Summary Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and that cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH and coenzyme Q10. Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

The “silent epidemic” of traumatic brain injury (TBI) has been placed in the spotlight following investigations and popular press coverage of athletes and returning soldiers with single and repetitive injuries; however, treatments to improve the outcome for patients with TBI across the spectrum from mild to severe TBI are lacking. Neuroinflammation may cause acute secondary injury after TBI, and it has been linked to chronic neurodegenerative diseases. Despite these findings, anti-inflammatory agents have failed to improve outcomes in clinical trials. We therefore propose in this review a new framework for future exploration of targeted immunomodulation after TBI that incorporates factors such as the time from injury, mechanism of injury, and secondary insults in considering potential treatment options. Structured around the dynamics of the immune response to TBI – from initial triggers to chronic neuroinflammation – the ability of soluble and cellular inflammatory mediators to promote repair and regeneration versus secondary injury and neurodegeneration is highlighted, with knowledge from human studies explicitly defined throughout this review. Recent advances in neuroimmunology and TBI-responsive neuroinflammation are incorporated, including inflammasomes, mechanisms of microglial polarization, and glymphatic clearance. In addition, we identify throughout this review where these findings may offer novel therapeutic targets for translational and clinical research, incorporate evidence from other brain injury models, and identify outstanding questions in the field.

We have observed an unexpected increase in mortality coincident with CPOE implementation. Although CPOE technology holds great promise as a tool to reduce human error during health care delivery, our unanticipated finding suggests that when implementing CPOE systems, institutions should continue to evaluate mortality effects, in addition to medication error rates, for children who are dependent on time-sensitive therapies.

Sex-dependent differences in adaptation to famine have long been appreciated, thought to hinge on female versus male preferences for fat versus protein sources, respectively. However, whether these differences can be reduced to neurons, independent of typical nutrient depots, such as adipose tissue, skeletal muscle, and liver, was heretofore unknown. A vital adaptation to starvation is autophagy, a mechanism for recycling amino acids from organelles and proteins. Here we show that segregated neurons from males in culture are more vulnerable to starvation than neurons from females. Nutrient deprivation decreased mitochondrial respiration, increased autophagosome formation, and produced cell death more profoundly in neurons from males versus females. Starvation-induced neuronal death was attenuated by 3-methyladenine, an inhibitor of autophagy; Atg7 knockdown using small interfering RNA; or L-carnitine, essential for transport of fatty acids into mitochondria, all more effective in neurons from males versus females. Relative tolerance to nutrient deprivation in neurons from females was associated with a marked increase in triglyceride and free fatty acid content and a cytosolic phospholipase A2-dependent increase in formation of lipid droplets. Similar sex differences in sensitivity to nutrient deprivation were seen in fibroblasts. However, although inhibition of autophagy using Atg7 small interfering RNA inhibited cell death during starvation in neurons, it increased cell death in fibroblasts, implying that the role of autophagy during starvation is both sex- and tissue-dependent. Thus, during starvation, neurons from males more readily undergo autophagy and die, whereas neurons from females mobilize fatty acids, accumulate triglycerides, form lipid droplets, and survive longer.