Altered sphingolipid profile in primary biliary cholangitis: associations with fibrosis and inflammation

Sphingolipids, key bioactive lipids implicated in inflammation, immune regulation, and fibrosis, are increasingly recognized as contributors to liver pathophysiology. However, their role in primary biliary cholangitis (PBC) remains poorly characterized. In this study, we examined plasma sphingolipid profiles in 45 patients with early-stage PBC receiving ursodeoxycholic acid therapy, comparing them to 30 healthy controls using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). PBC patients exhibited significantly reduced total sphingolipid levels, notably in phosphorylated species such as sphingosine-1-phosphate (S1P) and sphinganine-1-phosphate (SPA1P). In contrast, C18:1-ceramide was elevated and showed a trend toward association with increased liver stiffness. Very-long-chain ceramides were decreased in the PBC group. Correlation analyses revealed positive associations between sphingolipids and markers of inflammation, including a significant link between sphingosine and interleukin-6. Furthermore, reduced phosphorylated sphingolipids were related to portal hemodynamic changes assessed by Doppler ultrasound. These findings suggest that selective sphingolipid alterations may reflect or contribute to fibrogenesis, immune dysregulation, and portal circulation abnormalities in early PBC, pointing to their potential utility as biomarkers or therapeutic targets in cholestatic liver disease.