Antiferroptotic Drugs Reduce sFlt-1 Release and Placenta Damage in Preeclampsia.

Background: Preeclampsia is characterized by hypertension, proteinuria, and elevated antiangiogenic sFlt-1 (soluble fms-like tyrosine kinase-1) levels. Despite extensive research, mechanisms underlying sFlt-1 dysregulation remain unclear. This hypothesis-testing study investigated whether ferroptosis, a lipid peroxidation-driven cell death mechanism, contributes to preeclamptic placental pathogenesis and sFlt-1 release, and whether drug repurposing could identify novel therapeutic options.

15-Lipoxygenase-dependent radiomitigation by NO-Donors suppresses ferroptosis in intestinal Epithelium: Multiomics MS imaging and LC-MS evidence.

Threats of irradiation (IR) exposure increase the need for radiomitigators. An important contributor to radiation injury is ferroptosis, triggered by the disbalanced redox metabolism. We showed that 15-lipoxygenase (15-LOX) catalyzed peroxidation of arachidonoyl-phosphatidyl-ethanolamine is an essential ferroptotic response of ileum to total body IR (TBI).

Endoplasmic reticulum-mitochondria contacts are prime hotspots of phospholipid peroxidation driving ferroptosis.

The peroxidation of membrane phospholipids (PLs) is a hallmark of ferroptosis. The endoplasmic reticulum and mitochondria have been implicated in ferroptosis, but whether intracellular PL peroxidation ensues at their contact sites (endoplasmic reticulum-mitochondria contact sites, EMCSs) is unknown. Using super-resolution live imaging, we charted the spatiotemporal events triggered by ferroptosis at the interorganelle level.

The presence of substrate warrants oxygen access tunnels toward the catalytic site of lipoxygenases.

Ferroptosis is a regulated form of cell death driven by lipid peroxidation, with 15-lipoxygenase (15LOX) enzyme playing a critical role in catalyzing the oxygenation of polyunsaturated fatty acid-containing phospholipids, such as 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphoethanolamine (SAPE), to initiate this process. The molecular oxygen required for this catalytic reaction is subject to continuous competition among various oxygen-consuming enzymes, which influences the efficiency of lipid peroxidation. In this study, we utilized structure-based modeling and all-atom molecular dynamics simulations to explore the oxygen diffusion pathways in 15LOX-1 under varying oxygen concentrations and in the presence of key components, including a substrate, binding partner PE-binding protein 1 (PEBP1), and the membrane environment.

Oxidized phospholipid and transcriptomic signatures of THC-related vaping associated lung injury.

E-cigarette/vaping-associated lung injury (EVALI) is strongly associated with vitamin E acetate and often occurs with concomitant tetrahydrocannabinol (THC) use. To uncover pathways associated with EVALI, we examined cytokines, transcriptomic signatures, and lipidomic profiles in bronchoalveolar lavage fluid (BALF) from THC-EVALI patients. At a single center, we prospectively enrolled mechanically ventilated patients with EVALI from THC-containing products (N = 4) and patients with non-vaping acute lung injury and airway controls (N = 5).

Ferroptosis of select skin epithelial cells initiates and maintains chronic systemic immune-mediated psoriatic disease.

Dysregulations of epithelial-immune interactions frequently culminate in chronic inflammatory diseases of the skin, lungs, kidneys, and gastrointestinal tract. Yet, the intraepithelial processes that initiate and perpetuate inflammation in these organs are poorly understood. Here, by utilizing redox lipidomics we identified ferroptosis-associated peroxidation of polyunsaturated phosphatidylethanolamines in the epithelia of patients with asthma, cystic fibrosis, psoriasis, and renal failure.

Mitochondrial bioenergetics and cardiolipin remodeling abnormalities in mitochondrial trifunctional protein deficiency.

Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid β-oxidation. Mutations in HADHA and HADHB, which encode the TFP α and β subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.

Compartmentalized mitochondrial ferroptosis converges with optineurin-mediated mitophagy to impact airway epithelial cell phenotypes and asthma outcomes.

A stable mitochondrial pool is crucial for healthy cell function and survival. Altered redox biology can adversely affect mitochondria through induction of a variety of cell death and survival pathways, yet the understanding of mitochondria and their dysfunction in primary human cells and in specific disease states, including asthma, is modest. Ferroptosis is traditionally considered an iron dependent, hydroperoxy-phospholipid executed process, which induces cytosolic and mitochondrial damage to drive programmed cell death.

PHLDA2-mediated phosphatidic acid peroxidation triggers a distinct ferroptotic response during tumor suppression.

Although the role of ferroptosis in killing tumor cells is well established, recent studies indicate that ferroptosis inducers also sabotage anti-tumor immunity by killing neutrophils and thus unexpectedly stimulate tumor growth, raising a serious issue about whether ferroptosis effectively suppresses tumor development in vivo. Through genome-wide CRISPR-Cas9 screenings, we discover a pleckstrin homology-like domain family A member 2 (PHLDA2)-mediated ferroptosis pathway that is neither ACSL4-dependent nor requires common ferroptosis inducers. PHLDA2-mediated ferroptosis acts through the peroxidation of phosphatidic acid (PA) upon high levels of reactive oxygen species (ROS).

Strikingly High Activity of 15-Lipoxygenase Towards Di-Polyunsaturated Arachidonoyl/Adrenoyl-Phosphatidylethanolamines Generates Peroxidation Signals of Ferroptotic Cell Death.

The vast majority of membrane phospholipids (PLs) include two asymmetrically positioned fatty acyls: oxidizable polyunsaturated fatty acids (PUFA) attached predominantly at the sn2 position, and non-oxidizable saturated/monounsaturated acids (SFA/MUFA) localized at the sn1 position. The peroxidation of PUFA-PLs, particularly sn2-arachidonoyl(AA)- and sn2-adrenoyl(AdA)-containing phosphatidylethanolamines (PE), has been associated with the execution of ferroptosis, a program of regulated cell death. There is a minor subpopulation (≈1-2 mol %) of doubly PUFA-acylated phospholipids (di-PUFA-PLs) whose role in ferroptosis remains enigmatic.

Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome.

Barth syndrome (BTHS) is a life-threatening genetic disorder with unknown pathogenicity caused by mutations in TAFAZZIN (TAZ) that affect remodeling of mitochondrial cardiolipin (CL). TAZ deficiency leads to accumulation of mono-lyso-CL (MLCL), which forms a peroxidase complex with cytochrome c (cyt c) capable of oxidizing polyunsaturated fatty acid-containing lipids. We hypothesized that accumulation of MLCL facilitates formation of anomalous MLCL-cyt c peroxidase complexes and peroxidation of polyunsaturated fatty acid phospholipids as the primary BTHS pathogenic mechanism.

Membrane regulation of 15LOX-1/PEBP1 complex prompts the generation of ferroptotic signals, oxygenated PEs.

Ferroptosis is a regulated form of cell death, the mechanism of which is still to be understood. 15-lipoxygenase (15LOX) complex with phosphatidylethanolamine (PE)-binding protein 1 (PEBP1) catalyzes the generation of pro-ferroptotic cell death signals, hydroperoxy-polyunsaturated PE. We focused on gaining new insights into the molecular basis of these pro-ferroptotic interactions using computational modeling and liquid chromatography-mass spectrometry experiments.

Ferroptosis contributes to multiple sclerosis and its pharmacological targeting suppresses experimental disease progression.

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by central nervous (CNS) demyelination resulting in axonal injury and neurological deficits. Essentially, MS is driven by an auto-amplifying mechanism of inflammation and cell death. Current therapies mainly focus on disease modification by immunosuppression, while no treatment specifically focuses on controlling cell death injury.

Discovering selective antiferroptotic inhibitors of the 15LOX/PEBP1 complex noninterfering with biosynthesis of lipid mediators.

Programmed ferroptotic death eliminates cells in all major organs and tissues with imbalanced redox metabolism due to overwhelming iron-catalyzed lipid peroxidation under insufficient control by thiols (Glutathione (GSH)). Ferroptosis has been associated with the pathogenesis of major chronic degenerative diseases and acute injuries of the brain, cardiovascular system, liver, kidneys, and other organs, and its manipulation offers a promising new strategy for anticancer therapy. This explains the high interest in designing new small-molecule-specific inhibitors against ferroptosis.

The lipase cofactor CGI58 controls placental lipolysis.

In eutherians, the placenta plays a critical role in the uptake, storage, and metabolism of lipids. These processes govern the availability of fatty acids to the developing fetus, where inadequate supply has been associated with substandard fetal growth. Whereas lipid droplets are essential for the storage of neutral lipids in the placenta and many other tissues, the processes that regulate placental lipid droplet lipolysis remain largely unknown.

Melanoma-associated repair-like Schwann cells suppress anti-tumor T-cells via 12/15-LOX/COX2-associated eicosanoid production.

Peripheral glia, specifically the Schwann cells (SCs), have been implicated in the formation of the tumor microenvironment (TME) and in cancer progression. However, and analyses of how cancers reprogram SC functions in different organs of tumor-bearing mice are lacking. We generated Plp1-CreERT/tdTomato mice which harbor fluorescently labeled myelinated and non-myelin forming SCs.

Redox phospholipidomics discovers pro-ferroptotic death signals in A375 melanoma cells in vitro and in vivo.

Growing cancer cells effectively evade most programs of regulated cell death, particularly apoptosis. This necessitates a search for alternative therapeutic modalities to cause cancer cell's demise, among them - ferroptosis. One of the obstacles to using pro-ferroptotic agents to treat cancer is the lack of adequate biomarkers of ferroptosis.

Ferroptosis of tumour neutrophils causes immune suppression in cancer.

Ferroptosis is a non-apoptotic form of regulated cell death that is triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Ferroptosis inducers have shown considerable effectiveness in killing tumour cells in vitro, yet there has been no obvious success in experimental animal models, with the notable exception of immunodeficient mice. This suggests that the effect of ferroptosis on immune cells remains poorly understood.

Necroptosis triggers spatially restricted neutrophil-mediated vascular damage during lung ischemia reperfusion injury.

Ischemia reperfusion injury represents a common pathological condition that is triggered by the release of endogenous ligands. While neutrophils are known to play a critical role in its pathogenesis, the tissue-specific spatiotemporal regulation of ischemia-reperfusion injury is not understood. Here, using oxidative lipidomics and intravital imaging of transplanted mouse lungs that are subjected to severe ischemia reperfusion injury, we discovered that necroptosis, a nonapoptotic form of cell death, triggers the recruitment of neutrophils.

P. aeruginosa augments irradiation injury via 15-lipoxygenase-catalyzed generation of 15-HpETE-PE and induction of theft-ferroptosis.

Total body irradiation (TBI) targets sensitive bone marrow hematopoietic cells and gut epithelial cells, causing their death and inducing a state of immunodeficiency combined with intestinal dysbiosis and nonproductive immune responses. We found enhanced Pseudomonas aeruginosa (PAO1) colonization of the gut leading to host cell death and strikingly decreased survival of irradiated mice. The PAO1-driven pathogenic mechanism includes theft-ferroptosis realized via (a) curbing of the host antiferroptotic system, GSH/GPx4, and (b) employing bacterial 15-lipoxygenase to generate proferroptotic signal - 15-hydroperoxy-arachidonoyl-PE (15-HpETE-PE) - in the intestines of irradiated and PAO1-infected mice.

Keratinocyte death by ferroptosis initiates skin inflammation after UVB exposure.

The ultraviolet B radiation (UVB) causes skin inflammation, which contributes to the causality and the exacerbation of a number of cutaneous diseases. However, the mechanism of UVB-driven inflammation in the skin remains poorly understood. We show that ferroptosis, a non-apoptotic programmed cell death pathway that is promoted by an excessive phospholipid peroxidation, is activated in the epidermal keratinocytes after their exposure to UVB.

A new thiol-independent mechanism of epithelial host defense against Pseudomonas aeruginosa: iNOS/NO sabotage of theft-ferroptosis.

Ferroptosis is a redox-driven type of regulated cell death program arising from maladaptation of three metabolic pathways: glutathione homeostasis, iron handling and lipid peroxidation. Though GSH/Gpx4 is the predominant system detoxifying phospholipid hydroperoxides (PLOOH) in mammalian cells, recently Gpx4-independent regulators of ferroptosis like ferroptosis suppressor protein 1 (FSP1) in resistant cancer lines and iNOS/NO in M1 macrophages have been discovered. We previously reported that Pseudomonas aeruginosa (PA) utilizes its 15- lipoxygenase (pLoxA) to trigger ferroptotic death in epithelial cells by oxidizing the host arachidonoyl-phosphatidylethanolamine (ETE-PE) into pro-ferroptotic 15-hydroperoxy- arachidonyl-PE (15-HpETE-PE).