From Iron Addiction to Ferroptosis Vulnerability: Tricks and Backstage

Dear Colleagues,

Despite the significant efforts of the scientific community to define the morphological, genetic, and biochemical features of ferroptosis in cancer, several pertinent questions remain still unanswered.

Cancer cells are found to show the so-called “iron-addicted” phenotype, characterized by a marked iron uptake and a weak iron efflux, which may represent a metabolic determinant of ferroptosis sensitivity. Ferroptosis is a programmed cell death driven by the iron-dependent accumulation of reactive oxygen species (ROS) to detrimental levels. Many signaling pathways are involved in this process: the increase of intracellular iron, which increase ROS amounts and leads to severe membrane lipid peroxidation; the repression of the cystine-glutamate antiporter (system Xc-); the inactivation of the antioxidant glutathione-dependent peroxidase 4 (GPX4); the degradation of ferritin meditated by NCOA4 via ferritinophagy. Lately, ferroptosis has been identify as a potential therapeutic approach for the so-called “persister” cancer cells, a subset of cancer cells resistant to either standard chemotherapy or molecular-targeted therapies. Furthermore, this type of cell death has been linked to antitumor immunity and potentially included in the concept of immunogenic cell death (ICD), defined by the chronic release or membrane exposure of damage-associated molecular patterns (DAMPs), which act as danger signals to recruit and activate several immune cells in the TME. However, a powerful approach to molecularly dissect ferroptosis features are required.

To summarized, our final goal is to provide readers a deeper understanding of the backstage players of ferroptosis cell death. This Special Issue will cover, but is not limited to, the following topics:

• Identification of new potential hallmarks of ferroptosis in cancer;
• Ferroptosis as an alternative strategy to target apoptosis-resistant cancer cells;
• Characterization of genetic and metabolic determinants of susceptibility in ferroptosis-resistant cancer cells;
• Clarify the concept of ferroptosis as immunogenic cell death (ICD);
• Application of novel iron-based compounds as alternative therapeutic approach to induce ferroptosis.

Dr. Anna Martina Battaglia
Dr. Alessandro Sacco
Prof. Dr. Flavia Biamonte
Guest Editors

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• ferroptosis
• iron metabolism
• reactive oxygen species
• resistance mechanisms
• resistance biomarkers
• immunogenetic cell death