Calcium signals as regulators of ferroptosis in cancer
Ioana Stejerean‐Todoran, Christine S. Gibhardt, Ivan Bogeski
Abstract
• Ferroptosis represents a regulated cell death pathway dependent on iron and reactive oxygen species. • Cancer cells exhibit high susceptibility to ferroptotic cell death. • Calcium signaling plays a critical role in regulating cancer progression and cell death, including ferroptosis. • Modulation of Ca²⁺ homeostasis may impact tumor cell sensitivity to ferroptosis. • The relationship between Ca²⁺ signaling and ferroptosis remains incompletely understood. The field of ferroptosis research has grown exponentially since this form of cell death was first identified over a decade ago. Ferroptosis, an iron- and ROS-dependent type of cell death, is controlled by various metabolic pathways, including but not limited to redox and calcium (Ca 2+ ) homeostasis, iron fluxes, mitochondrial function and lipid metabolism. Importantly, therapy-resistant tumors are particularly susceptible to ferroptotic cell death, rendering ferroptosis a promising therapeutic strategy against numerous malignancies. Calcium signals are important regulators of both cancer progression and cell death, with recent studies indicating their involvement in ferroptosis. Cells undergoing ferroptosis are characterized by plasma membrane rupture and the formation of nanopores, which facilitate influx of ions such as Ca 2+ into the affected cells. Furthermore, mitochondrial Ca²⁺ levels have been implicated in directly influencing the cellular response to ferroptosis. Despite the remarkable progress made in the field, our understanding of the contribution of Ca 2+ signals to ferroptosis remains limited. Here, we summarize key connections between Ca²⁺ signaling and ferroptosis in cancer pathobiology and discuss their potential therapeutic significance.