Abstract
Ferroptosis is a regulated form of cell death characterized by iron dependency and increased lipid peroxidation. Initially assumed to be selectively induced in tumour cells, there is increasing evidence that ferroptosis plays an important role in pathophysiology and numerous cell types and tissues. Deregulated ferroptosis has been linked to human diseases, such as neurodegenerative diseases, cardiovascular disorders, and cancer. Along these lines, ferroptosis is a promising pathway to overcoming therapy resistance of cancer cells. It is therefore of utmost importance to understand the cellular signalling pathways and the molecular mechanisms underlying ferroptosis regulation, including context-specific effects mediated by the neighbouring cells through cell–cell contacts. Here, we give an overview on the molecular events and machinery linked to ferroptosis induction and commitment. We further summarize and discuss current knowledge about the role of cell–cell contacts, which differ in ferroptosis regulation between normal somatic cells and cancer cells. We present emerging concepts on the underlying mechanisms, address open questions, and discuss the possible impact of cell–cell contacts on exploiting ferroptosis in cancer therapy.
Highlights
Ferroptosis Meets Cell–Cell Contacts.Cell death can be executed in a regulated or accidental manner
Our findings demonstrate that the organic tertiary-butyl hydroperoxide the cellular antioxidative activity by idebenone, a synthetic and soluble analogue of (t-BuOOH) is a potent ferroptosis inducer in murine and human cell lines [62]
Using several murine and human cell lines, we demonstrated that cell–cell contacts protect against ferroptosis induced by erastin or the organic tertiary-butyl hydroperoxide (t-BuOOH) [130]
Summary
Cell death can be executed in a regulated or accidental manner. When RCD occurs in physiological contexts, e.g., embryonic development or maintenance of tissue homeostasis, it is referred to as programmed cell death [1]. Today we know that a myriad of different regulated cell death modalities exist, including necroptosis, parthanatos, mitochondrial permeability transition (MPT)-mediated necrosis, or ferroptosis, to name a few [2]. Each cell death pathway seems to be unique in its key elements and execution processes, mixed forms and crosstalk between these forms may exist. Necroptosis, a well-studied cell death mechanism, as well as ferroptosis have attracted broad attention in the scientific community due to their pathophysiological roles in various human diseases, such as cardiovascular disorders and neuro-degenerative diseases [3].
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