1c:I[419806,["/_next/static/chunks/bb923814e1f4d2e9.js","/_next/static/chunks/dd3ee9f5b7716ca6.js","/_next/static/chunks/4204a0ae82542ca8.js","/_next/static/chunks/30036bedc5269936.js","/_next/static/chunks/6e1aa89a642f40be.js","/_next/static/chunks/cd5e572bc3e4eb92.js","/_next/static/chunks/8ffd0b71567920d8.js","/_next/static/chunks/67ea6dfd21f16c5f.js","/_next/static/chunks/24eb4379f68013fd.js","/_next/static/chunks/b8cd775ffdf935bd.js","/_next/static/chunks/983103cd9eb7b428.js","/_next/static/chunks/d4ac9dcf27f6ff52.js","/_next/static/chunks/294b9525248c8e5f.js"],"default"] 1d:T4e1,Ferroptosis, a new form of regulated cell death, results from the iron-dependent accumulation of lipid peroxides that are associated with reactive oxygen species. However, it remains unclear how hydroxyl radical (^•OH) and cellular microenvironments such as viscosity alter in this process. Herein, we characterize for the first time the changing behavior of ^•OH and cytoplasmic viscosity during ferroptosis using a dual-functional fluorescence probe (H-V) that is designed via the molecular rotor strategy and the unique aromatic hydroxylation of ^•OH. Probe H-V shows completely separate spectral responses to ^•OH and viscosity with high sensitivity and selectivity, thereby achieving the detection of ^•OH and viscosity in two independent channels without spectral cross-interference. With the probe we find that ferroptosis is accompanied by significant ^•OH generation and cytoplasmic viscosity increase. Most notably, the raised ^•OH comprises the majority of the total reactive oxygen species in ferroptosis. H-V is biocompatible, ready to prepare, and may be expected to be used in the study of viscosity and ^•OH detection in more biosystems.1e:T447,Discovering compounds and mechanisms for inhibiting ferroptosis, a form of regulated, nonapoptotic cell death, has been of great interest in recent years. In this study, we demonstrate the ability of XJB-5-131, JP4-039, and other nitroxide-based lipid peroxidation mitigators to prevent ferroptotic cell death in HT-1080, BJeLR, and panc-1 cells. Several analogues of the reactive oxygen species (ROS) scavengers XJB-5-131 and JP4-039 were synthesized to probe structure-activity relationships and the influence of subcellular localization on the potency of these novel ferroptosis suppressors. Their biological activity correlated well over several orders of magnitude with their structure, relative lipophilicity, and respective enrichment in mitochondria, revealing a critical role of intramitochondrial lipid peroxidation in ferroptosis. These results also suggest that preventing mitochondrial lipid oxidation might offer a viable therapeutic opportunity in ischemia/reperfusion-induced tissue injury, acute kidney injury, and other pathologies that involve ferroptotic cell death pathways.

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