Sphingolipid homeostasis and dysregulation in liver function and disease

Abstract Sphingolipids regulate hepatic lipid homeostasis, cell survival, inflammation, and tissue repair. In the healthy liver, balanced de novo sphingolipid synthesis, salvage pathways, and sphingosine-1-phosphate (S1P)-related signals maintain metabolic flexibility, endothelial integrity, and immune quiescence. Dysregulation of sphingolipid metabolism drives the initiation and progression of chronic liver diseases. In metabolic dysfunction-associated steatohepatitis, the acyl chain length-specific remodeling of dihydroceramides and ceramides, together with increased neutral sphingomyelinase activity, triggers lipotoxic stress, abnormal anabolic signal transduction, and hepatic lobule inflammation. Liver fibrosis involves reprogramming of the hepatic stellate cell S1P receptor signaling from regenerative towards profibrotic pathways. In hepatocellular carcinoma, tumor cells utilize sphingolipid metabolism to promote angiogenesis, evade immune surveillance, and develop therapeutic resistance. Sphingolipid remodeling in viral hepatitis links viral persistence to distinct circulating lipid signatures that correlate with disease severity and prognosis. Importantly, multiple nodes in the sphingolipid network and their downstream effectors are emerging as therapeutic targets. Promising preclinical strategies include liver-targeted small interfering RNA against key biosynthetic enzymes, selective modulation of sphingolipid receptors, and nanoliposomal formulations of bioactive ceramides. To enable clinical translation, innovative approaches are being developed to overcome key challenges in delivery, specificity, and safety. Overall, this review integrates recent mechanistic insights, emphasizing that sphingolipids act as central regulators of liver pathophysiology and are also important biomarkers and therapeutic targets in chronic liver diseases.