Low expression of SGPL1 promotes HCC progression by modulating LacCer metabolism via the S1P-STAT3-B4GALT6 axis

Hepatocellular carcinoma (HCC) is a common malignancy associated with dysregulated sphingolipid metabolism. Sphingosine-1-phosphate (S1P), a key bioactive lipid, promotes tumor progression, whereas its degradation is governed by SGPL1. However, the role of SGPL1 in HCC remains unclear. Here, we demonstrate that SGPL1 is significantly downregulated in HCC, and its low expression correlates with poor prognosis and enhanced metastatic potential. Mechanistically, SGPL1 downregulation elevated S1P, which activated STAT3 to transcriptionally repress B4GALT6, leading to reduced lactosylceramide (LacCer) production. This S1P-STAT3-B4GALT6-LacCer axis represents a novel regulatory network linking two key sphingolipid metabolites. Furthermore, melatonin inhibited HCC malignancy by upregulating SGPL1, thereby decreasing S1P and increasing LacCer levels to suppress HCC progression. In summary, our findings reveal a previously unrecognized role of SGPL1 in orchestrating the interplay between S1P and LacCer metabolism, positioning it as a promising therapeutic target. Moreover, our study provides mechanistic insights into the anti-HCC activity of melatonin and offers a novel therapeutic strategy for the treatment of hepatocellular carcinoma.