Iron dysregulation has emerged as a pivotal factor in neurodegenerative pathologies, especially through its capacity to promote ferroptosis, a unique form of regulated cell death driven by iron-catalyzed lipid peroxidation. This review synthesizes current evidence on the molecular underpinnings of ferroptosis, focusing on how disruptions in iron homeostasis interact with key antioxidant defenses, such as the system Xc⁻-glutathione-GPX4 axis, to tip neurons toward lethal oxidative damage. Building on these mechanistic foundations, we explore how ferroptosis intersects with hallmark pathologies in Alzheimer’s disease (AD) and Parkinson’s disease (PD) and examine how iron accumulation in vulnerable brain regions may fuel disease-specific protein aggregation and neurodegeneration. We further surveyed the distinct components of ferroptosis, highlighting the role of lipid peroxidation enzymes, mitochondrial dysfunction, and recently discovered parallel pathways that either exacerbate or mitigate neuronal death. Finally, we discuss how these insights open new avenues for neuroprotective strategies, including iron chelation and lipid peroxidation inhibitors. By highlighting open questions, this review seeks to clarify the current state of knowledge and proposes directions to harness ferroptosis modulation for disease intervention.

Iron dysregulation has emerged as a pivotal factor in neurodegenerative pathologies, especially through its capacity to promote ferroptosis, a unique form of regulated cell death driven by iron-catalyzed lipid peroxidation. This review synthesizes current evidence on the molecular underpinnings of ferroptosis, focusing on how disruptions in iron homeostasis interact with key antioxidant defenses, such as the system Xc^−–glutathione–GPX4 axis, to tip neurons toward lethal oxidative damage. Building on these mechanistic foundations, we explore how ferroptosis intersects with hallmark pathologies in Alzheimer’s disease (AD) and Parkinson’s disease (PD) and examine how iron accumulation in vulnerable brain regions may fuel disease-specific protein aggregation and neurodegeneration. We further surveyed the distinct components of ferroptosis, highlighting the role of lipid peroxidation enzymes, mitochondrial dysfunction, and recently discovered parallel pathways that either exacerbate or mitigate neuronal death. Finally, we discuss how these insights open new avenues for neuroprotective strategies, including iron chelation and lipid peroxidation inhibitors. By highlighting open questions, this review seeks to clarify the current state of knowledge and proposes directions to harness ferroptosis modulation for disease intervention.

Hematopoietic stem cells (HSCs) receive a combination of biochemical and biomechanical signals within the bone marrow that guide their differentiation process. These include soluble factor signaling with cytokines, cellular confinement in the stem cell niche, and contact‐dependent receptor–ligand interactions with stromal cells. Recreating this complex microenvironment in vitro is a principal engineering challenge for regenerative therapies and tissue engineering. While cytokines can be easily supplemented in vitro, and several systems for confined HSC culture have been developed, integrating receptor‐based intercellular interactions found in stem cell niches has only been achieved with quantitatively undefined heterotypic co‐cultures. We report here the development of microwell‐based systems that integrate synthetic cells to mimic receptor–ligand interactions within hematopoietic niches. The synthetic cells are based on droplet‐supported lipid bilayers (dsLBs) with cytomimetic stiffness and present Notch receptor ligands on a laterally mobile lipid membrane. We show the system's applicability to individually tune the three signaling axes: soluble factors, confinement, and intercellular interactions for HSC differentiation. Introducing synthetic cells as an alternative to coculture and feeder cells opens the possibility to engineer precisely defined HSC niches with adjustable biochemical and biomechanical properties.