The coming decade in ferroptosis research: Five riddles

Ferroptosis is, in many ways, the odd one out among cell death modalities. It does not, at least as far as we know, require an activating signal. Instead, it represents a default cellular fate that is continuously repressed by a multilayered network of surveillance systems. At its core, ferroptosis is driven by the unchecked peroxidation of polyunsaturated phospholipids (PUFA-PLs), a vulnerability shaped by lipid bilayer composition. Glutathione peroxidase 4 is a central defense enzyme that reduces lipid hydroperoxides to their corresponding alcohols using glutathione as a cofactor. This is complemented by ferroptosis suppressor protein-1-mediated regeneration of coenzyme Q10 or vitamin K at the plasma membrane and reinforced by dietary or endogenous radical-trapping antioxidants, such as vitamin E, squalene, and 7-dehydrocholesterol. Still, ferroptosis sensitivity is not just a function of antioxidant failure but also a direct consequence of the architecture of the membrane itself: the abundance of PUFA-PLs, shaped by acyl-CoA synthetases like ACSL4 and others; the relative scarcity or abundance of monounsaturated fatty acids, which confer resistance; the regulation of membrane repair and remodeling enzymes; and the delicate balance of redox-active iron within organelles such as lysosomes. Together, these elements converge to determine whether ferroptosis remains a manageable threat or becomes lethal. Despite growing mechanistic insights, fundamental riddles endure: Why does ferroptosis exist at all? What is the precise role of iron: catalyst, signal, or peril? Where, within the cell or organism, does ferroptosis ignite? Can we safely harness this pathway for clinical benefit? And ultimately, is ferroptosis truly a form of regulated cell death, or the mere emergence of a primordial biochemical vulnerability? Inspired by Douglas Green’s iconic riddle framework, this review distils five unresolved questions that may define the coming decade of ferroptosis research. Rather than solving them, we aim to refine their silhouettes at the intersection of lipid (bio)chemistry, evolutionary biology, and translational opportunity.