PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals

Abstract

SUMMARY Ferroptosis is a form of programmed cell death pathogenic to several acute and chronic diseases and executed via oxygenation of polyunsaturated phosphatidylethanolamines (PE) by 15-lipoxygenases (15-LO) that normally use free polyunsaturated fatty acids as substrates. Mechanisms of the altered 15-LO substrate specificity are enigmatic. We sought a common ferroptosis regulator for 15LO. We discovered that PEBP1, a scaffold protein inhibitor of protein kinase cascades, complexes with two 15LO isoforms, 15LO1 and 15LO2, and changes their substrate competence to generate hydroperoxy-PE. Inadequate reduction of hydroperoxy-PE due to insufficiency or dysfunction of a selenoperoxidase, GPX4, leads to ferroptosis. We demonstrated the importance of PEBP1-dependent regulatory mechanisms of ferroptotic death in airway epithelial cells in asthma, kidney epithelial cells in renal failure and cortical and hippocampal neurons in brain trauma. As master regulators of ferroptotic cell death with profound implications for human disease, PEBP1/15LO complexes represent a new target for drug discovery.

Adipose‐Specific Lipin‐1 Overexpression Renders Hepatic Ferroptosis and Exacerbates Alcoholic Steatohepatitis in Mice

“…Although ethanol exposure rendered liver susceptible to the ferroptic process in Lpin1 ‐Tg mice, ethanol administration to WT mice was not sufficient to steer the hepatic ferroptosis signaling cascade of events and induce hepatic ferroptosis. Aside from aberrant iron metabolism and lipid peroxidation signaling, the coexistence of multiple factors is required to execute ferroptosis . For instance, inactivation of GPX4 is essential for the execution of ferroptosis .…”

“…Ferroptosis is an iron‐dependent form of oxidative programmed cell death featuring glutathione (GSH) depletion, detrimental glutathione peroxidase‐4 (GPX4) redox defense, disrupted glutamate antiporter xCT/SCL7A11 (system Xc ‐ ), and increased levels of lipid hydroperoxides . In recent years, ferroptosis has emerged as a central mediator of cell death, implicated in multiple pathological processes including ischemia/reperfusion‐induced kidney or liver damage, neurotoxicity, and neurodegenerative diseases …”

Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last?

“…The role of ferroptosis as a cell death mechanism contributing to organ damage in sepsis has been hardly explored. Nevertheless, ferroptosis has been implicated in acute kidney failure and could be an important alternative cell death pathway during sepsis (Linkermann et al , ; Müller et al , ; Wenzel et al , ). The precise contribution and impact of each of above‐mentioned altered cellular processes have not been properly delineated and seem to depend on lipid composition and cell type (Ghosh & Rodrigues, ).…”

Mitochondrial network responses in oxidative physiology and disease

“…Cluster 1 was a cation-response hub which included a gene encoding a proapoptic protein, Chac1, and two cation transporters. This hub could contribute to toxicity due to manganese (Mn) or iron (Fe) transport, PQ transport, activation of apoptosis, ferroptosis [70] or other mechanism. Some of the transcripts in other hubs would be more predictable because of known protective functions.…”