supplementation of soluble TNFSF10 could restore the expression of TNFSF10 in ICP cell model, which alleviated the autophagic damage and improved the invasion and migration ability of trophoblast cells. Conclusion: Our study established the causal linkage between autophagy and ICP, providing a potential therapeutic avenue to improve trophoblast function accounting for ICP by targeting autophagy gene TNFSF10.