Gallium disrupts endoplasmic reticulum iron metabolism to induce lipid metabolic reprogramming in glioblastoma cells.

Gallium based therapeutic strategies are thought to be an effective means to promote tumor cell killing that are currently being investigated in glioblastoma. Gallium is a group IIIa metal that is redox inactive, however, its atomic similarity to iron allows it to serve as an iron mimic that may disrupt Fe metabolism. The current understanding of its mechanism of action is related to its ability to inhibit ribonucleotide reductase and the electron transport chain, however, its effects on other iron-dependent metabolic processes (e.g., lipid metabolism) are unknown. Ferroptosis is a unique iron-dependent form of cell death, thus, the goal of this study is to evaluate the effects of Ga(NO(3))(3) on the induction of ferroptosis. Despite its redox inactivity, Ga(NO(3))(3) promotes the formation of oxidized lipid droplets. Moreover, Ga(NO(3))(3) enhances the toxicity of the ferroptosis inducer, erastin, and decreases cell stiffness, indicating an exacerbation of ferroptosis. Ga(NO(3))(3) also enhances the toxicity of the stearoyl CoA desaturase (SCD) inhibition, and its toxicity can be reversed by oleic acid supplementation, suggesting that Ga(NO(3))(3) can potentially inhibit SCD. Lipidomic analysis revealed a significant increase in oxidizable triglycerides following Ga(NO(3))(3) treatment. Thus, it appears that Ga(NO(3))(3) exacerbates ferroptosis in glioblastoma cells by disrupting the di-ferric lipid metabolic regulator SCD and warrants further investigation as an alternate mechanism of action for Ga-based therapy.