Eliglustat-Induced Remodeling of Sulfo-Glycosphingolipid Metabolism and Gene Expression in hepatocellular carcinoma cells

Lipidomic analysis revealed differential sensitivity of Sulfo-GSL molecular species, with preferential depletion of non-hydroxylated forms and relative preservation of hydroxylated species, indicating distinct metabolic responses within the same lipid class. Transcriptomic changes were limited at 20 µM eliglustat, whereas 30 µM induced extensive transcriptional reprogramming involving activation of immediate-early response genes, including EGR, FOS/JUN, and KLF family members, together with enrichment of inflammatory, stress-response, and senescence-associated pathways.

Conversely, pathways related to cell-cycle progression, DNA replication, and chromatin organization were suppressed. Genes involved in GSL metabolism were also modulated, suggesting activation of compensatory mechanisms to restore lipid homeostasis. These findings demonstrate that UGCG inhibition induces coordinated lipidomic and transcriptional remodeling in HepG2, revealing both tumor-suppressive molecular features and adaptive responses to metabolic stress providing new insights into the cellular consequences of targeting GSL metabolism in HCC.