Low concentrations of sorafenib increase dihydrosphingomyelin during antifibrotic processes in human hepatic stellate cells.

Inhibiting hepatic stellate cells (HSCs) activation, which represents the initial step of liver fibrosis, is a key strategy for fibrosis treatment. Sorafenib has been repurposed as an antifibrotic agent; however, its reported effects largely rely on cytotoxic mechanisms. The antifibrotic mechanisms induced by minimally cytotoxic sorafenib remain unclear. We aimed to elucidate the dynamic changes in gene expression and lipid metabolites that occur during HSC inactivation using low-concentration sorafenib. Human HSCs (LX-2) were activated by treatment with transforming growth factor (TGF)-β to create a fibrotic environment. The activated cells were treated with sorafenib and then subjected to transcriptomic and lipidomic analyses. In the transcriptomic analysis, statistical significance was assessed using adjusted P-values based on the Benjamini-Hochberg method, whereas significance in the lipidomic analysis was evaluated using MetaboAnalyst. During fibrogenesis, we observed upregulation of extracellular matrix-related genes (COL1A1 (P < .001), FN1 (P < .001), THBS1 (P < .001), P4HA3 (P < .01)) and CXCL12 (P < .01), which is an upstream regulator of the Raf/MEK/ERK and PI3K/AKT signaling pathways. Meanwhile, dihydroceramide (dhCer) and dihydrosphingomyelin (dhSM) levels decreased (both P < .001). In contrast, sorafenib-induced antifibrotic conditions significantly reversed these molecular and lipidomic trends (all P < .01). In light of the observed trends, we propose that activating the dhSM synthesis pathway may play a regulatory role in fibrosis. Collectively, our study provides novel lipid-based insights into the molecular mechanisms underlying antifibrotic responses.