Safranal's impact on hepatocellular carcinomas revealed through multi-omics

Saffron, or Crocus sativus, is a spice that has recently received substantial attention for its ability to prevent and cure cancer of different tissues. This study follows up on reports of the effects of saffron on hepatocellular carcinomas by examining the cellular response through metabolomics. Specifically, we investigated the impact of safranal, a small molecule constituent compound of saffron, on an HCC cell line. We have previously reported the increase in apoptotic pathway activity through transcriptomics of safranal-treated cells. Here we correlate those results with metabolomics of extracts from treated cells and show an increase in intracellular hypoxanthine, a known free radical generator, and its derivatives after safranal treatment. We report up-regulation of arachidonic acid and linoleic acid metabolic pathways from both RNA-seq and metabolomic datasets and decreases in cholesterol and lanosterol. These shifts outline potential forced alternative metabolisms in HCC cells by safranal; most changes centered around beta-oxidation precursors (e.g., oxygen). Systems biology analysis showed that predominant metabolites differentially accumulated in treated vs. control cells directly interact with oxygen. Our data and analyses suggest that an increase in oxidative species caused by safranal, including hypoxanthine, may be responsible for the DNA damage and resultant apoptosis in HCC cells.