<p>Primary biliary cholangitis (PBC) is an immune-mediated, non-suppurative cholestatic liver disease. Liver sinusoidal endothelial cells (LSECs) play a pivotal role in maintaining hepatic immune tolerance. Emerging research indicates that under certain stimuli, LSECs can transition from a tolerogenic to an immunogenic role. We hypothesize that LSECs may be implicated in the pathogenesis of PBC. Single-cell RNA sequencing (scRNA-seq) data were initially analyzed using R statistical software and Cell Ranger. Differentially expressed genes and marker genes were identified using Seurat. Preliminary cell type identification was conducted with SingleR cell clustering. Differential gene expression was determined using t-tests, and significance analysis was performed with the Limma package. Pseudotime analysis was conducted with Monocle2. Compared to the control (CTR) group, the number of endothelial cells in the PBC group was significantly reduced (P &lt; 0.05). Further analysis of these endothelial cells revealed seven distinct subpopulations, including a newly defined CPE⁺ vWF⁺ endothelial cell type. Interaction between CPE⁺ vW ⁺ endothelial cells and bile duct cells was mediated through the APP-CD74 axis. Expression levels of CD74 and MIF were significantly higher in patients with PBC compared to CTR. CD74, serving as a receptor for the pro-inflammatory cytokine MIF, may counteract the anti-inflammatory effects of glucocorticoids. Expression levels of PTPRC and CCL5 were positively correlated with hepatic inflammation and fibrosis severity and were elevated in patients with PBC. CPE⁺ vWF⁺ endothelial cells might play a promising role in contributing to bile duct cell injury in patients with PBC by upregulating the pro-inflammatory factor MIF and interacting with CD74. Additionally, another unidentified endothelial cell type was suggested to exacerbate biliary damage and fibrosis by upregulating PTPRC and CCL5 expression.</p>