Egg-derived sphingomyelin induces ferroptosis in cancer cells, depending on intracellular labile iron pool levels

Abstract

Sphingomyelin (SPM), a sphingolipid abundant in animal cell membranes and animal-derived foods, plays a crucial role in maintaining cell membranes and intracellular signaling. Additionally, although previous studies have suggested that SPM has anticancer effects, the molecular entity underlying its effect on cancer cell viability remains unclear. Moreover, the effects of exogenous SPM on cancer cells have not yet been thoroughly explored. In this study, we investigated the mechanisms underlying SPM-induced cell death in cancer cell lines. For the analyses of cell death, we used five cancer cell lines—COV362, AH109A, HepG2, A549, and Colo201—as cancer models and primary cultured rat hepatocytes and normal human dermal fibroblasts (NHDF) as normal cell models. We demonstrated that SPM induces a type of cell death, ferroptosis, in several cancer cell lines, including COV362, AH109A, HepG2, and A549. Furthermore, SPM application increased the production of reactive oxygen species (ROS) and induced ferroptosis. Since one of the key factors regulating ferroptosis sensitivity is the intracellular labile iron pool (LIP), we examined LIP levels in each cell and found that cells with higher LIP levels were more susceptible to SPM-induced cell death; exogenous iron further enhanced this effect, confirming that LIP plays a crucial role in ferroptosis induction. Our findings demonstrate that SPM can selectively induce ferroptosis in cancer cells through ROS production and, possibly, iron-dependent lipid peroxidation. These findings may provide a potential therapeutic strategy for the selective induction of ferroptosis in cancer cells.