Polyunsaturated Fatty Acid Metabolism Research Articles

Relationship between Polyunsaturated Fatty Acid Metabolism and Atherosclerosis

Relationship between Polyunsaturated Fatty Acid Metabolism and Atherosclerosis

Cardioprotective Response and Senescence in Aged sEH Null Female Mice Exposed to LPS.

Deterioration of physiological systems, like the cardiovascular system, occurs progressively with age impacting an individual's health and increasing susceptibility to injury and disease. Cellular senescence has an underlying role in age-related alterations and can be triggered by natural aging or prematurely by stressors such as the bacterial toxin, lipopolysaccharide (LPS). The metabolism of polyunsaturated fatty acids (PUFAs) by CYP450 enzymes produces numerous bioactive lipid mediators that can be further metabolized by soluble epoxide hydrolase (sEH) into diol metabolites, often with reduced biological effects. In our study, we observed age-related cardiac differences in female mice, where young mice demonstrated resistance to LPS injury, and genetic deletion or pharmacological inhibition of sEH using trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB) attenuated LPS-induced cardiac dysfunction in aged female mice. Bulk RNA-sequencing analyses revealed transcriptomics differences in aged female hearts. Confirmatory analysis demonstrated changes to inflammatory and senescence genes markers such as Il-6, Mcp1, Il-1β, Nlrp3, p21, p16, SA-β-gal, and Gdf15 were attenuated in the hearts of aged female mice where sEH was deleted or inhibited. Collectively, these findings highlight the role of sEH in modulating the aging process of the heart, whereby targeting sEH is cardioprotective.

Abstract 2176 The Molecular Crosstalk between Cytochrome P450-Epoxide Hydrolase Metabolism of Polyunsaturated Fatty Acid and Neurodegeneration

Abstract 2176 The Molecular Crosstalk between Cytochrome P450-Epoxide Hydrolase Metabolism of Polyunsaturated Fatty Acid and Neurodegeneration

Disruption of polyunsaturated fatty acid biosynthesis drives STING-dependent acute myeloid leukemia cell maturation and death

The role of polyunsaturated fatty acid (PUFA) biosynthesis in acute myeloid leukemia (AML) remains largely undefined. A comparative expression analysis of 35 genes encoding fatty acid biosynthesis enzymes showed that Fatty Acid Desaturase 1 (FADS1) was highly expressed across multiple AML subtypes relative to health controls, and that elevated FADS1 expression correlates with worse overall AML patient survival. Functionally, shRNA-mediated inhibition of FADS1 reduced AML cell growth in vitro and significantly delayed leukemia onset in an AML mouse model. AML cell lines depleted of FADS1 arrested in the G1/S-phase of the cell cycle, acquired characteristics of myeloid maturation and subsequently died. To understand the molecular consequences of FADS1 inhibition, a combination of mass spectrometry-based analysis of complex lipids and gene expression analysis (RNA-seq) was performed. FADS1 inhibition caused AML cells to exhibit significant lipidomic remodeling including depletion of PUFAs from the phospholipids, phosphatidylserine and phosphatidylethanolamine. These lipidomic alterations were accompanied by an induction of inflammatory and STING-mediated type-1 interferon signaling. Remarkably, genetic deletion of STING largely prevented the AML cell maturation and death phenotypes mediated by FADS1 inhibition. Highlighting the therapeutic implications of these findings, pharmacological blockade of PUFA biosynthesis reduced patient-derived AML (PD-AML) cell numbers ex vivo but not that of healthy donor cells. Similarly, STING agonism attenuated PD-AML survival, however, STING activation also reduced healthy granulocyte numbers. Collectively, these data unveil a previously unrecognized importance of PUFA biosynthesis in leukemogenesis and that imbalances in PUFA metabolism can drive STING-mediated AML maturation and death.

Astragalus polysaccharides attenuate chemotherapy-induced immune injury by modulating gut microbiota and polyunsaturated fatty acid metabolism

BackgroundThe damage of chemotherapy drugs to immune function and intestinal mucosa is a common side effect during chemotherapy. Astragalus polysaccharides (APS) exhibit immunomodulatory properties and are recognized for preserving the integrity of the human intestinal barrier. Nevertheless, their application and mechanisms of action in chemotherapy-induced immune damage and intestinal barrier disruption remain insufficiently explored. PurposeThis study delved into investigating how APS mitigates chemotherapy-induced immune dysfunction and intestinal mucosal injury, while also providing deeper insights into the underlying mechanisms. MethodsIn a chemotherapy mice model induced by 5-fluorouracil (5-Fu), the assessment of APS's efficacy encompassed evaluations of immune organ weight, body weight, colon length, and histopathology. The regulation of different immune cells in spleen was detected by flow cytometry. 16S rRNA gene sequencings, ex vivo microbiome assay, fecal microbiota transplantation (FMT), and targeted metabolomics analysis were applied to explore the mechanisms of APS effected on chemotherapy-induced mice. ResultsAPS ameliorated chemotherapy-induced damage to immune organs and regulated immune cell differentiation disorders, including CD4+T, CD8+T, CD19+B, F4/80+CD11B+ macrophages. APS also alleviated colon shortening and upregulated the expression of intestinal barrier proteins. Furthermore, APS significantly restored structure of gut microbiota following chemotherapy intervention. Ex vivo microbiome assays further demonstrated the capacity of APS to improve 5-Fu-induced microbiota growth inhibition and compositional change. FMT demonstrated that the regulation of gut microbiota by APS could promote the recovery of immune functions and alleviate shortening of the colon length. Remarkably, APS significantly ameliorated the imbalance of linoleic acid (LA) and α-linolenic acid in polyunsaturated fatty acid (PUFA) metabolism. Further in vitro experiments showed that LA could promote splenic lymphocyte proliferation. In addition, both LA and DGLA down-regulated the secretion of NO and partially up-regulated the percentage of F4/80+CD11B+CD206+ cells. ConclusionAPS can effectively ameliorate chemotherapy-induced immune damage and intestinal mucosal disruption by regulating the composition of the gut microbiota and further restoring PUFA metabolism. These findings indicate that APS can serve as an adjuvant to improve the side effects such as intestinal and immune damage caused by chemotherapy.

Role of soluble epoxide hydrolase in pain and depression comorbidity

The coexistence of chronic pain and depression in clinical practice places a substantial social burden and profoundly impacts in patients. Although a clear correlation exists, the underlying mechanism of comorbidity between chronic pain and depression remains elusive. Research conducted in recent decades has uncovered that soluble epoxide hydrolase, a pivotal enzyme in the metabolism of polyunsaturated fatty acids, plays a crucial role in inflammation. Interestingly, this enzyme is intricately linked to the development of both pain and depression. With this understanding, this review aims to summarize the roles of soluble epoxide hydrolase in pain, depression, and their comorbidity. Simultaneously, we will also explore the underlying mechanisms, providing guidance for future research and drug development.

Abnormal energy metabolism, oxidative stress, and polyunsaturated fatty acid metabolism in depressed adolescents associated with childhood maltreatment: A targeted metabolite analysis

The purpose of this study was to explore the metabolomic differences between Major depressive disorder (MDD) and healthy individuals among adolescents and the association between childhood maltreatment (CM) and differentially abundant metabolites. The exploratory study included 40 first-episode drug-naïve adolescents with MDD and 20 healthy volunteers. We used the Beck Depression Inventory (BDI-13) to assess the severity of depression and the Childhood Trauma Questionnaire (CTQ) to assess the presence of childhood maltreatment. The plasma samples from all participants were collected for targeted metabolomics analysis using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC‒MS/MS) methods. Spearman correlation was applied to analyse the correlations between clinical variables and metabolites. We found 11 increased metabolites and 37 decreased metabolites that differed between adolescents with MDD and healthy individuals. Pathway enrichment analysis of differentially abundant metabolites showed abnormalities in energy metabolism and oxidative stress in MDD. Importantly, we found that creatine, valine, isoleucine, glutamic acid and pyroglutamic acid were negatively correlated with the BDI-13, while isocitric acid, fatty acid and acylcarnitine were negatively associated with CTQ, and 4-hydroxyproline was positively related to CTQ in adolescents with MDD. These studies provide new ideas for the pathogenesis and potential treatment of adolescents with MDD.

Dysregulated palmitic acid metabolism promotes the formation of renal calcium-oxalate stones through ferroptosis induced by polyunsaturated fatty acids/phosphatidic acid

The pathogenesis of renal calcium-oxalate (CaOx) stones is complex and influenced by various metabolic factors. In parallel, palmitic acid (PA) has been identified as an upregulated lipid metabolite in the urine and serum of patients with renal CaOx stones via untargeted metabolomics. Thus, this study aimed to mechanistically assess whether PA is involved in stone formation. Lipidomics analysis of PA-treated renal tubular epithelial cells compared with the control samples revealed that α-linoleic acid and α-linolenic acid were desaturated and elongated, resulting in the formation of downstream polyunsaturated fatty acids (PUFAs). In correlation, the levels of fatty acid desaturase 1 and 2 (FADS1 and FADS2) and peroxisome proliferator-activated receptor α (PPARα) in these cells treated with PA were increased relative to the control levels, suggesting that PA-induced upregulation of PPARα, which in turn upregulated these two enzymes, forming the observed PUFAs. Lipid peroxidation occurred in these downstream PUFAs under oxidative stress and Fenton Reaction. Furthermore, transcriptomics analysis revealed significant changes in the expression levels of ferroptosis-related genes in PA-treated renal tubular epithelial cells, induced by PUFA peroxides. In addition, phosphatidyl ethanolamine binding protein 1 (PEBP1) formed a complex with 15-lipoxygenase (15-LO) to exacerbate PUFA peroxidation under protein kinase C ζ (PKC ζ) phosphorylation, and PKC ζ was activated by phosphatidic acid derived from PA. In conclusion, this study found that the formation of renal CaOx stones is promoted by ferroptosis of renal tubular epithelial cells resulting from PA-induced dysregulation of PUFA and phosphatidic acid metabolism, and PA can promote the renal adhesion and deposition of CaOx crystals by injuring renal tubular epithelial cells, consequently upregulating adhesion molecules. Accordingly, this study provides a new theoretical basis for understanding the correlation between fatty acid metabolism and the formation of renal CaOx stones, offering potential targets for clinical applications.

Different Lengths of Diet Supplementation with 10% Flaxseed Alter the Hormonal Profile and the Follicular Fluid Fatty Acid Content of Fattening Gilts.

The effect of 10% dietary flaxseed fed for 3 and 6 weeks on serum hormone levels of fattening gilts, the fatty acid (FA) follicular fluid (FF) composition of small and large antral follicles, and the steroidogenesis and IGF-I secretion by isolated small antral follicles and their response to regulatory hormones (LH, FSH, IGF-I) was studied using immunoassay and gas chromatography analyses. Both supplemental periods increased levels of P4 and IGF-I in blood serum. A shorter period inhibited steroidogenesis (P4, T, E2) and IGF-I secretion by small antral follicles, which was associated with decreased levels of monounsaturated FAs (MUFA) and preferred n-6 polyunsaturated FA (PUFA) metabolism. A longer period stimulated hormone secretion at elevated levels of saturated FAs (SFA) at the expense of MUFAs and PUFAs preferring the n-3 PUFA metabolism. Out of ovarian regulators, only LH and IGF-I were able to alter the secretion of steroids and IGF-I by small follicles of fattening pigs fed a basal diet. The effect of flaxseed on the secretion of follicular hormones after both supplemental periods was altered by all regulatory hormones in a dose-dependent manner. The level of SFAs and PUFAs in FF of large follicles increased with the length of flaxseed feeding, suggesting the suppression of ovulation.

Ginsenoside Rk3 Ameliorates Obesity-Induced Colitis by Modulating Lipid Metabolism in C57BL/6 Mice.

Lipid metabolism is closely related to obesity and its complications. Our previous study found that ginsenoside Rk3 (Rk3), a natural bioactive substance derived from ginseng, can effectively alleviate obesity-induced colitis, while its impact on the improvement of the lipid metabolism disorder remains unclear. Here, we demonstrated that Rk3 significantly alleviated inflammation, oxidative stress, and lipid dysregulation in high-fat diet-induced colitis C57BL/6 mice. The potential mechanism by which Rk3 mitigated colon inflammation in the context of obesity may involve the modulation of polyunsaturated fatty acid metabolism with specific attention to n-6 fatty acids, linoleic acid, and arachidonic acid. Rk3 intervention markedly reduced the production of pro-inflammatory factors (PGE2, PGD2, TXB2, HETE, and HODE) by inhibiting cyclooxygenase and lipoxygenase pathways, while enhancing the production of anti-inflammatory factors (EET and diHOME) via cytochrome P450 pathways. Our findings suggest that Rk3 is a potential anti-inflammatory natural drug that can improve obesity-induced intestinal inflammation by regulating lipid metabolism.

A critical review of advances on tumor metabolism abnormalities induced by nitrosamine disinfection by-products in drinking water.

Intensified sanitation practices amid the recent SARS-CoV-2 outbreak might result in the increased release of chloramine disinfectants into surface water, significantly promoting the formation of nitrosamine disinfection by-products (DBPs) in drinking water. Unfortunately, these nitrosamine DBPs exhibit significant genotoxic, carcinogenic, and mutagenic properties, while chlorinating disinfectants remain in global practice. The current review provides valuable insights into the occurrence, identification, contamination status, exposure limits, and toxicity of the new unregulated disinfection by-products (nitrosamine DBPs) in drinking water. As a result, concentrations of nitrosamine DBPs far exceed allowable limits in drinking water, and prolonged exposure has the potential to cause metabolic disorders, a critical step in tumor initiation and progression. Importantly, based on recent research, we have concluded the role of nitrosamines DBPs in different metabolic pathways. Remarkably, nitrosamine DBPs can induce chronic inflammation and initiate tumors by activating sphingolipid and polyunsaturated fatty acid metabolism. Regarding amino acid and nucleotide metabolism, nitrosamine DBPs can inhibit tryptophan (TRP) metabolism and de novo nucleotide synthesis. Moreover, inhibition of de novo nucleotide synthesis fails to repair DNA damage induced by nitrosamines. Additionally, the accumulation of lactate induced by nitrosamine DBPs may act as a pivotal signaling molecule in communication within the tumor microenvironment. However, with the advancement of tumor metabolomics, understanding the role of nitrosamine DBPs in causing cancer by inducing metabolic abnormalities significantly lags behind, and specific mechanisms of toxic effects are not clearly defined. Urgently, further studies exploring this promising area are needed.

Targeting LTA4H facilitates the reshaping of the immune microenvironment mediated by CCL5 and sensitizes ovarian cancer to Cisplatin.

Ovarian cancer is the most lethal and aggressive gynecological cancer with a high recurrence rate and is often diagnosed late. In ovarian cancer, multiple metabolic enzymes of lipid metabolism are abnormally expressed, resulting in metabolism disorder. As a characteristic pathway in polyunsaturated fatty acid (PUFA) metabolism, arachidonic acid (AA) metabolism is disturbed in ovarian cancer. Therefore, we established a 10-gene signature model to evaluate the prognostic risk of PUFA-related genes. This 10-gene signature has strong robustness and can play a stable predictive role in datasets of various platforms (TCGA, ICGC, and GSE17260). The high association between the risk subgroups and clinical characteristics indicated a good performance of the model. Our data further indicated that the high expression of LTA4H was positively correlated with poor prognosis in ovarian cancer. Deficiency of LTA4H enhanced sensitivity to Cisplatin and modified the characteristics of immune cell infiltration in ovarian cancer. Additionally, our results indicate that CCL5 was involved in the aberrant metabolism of the AA/LTA4H axis, which contributes to the reduction of tumor-infiltrating CD8+ T cells and immune escape in ovarian cancer. These findings provide new insights into the prognosis and potential target of LTA4H/CCL5 in treating ovarian cancer.

Long-chain polyunsaturated fatty acids influence colorectal cancer progression via the interactions between the intestinal microflora and the macrophages.

The metabolism of long-chain polyunsaturated fatty acids (LCPUFAs) is closely associated with the risk and progression of colorectal cancer (CRC). This paper aims to investigate the role of LCPUFA in the crosstalk between intestinal microflora and macrophages, as well as the effects of these three parties on the progression of CRC. The metabolism and function of LCPUFA play important roles in regulating the composition of the human gut microflora and participating in the regulation of inflammation, ultimately affecting macrophage function and polarization, which is crucial in the tumor microenvironment. The effects of LCPUFA on cellular interactions between the two species can ultimately influence the progression of CRC. In this review, we explore the molecular mechanisms and clinical applications of LCPUFA in the interactions between intestinal microflora and intestinal macrophages, as well as its significance for CRC progression. Furthermore, we reveal the role of LCPUFA in the construction of the CRC microenvironment and explore the key nodes of the interactions between intestinal flora and intestinal macrophages in the environment. It provides potential targets for the metabolic diagnosis and treatment of CRC.

Precision nutrition in pediatric IBD: A position paper from the ESPGHAN special interest group for basic science and translational research, the IBD Porto group, and allied health professionals.

Stratified and precision nutrition refers to disease management or prevention of disease onset, based on dietary interventions tailored to a person's characteristics, biology, gut microbiome, and environmental exposures. Such treatment models may lead to more effective management of inflammatory bowel disease (IBD) and reduce risk of disease development. This societal position paper aimed to report advances made in stratified and precision nutritional therapy in IBD. Following a structured literature search, limited to human studies, we identified four relevant themes: (a) nutritional epidemiology for risk prediction of IBD development, (b) food-based dietary interventions in IBD, (c) exclusive enteral nutrition (EEN) for Crohn's disease (CD) management, and (d) pre- and probiotics for IBD management. There is scarce literature upon which we can make recommendations for precision or stratified dietary therapy for IBD, both for risk of disease development and disease management. Certain single-nucleotide polymorphisms related to polyunsaturated fatty acid (PUFA) metabolism may modify the effect dietary PUFA have in increasing the risk of IBD development. Non-colonic CD, mild-to-moderate CD, and high microbiota richness may predict success of EEN and may be used both for prediction of treatment continuation, but also for early cessation in nonresponders. There is currently insufficient evidence to make recommendations for precision or stratified dietary therapy for patients with established IBD. Despite the great interest in stratified and precision nutrition, we currently lack data to support conclusive recommendations. Replication of early findings by independent research groups and within structured clinical interventions is required.

Metabolic Patterns of High-Invasive and Low-Invasive Oral Squamous Cell Carcinoma Cells Using Quantitative Metabolomics and 13C-Glucose Tracing.

Most current metabolomics studies of oral squamous cell carcinoma (OSCC) are mainly focused on identifying potential biomarkers for early screening and diagnosis, while few studies have investigated the metabolic profiles promoting metastasis. In this study, we aimed to explore the altered metabolic pathways associated with metastasis of OSCC. Here, we identified four OSCC cell models (CAL27, HN6, HSC-3, SAS) that possess different invasive heterogeneity via the transwell invasion assay and divided them into high-invasive (HN6, SAS) and low-invasive (CAL27, HSC-3) cells. Quantitative analysis and stable isotope tracing using [U-13C6] glucose were performed to detect the altered metabolites in high-invasive OSCC cells, low-invasive OSCC cells and normal human oral keratinocytes (HOK). The metabolic changes in the high-invasive and low-invasive cells included elevated glycolysis, increased fatty acid metabolism and an impaired TCA cycle compared with HOK. Moreover, pathway analysis demonstrated significant differences in fatty acid biosynthesis; arachidonic acid (AA) metabolism; and glycine, serine and threonine metabolism between the high-invasive and low-invasive cells. Furthermore, the high-invasive cells displayed a significant increase in the percentages of 13C-glycine, 13C-palmitate, 13C-stearic acid, 13C-oleic acid, 13C-AA and estimated FADS1/2 activities compared with the low-invasive cells. Overall, this exploratory study suggested that the metabolic differences related to the metastatic phenotypes of OSCC cells were concentrated in glycine metabolism, de novo fatty acid synthesis and polyunsaturated fatty acid (PUFA) metabolism, providing a comprehensive understanding of the metabolic alterations and a basis for studying related molecular mechanisms in metastatic OSCC cells.

Hepatic oxylipin profiles in mouse models of Wilson disease: New insights into early hepatic manifestations

Hepatic inflammation is commonly identified in Wilson disease (WD), a genetic disease of hepatic and brain copper accumulation. Copper accumulation is associated with increased oxidative stress and reactive oxygen species generation which may result in non-enzymatic oxidation of membrane-bound polyunsaturated fatty acids (PUFA). PUFA can be oxidized enzymatically via lipoxygenases (LOX), cyclooxygenases (COX), and cytochrome P450 monooxygenases (CYP). Products of PUFA oxidation are collectively known as oxylipins (OXL) and are bioactive lipids that modulate hepatic inflammation. We examined hepatic OXL profiles at early stages of WD in two mouse models, the toxic milk mouse from The Jackson Laboratory (tx-j) and the Atp7b knockout on a C57Bl/6 background (Atp7b−/−B6). Targeted lipidomic analysis performed by ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry showed that in both tx-j and Atp7b−/−B6 mice, hepatic OXL profiles were altered with higher thromboxane and prostaglandins levels. The levels of oxidative stress marker, 9-HETE were increased more markedly in tx-j mice. However, both genotypes showed upregulated transcript levels of many genes related to oxidative stress and inflammation. Both genotypes showed higher prostaglandins, thromboxin along with higher PUFA-derived alcohols, diols, and ketones with altered epoxides; the expression of Alox5 was upregulated and many CYP-related genes were dysregulated. Pathway analyses show dysregulation in arachidonic acid and linoleic acid metabolism characterizes mice with WD. Our findings indicate alterations in hepatic PUFA metabolism in early-stage WD and suggest the upregulation of both, non-enzymatic ROS-dependent and enzymatic PUFA oxidation, which could have implications for hepatic manifestations in WD and represent potential targets for future therapies.

Gp78 deficiency in hepatocytes alleviates hepatic ischemia-reperfusion injury via suppressing ACSL4-mediated ferroptosis

Ferroptosis, which is driven by iron-dependent lipid peroxidation, plays an essential role in liver ischemia-reperfusion injury (IRI) during liver transplantation (LT). Gp78, an E3 ligase, has been implicated in lipid metabolism and inflammation. However, its role in liver IRI and ferroptosis remains unknown. Here, hepatocyte-specific gp78 knockout (HKO) or overexpressed (OE) mice were generated to examine the effect of gp78 on liver IRI, and a multi-omics approach (transcriptomics, proteomics, and metabolomics) was performed to explore the potential mechanism. Gp78 expression decreased after reperfusion in LT patients and mice with IRI, and gp78 expression was positively correlated with liver damage. Gp78 absence from hepatocytes alleviated liver damage in mice with IRI, ameliorating inflammation. However, mice with hepatic gp78 overexpression showed the opposite phenotype. Mechanistically, gp78 overexpression disturbed lipid homeostasis, remodeling polyunsaturated fatty acid (PUFA) metabolism, causing oxidized lipids accumulation and ferroptosis, partly by promoting ACSL4 expression. Chemical inhibition of ferroptosis or ACSL4 abrogated the effects of gp78 on ferroptosis and liver IRI. Our findings reveal a role of gp78 in liver IRI pathogenesis and uncover a mechanism by which gp78 promotes hepatocyte ferroptosis by ACSL4, suggesting the gp78-ACSL4 axis as a feasible target for the treatment of IRI-associated liver damage.

Loss of carnitine palmitoyltransferase 1a reduces docosahexaenoic acid-containing phospholipids and drives sexually dimorphic liver disease in mice

Background and aimsGenome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the role of liver-specific CPT1a on hepatic lipid metabolism. Approach and resultsMale and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (60% kcal fat) for 15 weeks. Mice were necropsied after a 16 h fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging, kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine aminotransferase levels which were associated with greater deposition of hepatic lipids, while male mice were not affected by CPT1a deletion relative to male control mice. Mice with CPT1a deletion had reductions in DHA-containing phospholipids at the expense of monounsaturated fatty acids (MUFA)-containing phospholipids in whole liver and at the level of the lipid droplet (LD). Male and female LKO mice increased RNA levels of genes involved in LD lipolysis (Plin2, Cidec, G0S2) and in polyunsaturated fatty acid metabolism (Elovl5, Fads1, Elovl2), while only female LKO mice increased genes involved in inflammation (Ly6d, Mmp12, Cxcl2). Kinase profiling showed decreased protein kinase A activity, which coincided with increased PLIN2, PLIN5, and G0S2 protein levels and decreased triglyceride hydrolysis in LKO mice. ConclusionsLiver-specific deletion of CPT1a promotes sexually dimorphic steatotic liver disease (SLD) in mice, and here we have identified new mechanisms by which females are protected from HFD-induced liver injury.

The interplay of miRNAs and ferroptosis in diseases related to iron overload.

Ferroptosis has been conceptualized as a novel cell death modality distinct from apoptosis, necroptosis, pyroptosis and autophagic cell death. The sensitivity of cellular ferroptosis is regulated at multiple layers, including polyunsaturated fatty acid metabolism, glutathione-GPX4 axis, iron homeostasis, mitochondria and other parallel pathways. In addition, microRNAs (miRNAs) have been implicated in modulating ferroptosis susceptibility through targeting different players involved in the execution or avoidance of ferroptosis. A growing body of evidence pinpoints the deregulation of miRNA-regulated ferroptosis as a critical factor in the development and progression of various pathophysiological conditions related to iron overload. The revelation of mechanisms of miRNA-dependent ferroptosis provides novel insights into the etiology of diseases and offers opportunities for therapeutic intervention. In this review, we discuss the interplay of emerging miRNA regulators and ferroptosis players under different pathological conditions, such as cancers, ischemia/reperfusion, neurodegenerative diseases, acute kidney injury and cardiomyopathy. We emphasize on the relevance of miRNA-regulated ferroptosis to disease progression and the targetability for therapeutic interventions.

In vitro CRISPR screening uncovers CRTC3 as a regulator of IFN-γ-induced ferroptosis of hepatocellular carcinoma

Interferon-gamma (IFN-γ) exerts anti-tumor effects by inducing ferroptosis. Based on CRISPR/Cas9 knockout screening targeting genome-wide protein encoding genes in HepG2 and SK-Hep-1 cell lines, we found that cAMP response element-binding protein (CREB) regulated transcription coactivator 3 (CRTC3) protects tumor cells from drug-induced ferroptosis and significantly inhibits the efficacy of IFN-γ treatment in hepatocellular carcinoma (HCC). Mechanistically, CRTC3 knockout altered tumor cell lipid patterns and increased the abundance of polyunsaturated fatty acids (PUFAs), which enables lipid peroxidation and enhances the susceptibility of HCC cells to ferroptosis inducers. To scavenge for accumulated lipid peroxides (LPO) and maintain redox equilibrium, HCC cells up-regulate SLC7A11 and glutathione peroxidase 4 (GPx4) expressions to enhance the activities of glutamate-cystine antiporter (system xc−) and LPO clearance. As IFN-γ inhibiting system xc−, simultaneous treatment with IFN-γ disrupts the compensatory mechanism, and generates a synergistic effect with CRTC3 knockout to facilitate ferroptosis. Sensitizing effects of CRTC3 depletion were confirmed using typical ferroptosis inducers, including RSL3 and erastin. Sorafeinib, a commonly used target drug in HCC, was repeatedly reported as a ferroptosis inducer. We then conducted both in vitro and vivo experiments and demonstrated that CRTC3 depletion sensitized HCC cells to sorafenib treatment. In conclusion, CRTC3 is involved in the regulation of PUFAs metabolism and ferroptosis. Targeting CRTC3 signaling in combination with ferroptosis inducers present a viable approach for HCC treatment and overcoming drug resistance.