Superior sodiophilicity and molecule crowding of crown ether boost the electrochemical performance of all-climate sodium-ion batteries.

Sodium-ion batteries (SIBs) as one of the promising alternatives to lithium-ion batteries have achieved remarkable progress in the past. However, the all-climate performance is still very challenging for SIBs. Herein, 15-Crown-5 (15-C-5) is screened as an electrolyte additive from a number of ether molecules theoretically. The good sodiophilicity, high molecule rigidity, and bulky size enable it to reshape the solvation sheath and promote the anion engagement in the solvated structures by molecule crowding. This change also enhances Na-ion transfer, inhibits side reactions, and leads to a thin and robust solid-electrolyte interphase. Furthermore, the electrochemical stability and operating temperature windows of the electrolyte are extended. These profits improve the electrochemical performance of SIBs in all climates, much better than the case without 15-C-5. This improvement is also adopted to µ-Sn, µ-Bi, hard carbon, and MoS2. This work opens a door to prioritize the potential molecules in theory for advanced electrolytes.

Self-terminating, heterogeneous solid-electrolyte interphase enables reversible Li-ether cointercalation in graphite anodes.

Ether solvents are suitable for formulating solid-electrolyte interphase (SEI)-less ion-solvent cointercalation electrolytes in graphite for Na-ion and K-ion batteries. However, ether-based electrolytes have been historically perceived to cause exfoliation of graphite and cell failure in Li-ion batteries. In this study, we develop strategies to achieve reversible Li-solvent cointercalation in graphite through combining appropriate Li salts and ether solvents. Specifically, we design 1M LiBF4 1,2-dimethoxyethane (G1), which enables natural graphite to deliver ~91% initial Coulombic efficiency and >88% capacity retention after 400 cycles. We captured the spatial distribution of LiF at various length scales and quantified its heterogeneity. The electrolyte shows self-terminated reactivity on graphite edge planes and results in a grainy, fluorinated pseudo-SEI. The molecular origin of the pseudo-SEI is elucidated by ab initio molecular dynamics (AIMD) simulations. The operando synchrotron analyses further demonstrate the reversible and monotonous phase transformation of cointercalated graphite. Our findings demonstrate the feasibility of Li cointercalation chemistry in graphite for extreme-condition batteries. The work also paves the foundation for understanding and modulating the interphase generated by ether electrolytes in a broad range of electrodes and batteries.

Selenoprotein I is indispensable for ether lipid homeostasis and proper myelination.

Selenoprotein I (SELENOI) catalyzes the final reaction of the CDP-ethanolamine branch of the Kennedy pathway, generating the phospholipids phosphatidylethanolamine (PE) and plasmenyl-PE. Plasmenyl-PE is a key component of myelin and is characterized by a vinyl ether bond that preferentially reacts with oxidants, thus serves as a sacrificial antioxidant. In humans, multiple loss-of-function mutations in genes affecting plasmenyl-PE metabolism have been implicated in hereditary spastic paraplegia, including SELENOI. Herein, we developed a mouse model of nervous system-restricted SELENOI deficiency that circumvents embryonic lethality caused by constitutive deletion and recapitulates phenotypic features of hereditary spastic paraplegia. Resulting mice exhibited pronounced alterations in brain lipid composition, which coincided with motor deficits and neuropathology including hypomyelination, elevated reactive gliosis, and microcephaly. Further studies revealed increased lipid peroxidation in oligodendrocyte lineage cells and disrupted oligodendrocyte maturation both in vivo and in vitro. Altogether, these findings detail a critical role for SELENOI-derived plasmenyl-PE in myelination that is of paramount importance for neurodevelopment.

A calibrated functional patch-clamp assay to enhance clinical variant interpretation in KCNH2-related long QT syndrome.

Modern sequencing technologies have revolutionized our detection of gene variants. However, in most genes, including KCNH2, the majority of missense variants are currently classified as variants of uncertain significance (VUSs). The aim of this study was to investigate the utility of an automated patch-clamp assay for aiding clinical variant classification in KCNH2. The assay was designed according to recommendations proposed by the Clinical Genome Sequence Variant Interpretation Working Group. Thirty-one variants (17 pathogenic/likely pathogenic, 14 benign/likely benign) were classified internally as variant controls. They were heterozygously expressed in Flp-In HEK293 cells for assessing the effects of variants on current density and channel gating in order to determine the sensitivity and specificity of the assay. All 17 pathogenic variant controls had reduced current density, and 13 of 14 benign variant controls had normal current density, which enabled determination of normal and abnormal ranges for applying evidence of moderate or supporting strength for VUS reclassification. Inclusion of functional assay evidence enabled us to reclassify 6 out of 44 KCNH2 VUSs as likely pathogenic. The high-throughput patch-clamp assay can provide moderate-strength evidence for clinical interpretation of clinical KCNH2 variants and demonstrates the value of developing automated patch-clamp assays for functional characterization of ion channel gene variants.

Hydration-Accelerated Crown Ether Diffusion within Single Three-Dimensional Covalent Organic Frameworks.

In this contribution, we report on the visualization of 12-crown-4 molecular diffusion behavior within a single-crystal particle of covalent organic framework-300 (COF-300) using operando dark-field optical microscopy. The diffusion area and front of 12-crown-4 are directly tracked in real time, offering key information for quantifying the diffusion coefficient (D). The direction of the diffusion and variation of D reveal intraparticle and interparticle heterogeneity. Notably, an unexpected hydration-accelerated diffusion process of 12-crown-4 within the pore channels of COF-300 is captured, in which a relatively low concentration of 12-crown-4 aqueous solution induces a fast diffusion, whereas the pure 12-crown-4 liquid cannot access the framework. The observed acceleration diffusion is demonstrated to arise from the hydrogen-bonding interactions between surface water molecules of hydrated 12-crown-4 and the imine groups of COF-300. These findings expand the mechanistic understanding of the noncovalent interactions between COFs and crown ethers (CEs), which will help to design and prepare CE-based COFs with improved performance.

60Co-γ Irradiation-Induced Shift and Polarity Reversal in the Triboelectric Series of Poly(ether sulfone)s.

The sensitivity of triboelectric nanogenerators (TENGs) to the surface charge density highlights the significance of triboelectric materials and their modifications. Efforts have been directed toward developing effective strategies for increasing the surface charge density, expanding the potential applications of TENGs. This study proposes the use of irradiation technology for grafting to modify the electron-donating capability of poly(ether sulfone) (PES), thereby affording a dual benefit of enhancing the surface charge density and inducing a shift in the position of PES from negative to positive within the triboelectric series. The TENG based on grafted PES has resulted in a significant 3-fold increase in surface charge density compared to that of pristine PES, reaching 263 µC m-2. The surface charge density can be further increased to 502 µC m-2 through charge pumping. Notably, irradiation technology presents advantages over chemical grafting methods, particularly in terms of sustainability and environmental friendliness. This innovative approach shows great potential in advancing the domain of TENGs.

Endogenous ether lipids differentially promote tumor aggressiveness by regulating the SK3 channel.

SK3 channels are potassium channels found to promote tumor aggressiveness. We have previously demonstrated that SK3 is regulated by synthetic ether lipids, but the role of endogenous ether lipids is unknown. Here, we have studied the role of endogenous alkyl- and alkenyl-ether lipids on SK3 channels and on the biology of cancer cells. Experiments revealed that the suppression of alkylglycerone phosphate synthase or plasmanylethanolamine desaturase 1, which are key enzymes for alkyl- and alkenyl-ether-lipid synthesis, respectively, decreased SK3 expression by increasing micro RNA (miR)-499 and miR-208 expression, leading to a decrease in SK3-dependent calcium entry, cell migration, and matrix metalloproteinase 9-dependent cell adhesion and invasion. We identified several ether lipids that promoted SK3 expression and found a differential role of alkyl- and alkenyl-ether lipids on SK3 activity. The expressions of alkylglycerone phosphate synthase, SK3, and miR were associated in clinical samples emphasizing the clinical consistency of our observations. To our knowledge, this is the first report showing that ether lipids differentially control tumor aggressiveness by regulating an ion channel. This insight provides new possibilities for therapeutic interventions, offering clinicians an opportunity to manipulate ion channel dysfunction by adjusting the composition of ether lipids.

Development of a Global Metabo-Lipid-Prote-omics Workflow to Compare Healthy Proximal and Distal Colonic Epithelium in Mice.

A multimetabo-lipid-prote-omics workflow was developed to characterize the molecular interplay within proximal (PC) and distal (DC) colonic epithelium of healthy mice. This multiomics data set lays the foundation to better understand the two tissue types and can be used to study, for example, colon-related diseases like colorectal cancer or inflammatory bowel disease. First, the methyl tert-butyl ether extraction method was optimized, so that from a single tissue biopsy >350 reference-matched metabolites, >1850 reference-matched lipids, and >4500 proteins were detected by using targeted and untargeted metabolomics, untargeted lipidomics, and proteomics. Next, each omics-data set was analyzed individually and then merged with the additional omics disciplines to generate a deep understanding of the underlying complex regulatory network within the colon. Our data demonstrates, for example, differences in mucin formation, detected on substrate level as well as on enzyme level, and altered lipid metabolism by the detection of phospholipases hydrolyzing sphingomyelins to ceramides. In conclusion, the combination of the three mass spectrometry-based omics techniques can better entangle the functional and regional differences between PC and DC tissue compared to each single omics technique.

Vanillyl alcohol oxidase from Diplodia corticola: Residues Ala420 and Glu466 allow for efficient catalysis of syringyl derivatives.

Vanillyl alcohol oxidases (VAOs) belong to the 4-phenol oxidases family and are found predominantly in lignin-degrading ascomycetes. Systematical investigation of the enzyme family at the sequence level resulted in discovery and characterization of the second recombinantly produced VAO member, DcVAO, from Diplodia corticola. Remarkably high activities for 2,6-substituted substrates like 4-allyl-2,6-dimethoxy-phenol (3.5 ± 0.02 U mg-1) or 4-(hydroxymethyl)-2,6-dimethoxyphenol (6.3 ± 0.5 U mg-1) were observed, which could be attributed to a Phe to Ala exchange in the catalytic center. In order to rationalize this rare substrate preference among VAOs, we resurrected and characterized three ancestral enzymes and performed mutagenesis analyses. The results indicate that a Cys/Glu exchange was required to retain activity for É£-hydroxylations and shifted the acceptance towards benzyl ethers (up to 4.0 ± 0.1 U mg-1). Our findings contribute to the understanding of the functionality of VAO enzyme group, and with DcVAO, we add a new enzyme to the repertoire of ether cleaving biocatalysts.

Maize Root Exudates Promote Bacillus sp. Za Detoxification of Diphenyl Ether Herbicides by Enhancing Colonization and Biofilm Formation.

Diphenyl ether herbicides are extensively utilized in agricultural systems, but their residues threaten the health of sensitive rotation crops. Functional microbial strains can degrade diphenyl ether herbicides in the rhizosphere of crops, facilitating the restoration of a healthy agricultural environment. However, the interplay between microorganisms and plants in diphenyl ether herbicides degradation remains unclear. Thus, the herbicide-degrading strain Bacillus sp. Za and the sensitive crop, maize, were employed to uncover the interaction mechanism. The degradation of diphenyl ether herbicides by strain Bacillus sp. Za was promoted by root exudates. The strain induced root exudate re-secretion in diphenyl ether herbicide-polluted maize. We further showed that root exudates enhanced the rhizosphere colonization and the biofilm biomass of strain Za, augmenting its capacity to degrade diphenyl ether herbicide. Root exudates regulated gene fliZ, which is pivotal in biofilm formation. Wild-type strain Za significantly reduced herbicide toxicity to maize compared to the ZaΔfliZ mutant. Moreover, root exudates promoted strain Za growth and chemotaxis, which was related to biofilm formation. This mutualistic relationship between the microorganisms and the plants demonstrates the significance of plant-microbe interactions in shaping diphenyl ether herbicide degradation in rhizosphere soils. [Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 "No Rights Reserved" license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law, 2024.

Epoxyalcohol Synthase Branch of Lipoxygenase Cascade.

Oxylipins are one of the most important classes of bioregulators, biosynthesized through the oxidative metabolism of unsaturated fatty acids in various aerobic organisms. Oxylipins are bioregulators that maintain homeostasis at the cellular and organismal levels. The most important oxylipins are mammalian eicosanoids and plant octadecanoids. In plants, the main source of oxylipins is the lipoxygenase cascade, the key enzymes of which are nonclassical cytochromes P450 of the CYP74 family, namely allene oxide synthases (AOSs), hydroperoxide lyases (HPLs), and divinyl ether synthases (DESs). The most well-studied plant oxylipins are jasmonates (AOS products) and traumatin and green leaf volatiles (HPL products), whereas other oxylipins remain outside of the focus of researchers' attention. Among them, there is a large group of epoxy hydroxy fatty acids (epoxyalcohols), whose biosynthesis has remained unclear for a long time. In 2008, the first epoxyalcohol synthase of lancelet Branchiostoma floridae, BfEAS (CYP440A1), was discovered. The present review collects data on EASs discovered after BfEAS and enzymes exhibiting EAS activity along with other catalytic activities. This review also presents the results of a study on the evolutionary processes possibly occurring within the P450 superfamily as a whole.

Cyclic Ether Derived Stable Solid Electrolyte Interphase on Bismuth Anodes for Ultrahigh-Rate Sodium-Ion Storage.

The bismuth anode has garnered significant attention due to its high theoretical Na-storage capacity (386 mAh g-1). There have been numerous research reports on the stable solid electrolyte interphase (SEI) facilitated by electrolytes utilizing ether solvents. In this contribution, cyclic tetrahydrofuran (THF) and 2-methyltetrahydrofuran (MeTHF) ethers are employed as solvents to investigate the sodium-ion storage properties of bismuth anodes. A series of detailed characterizations are utilized to analyze the impact of electrolyte solvation structure and SEI chemical composition on the kinetics of sodium-ion storage. The findings reveal that bismuth anodes in both THF and MeTHF-based electrolytes exhibit exceptional rate performance at low current densities, but in THF-based electrolytes, the reversible capacity is higher at high current densities (316.7 mAh g-1 in THF compared to 9.7 mAh g-1 in MeTHF at 50 A g-1). This stark difference is attributed to the formation of an inorganic-rich, thin, and uniform SEI derived from THF-based electrolyte. Although the SEI derived from MeTHF-based electrolyte also consists predominantly of inorganic components, it is thicker and contains more organic species compared to the THF-derived SEI, impeding charge transfer and ion diffusion. This study offers valuable insights into the utilization of cyclic ether electrolytes for Na-ion batteries.

Ion Resource Recovery via Electrodialysis Fabricated with Poly(Arylene Ether Sulfone)-Based Anion Exchange Membrane in Organic Solvent System.

Ion resource recovery from organic wastewater is beneficial for achieving emission peaks and carbon neutrality targets. Advanced organic solvent-resistant anion exchange membranes (AEMs) for treating organic wastewater via electrodialysis (ED) are of significant interest. Herein, a kind of 3D network AEM based on poly(arylene ether sulfone) cross-linked with a flexible cross-linker (DBH) for ion resource recovery via ED in organic solvent system is reported. Investigations demonstrate that the as-prepared AEMs show excellent dimensional stability in 60% DMSO (aq.), 60% ethanol (aq.), and 60% acetone (aq.), respectively. For example, the optimized AEM shows very low swelling ratios of 1.04-1.10% in the organic solvents. ED desalination ratio can reach 99.1% after exposure of the AEM to organic solvents for 30 days, and remain > 99% in a mixture solution containing organic solvents and 0.5 m NaCl. Additionally, at a current density of 2.5 mA cm-2, the optimized AEM soaked in organic solvents for 30 days shows a high perm-selectivity (Cl-/SO4 2-) of 133.09 (vs 13.11, Neosepta ACS). The superior ED performance is attributed to the stable continuous sub-nanochannels within AEM confirmed by SAXS, rotational energy barriers, etc. This work shows the potential application of cross-linked AEMs for resource recovery in organic wastewater.

Hybrid Membrane of Sulfonated Poly(aryl ether ketone sulfone) Modified by Molybdenum Clusters with Enhanced Proton Conductivity.

Developing novel proton exchange membranes (PEMs) with low cost and superior performance to replace Nafion is of great significance. Polyoxometalate-doped sulfonated poly(aryl ether ketone sulfone) (SPAEKS) allows for the amalgamation of the advantages in each constituent, thereby achieving an optimized performance for the hybrid PEMs. Herein, the hybrid membranes by introducing 2MeIm-{Mo132} into SPAEKS are obtained. Excellent hydrophilic properties of 2MeIm-{Mo132} can help more water molecules be retained in the hybrid membrane, providing abundant carriers for proton transport and proton hopping sites to build successive hydrophilic channels, thus lowering the energy barrier, accelerating the proton migration, and significantly fostering the proton conductivity of hybrid membranes. Especially, SP-2MIMo132-5 exhibits an enhanced proton conductivity of 75 mS cm-1 at 80 °C, which is 82.9% higher than pristine SPAEKS membrane. Additionally, this membrane is suitable for application in proton exchange membrane fuel cells, and a maximum power density of 266.2 mW cm-2 can be achieved at 80 °C, which far exceeds that of pristine SPAEKS membrane (54.6 mW cm-2). This work demonstrates that polyoxometalate-based clusters can serve as excellent proton conduction sites, opening up the choice of proton conduction carriers in hybrid membrane design and providing a novel idea to manufacture high-performance PEMs.

Cyclic Ether-Based Electrolyte with a Weak Solvation Structure for Advanced Potassium Metal Batteries.

Potassium metal batteries (PMBs) are promising candidates for large-scale energy storage. Conventional carbonate electrolytes exhibit unsatisfactory thermodynamic stability against potassium (K) metal anode. Linear ether is widely adopted because of its compatibility with K metal, but the poor oxidation stability restricts the application with high-voltage cathodes. Herein, a weakly solvating cyclic ether is proposed as a solvent to stabilize the K-electrolyte interface and build a robust solid-electrolyte interphase (SEI). This weakly solvating electrolyte (WSE) possesses an anion-dominated solvation structure, which facilitates the anion decomposition for constructing an inorganic-rich SEI. The superior mechanical properties of the SEI, as examined by atomic force microscopy, prevent the SEI from fracture. Consequently, this WSE achieves highly reversible plating/stripping behavior of K metal for 1300 h with a high average Coulombic efficiency of 99.20%. Stable full cells are also demonstrated with a high-voltage cathode at harsh conditions. This work complements the design of WSEs for advanced PMBs by cyclic ether solvents.

Regulation of Zn2+ Solvation Configuration in Aqueous Batteries via Selenium-Substituted Crown Ether Engineering.

The efficient utilization of the metallic Zn in rechargeable aqueous Zn-ion batteries (RAZBs) struggle to suffer from parasitic Zn dendrite formation, hydrogen evolution reactions as well as severe interfacial degradation at high areal capacity loadings. This study thus proposes to employ the modified crown ether as an aqueous electrolyte additive to regulate the Zn2+ desolvation kinetic and facilitates the horizontally oriented (002) deposition of Zn, extending the lifespan of both the symmetric cell and full cell models. Specifically, zincophilic cyano and hydrophobic selenium atoms are incorporated into the crown ether supramolecule to enhance Zn2+ coordination and desolvation capability. The addition of 4-cyanobenzo-21-crown-7-selenium at a low concentration of 0.5 wt.% effectively mitigates hydrogen evolution and Zn corrosion caused by water, promoting the oriented deposition of Zn2+. The Zn||V2O5 full cell prototype, assembled with the areal capacity loadings of 2 mAh cm-2 and N/P ratio of 2.95, exhibits negligible capacity fading at 2.0A g-1 for 300 cycles, highlighting the commercial feasibility of supramolecular macrocycles additive for practical RAZBs applications.

Fluorine-Containing Poly(Fluorene)-Based Anion Exchange Membrane with High Hydroxide Conductivity and Physicochemical Stability for Water Electrolysis.

Improving the hydroxide conductivity and dimensional stability of anion exchange membranes (AEMs) while retaining their high alkaline stability is necessary to realize the commercialization of AEM water electrolysis (AEMWE). A strategy for improving the hydroxide conductivity and dimensional stability of AEMs by inserting fluorine atoms in the core structure of the backbone is reported, which not only reduces the glass transition temperature of the polymer due to steric strain, but also induces distinct phase separation by inducing polarity discrimination to facilitate the formation of ion transport channels. The resulting PFPFTP-QA AEM with fluorine into the core structure shows high hydroxide conductivity (>159 mS cm-1 at 80 °C), favorable dimensional stability (>25% at 80 °C), and excellent alkaline stability for 1000 h in 2 m KOH solution at 80 °C. Moreover, the PFPFTP-QA is used to construct an AEMWE cell with a platinum group metal (PGM)-free NiFe anode, which exhibits the current density of 6.86 A cm-2 at 1.9 V at 80 °C, the highest performance in Pt/C cathode and PGM-free anode reports so far and operates stably for over 100 h at a constant current of 0.5 A cm-2.

Dual Activation for Tuning N, S Co-Doping in Porous Carbon Sheets Toward Superior Sodium Ion Storage.

Porous carbon has been widely focused to solve the problems of low coulombic efficiency (ICE) and low multiplication capacity of Sodium-ion batteries (SIBs) anodes. The superior energy storage properties of two-dimensional(2D) carbon nanosheets can be realized by modulating the structure, but be limited by the carbon sources, making it challenging to obtain 2D structures with large surface area. In this work, a new method for forming carbon materials with high N/S doping content based on combustion activation using the dual activation effect of K2SO4/KNO3 is proposed. The synthesized carbon material as an anode for SIBs has a high reversible capacity of 344.44 mAh g-1 at 0.05 A g-1. Even at the current density of 5 Ag-1, the capacity remained at 143.08 mAh g-1. And the ICE of sodium-ion in ether electrolytes is ≈2.5 times higher than that in ester electrolytes. The sodium storage mechanism of ether/ester-based electrolytes is further explored through ex-situ characterizations. The disparity in electrochemical performance can be ascribed to the discrepancy in kinetics, wherein ether-based electrolytes exhibit a higher rate of Na+ storage and shedding compared to ester-based electrolytes. This work suggests an effective way to develop doubly doped carbon anode materials for SIBs.

PEPICO analysis of catalytic reactor effluents towards quantitative isomer discrimination: DME conversion over a ZSM-5 zeolite.

The methanol-to-hydrocarbons (MTH) process involves the conversion of methanol, a C1 feedstock that can be produced from green sources, into hydrocarbons using shape-selective microporous acidic catalysts - zeolite and zeotypes. This reaction yields a complex mixture of species, some of which are highly reactive and/or present in several isomeric forms, posing significant challenges for effluent analysis. Conventional gas-phase chromatography (GC) is typically employed for the analysis of reaction products in laboratory flow reactors. However, GC is not suitable for the detection of highly reactive intermediates such as ketene or formaldehyde and is not suitable for kinetic studies under well defined low pressure conditions. Photoelectron-photoion coincidence (PEPICO) spectroscopy has emerged as a powerful analytical tool for unraveling complex compositions of catalytic effluents, but its availability is limited to a handful of facilities worldwide. Herein, PEPICO analysis of catalytic reactor effluents has been implemented at the FinEstBeAMS beamline of MAX IV Laboratory. The conversion of dimethyl ether (DME) on a zeolite catalyst (ZSM-5-MFI27) is used as a prototypical model reaction producing a wide distribution of hydrocarbon products. Since in zeolites methanol is quickly equilibrated with DME, this reaction can be used to probe vast sub-networks of the full MTH process, while eliminating or at least slowing down methanol-induced secondary reactions and catalyst deactivation. Quantitative discrimination of xylene isomers in the effluent stream is achieved by deconvoluting the coincidence photoelectron spectra.

Sodium-glucose cotransporter 2 inhibitors induce anti-inflammatory and anti-ferroptotic shift in epicardial adipose tissue of subjects with severe heart failure.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure. METHODS: 26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed. RESULTS: SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects. CONCLUSIONS: Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.