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Acne vulgaris is a complex condition involving factors that affect the pilosebaceous unit. A primary manifestation of acne pathology is the development of comedones, often linked to the overproduction of sebum resulting from 5α-dihydrotestosterone (5α-DHT) and insulin activity. Ozenoxacin is a topical quinolone that exhibits potent antibacterial activity against Cutibacterium acnes (C. acnes). It is commonly used to treat acne associated with this bacterium; however, its effect on sebum production within the sebaceous glands remains unclear. In this study, the effects of ozenoxacin on sebum production were examined using insulin- and 5α-DHT-differentiated hamster sebocytes. Ozenoxacin showed a dose-dependent inhibition of lipid droplet formation and triacylglycerol (TG) production, which is a major component of sebum. In addition, it suppressed the expression of diacylglycerol acyltransferase 1, stearoyl-CoA desaturase-1, and perilipin-1 mRNA, all important factors involved in sebum synthesis, in a dose-dependent manner. Moreover, ozenoxacin decreased phosphorylated 40S ribosomal protein S6 levels downstream of the mechanistic/mammalian target of rapamycin complex 1 (mTORC1), without altering the phosphorylation of Akt, an upstream regulator of mTORC1, in both insulin- and 5α-DHT-treated hamster sebocytes. Interestingly, nadifloxacin, but not clindamycin, exhibited a similar suppression of sebum production, albeit with lesser potency compared with ozenoxacin. Furthermore, a topical application of a 2% ozenoxacin-containing lotion to the auricle skin of hamsters did not affect the size of the sebaceous glands or epidermal thickness. Notably, it decreased the amount of TG on the skin surface. The results provide novel insights into the sebum-inhibitory properties of ozenoxacin, indicating its potential efficacy in controlling microbial growth and regulating sebum production for acne management., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Hypertriglyceridemia is a risk factor for type 2 diabetes and cardiovascular disease (CVD). Plasma triglycerides (TGs) are a key factor for assessing the risk of diabetes or CVD. However, previous lipidomics studies have demonstrated that not all TG molecules behave the same way. Individual TGs with different fatty acid compositions are regulated differentially under various conditions. In addition, distinct groups of TGs were identified to be associated with increased diabetes risk (TGs with lower carbon number [C#] and double-bond number [DB#]), or with decreased risk (TGs with higher C# and DB#). In this study, we examined the effects of high-fat feeding in rats on plasma lipid profiles with special attention to TG profiles. Wistar rats were maintained on either a low-fat (control) or high-fat diet (HFD) for 2 weeks. Plasma samples were obtained before and 2.5 h after a meal ( n = 10 each) and subjected to lipidomics analyses. High-fat feeding significantly impacted circulating lipid profiles, with the most significant effects observed on TG profile. The effects of an HFD on individual TG species depended on DB# in their fatty acid chains; an HFD increased TGs with low DB#, associated with increased diabetes risk, but decreased TGs with high DB#, associated with decreased risk. These changes in TGs with an HFD were associated with decreased indices of hepatic stearoyl-CoA desaturase (SCD) activity, assessed from hepatic fatty acid profiles. Decreased SCD activity would reduce the conversion of saturated to monounsaturated fatty acids, contributing to the increases in saturated TGs or TGs with low DB#. In addition, an HFD selectively depleted ω-3 polyunsaturated fatty acids (PUFAs), contributing to the decreases in TGs with high DB#. Thus, an HFD had profound impacts on circulating TG profiles. Some of these changes were at least partly explained by decreased hepatic SCD activity and depleted ω-3 PUFA.

The senescence of bone marrow mesenchymal stromal cells (MSCs) leads to the impairment of stemness and osteogenic differentiation capacity. In a previous study, we screened out stearoyl-CoA desaturase 2 (SCD2), the most evidently changed differential gene in lipid metabolism, using combined transcriptomic and metabolomic analyses, and verified that SCD2 could mitigate MSC senescence. However, the underlying molecular mechanism by which the rate-limiting enzyme of lipogenesis SCD2 manipulates MSC senescence has not been completely understood. In this study, we demonstrate that SCD2 over-expression alleviates MSC replicative senescence and ameliorates their osteogenic differentiation through the regulation of lipogenesis. Furthermore, SCD2 expression is reduced, whereas miR-200c-3p expression is elevated in replicative senescent MSCs. SCD2 is the direct target gene of miR-200c-3p, which can bind to the 3'-UTR of SCD2. MiR-200c-3p replenishment in young MSCs is able to diminish SCD2 expression levels due to epigenetic modulation. In addition, SCD2-rescued MSC senescence and enhanced osteogenic differentiation can be attenuated by miR-200c-3p repletion via suppressing lipogenesis. Taken together, we reveal the potential mechanism of SCD2 influencing MSC senescence from the perspective of lipid metabolism and epigenetics, which provides both an experimental basis for elucidating the mechanism of stem cell senescence and a novel target for delaying stem cell senescence.

Acidic microenvironments is a cancer progression driver, unclear core mechanism hinders the discovery of new diagnostic or therapeutic targets. ASIC3 is an extracellular proton sensor and acid-sensitive, but its role in acidic tumor microenvironment of colorectal cancer is not reported. Functional analysis data show that colorectal cancer cells respond to specific concentration of lactate to accelerate invasion and metastasis, and ASIC3 is the main actor in this process. Mechanism reveal de novo lipid synthesis is a regulatory process of ASIC3, down-regulated ASIC3 increases and interacts with ACC1 and SCD1, which are key enzymes in de novo lipid synthesis pathway, this interaction results in increased unsaturated fatty acids, which in turn induce EMT to promote metastasis, and overexpression of ASIC3 reduces acidic TME-enhanced colorectal cancer metastasis. Clinical samples of colorectal cancer also exhibit decreased ASIC3 expression, and low ASIC3 expression is associated with metastasis and stage of colorectal cancer. This study is the first to identify the role of the ASIC3-ACC1/SCD1 axis in acid-enhanced colorectal cancer metastasis. The expression pattern of ASIC3 in colorectal cancer differs significantly from that in other types of cancers, ASIC3 may serve as a novel and reliable marker for acidic microenvironmental in colorectal cancer, and potentially a therapeutic target., (© 2024. The Author(s).)

Cancer stem cells (CSCs) play a substantial role in cancer onset and recurrence. Anomalous iron and lipid metabolism have been documented in CSCs, suggesting that ferroptosis, a recently discovered form of regulated cell death characterised by lipid peroxidation, could potentially exert a significant influence on CSCs. However, the precise role of ferroptosis in gastric cancer stem cells (GCSCs) remains unknown. To address this gap, we screened ferroptosis-related genes in GCSCs using The Cancer Genome Atlas and corroborated our findings through quantitative polymerase chain reaction and western blotting. These results indicate that stearoyl-CoA desaturase (SCD1) is a key player in the regulation of ferroptosis in GCSCs. This study provides evidence that SCD1 positively regulates the transcription of squalene epoxidase (SQLE) by eliminating transcriptional inhibition of P53. This mechanism increases the cholesterol content and the elevated cholesterol regulated by SCD1 inhibits ferroptosis via the mTOR signalling pathway. Furthermore, our in vivo studies showed that SCD1 knockdown or regulation of cholesterol intake affects the stemness of GCSCs and their sensitivity to ferroptosis inducers. Thus, targeting the SCD1/squalene epoxidase/cholesterol signalling axis in conjunction with ferroptosis inducers may represent a promising therapeutic approach for the treatment of gastric cancer based on GCSCs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Bladder cancer (BC) is one of the most common malignancies in the male urinary system and currently lacks an optimal treatment strategy. To elucidate the pathogenic mechanisms of BC from the perspective of circular RNAs, we conducted this study. Building upon our previous research, a novel circRNA, circPKN2, captured our interest due to its significant downregulation in BC, and its close association with the prognosis of BC patients. Our research findings indicate that circPKN2 can inhibit the proliferation and migration of BC cells in vitro. Furthermore, we discovered that circPKN2 exerts its anti-cancer effects in BC by promoting ferroptosis. Mechanistic studies revealed that circPKN2 recruits STUB1 to facilitate the ubiquitination of SCD1, thereby suppressing the WNT pathway and promoting ferroptosis in BC. Additionally, our research unveiled the regulatory role of the splicing factor QKI in the biogenesis of circPKN2. Animal studies demonstrated that circPKN2 enhances ferroptosis in BC cells in vivo, inhibiting tumor growth and metastasis. The discovery of the anti-cancer factor circPKN2 holds promise for providing new therapeutic targets in the prevention and treatment of BC., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Colon cancer (CC) is a malignant disease of the digestive tract, and its rising prevalence poses a grave threat to people's health. N6-methyladenosine (m6A) modification is essential for various crucial life processes through modulating gene expression. Methyltransferase-like 14 (METTL14), the m6A methylation transferase core protein, and its aberrant expression is intimately correlated to tumor development. This study was conducted to probe the impacts and specific mechanisms of METTL14 on the biological process of CC. Bioinformatics data disclosed that METTL14 was significantly attenuated in CC. Functional assays were executed to ascertain how METTL14 affected CC tumorigenicity, and METTL14 overexpression caused a notable decline in viability, migration, invasion, and stemness phenotype of CC cells. Then, in-depth mechanistic studies displayed that stearoyl-CoA desaturase 1 (SCD1) was a downstream target gene of METTL14-mediated m6A modification. METTL14 overexpression substantially augmented the m6A modification of SCD1 mRNA and diminished the SCD1 mRNA level. In addition, we revealed that YTHDF2 was the m6A reader to recognize METTL14 m6A-modified SCD1 mRNA and abolish its stability. Finally, we also validated that METTL14 might impede the tumorigenic process of CC through SCD1 mediated Wnt/β-catenin signaling. Taken together, this study presented that METTL14 performed as a potential therapeutic target in CC with important implications for the prognosis amelioration of CC patients., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Iron is a vital trace element for our bodies and its imbalance can lead to various diseases. The progression of metabolic-associated fatty liver disease (MAFLD) is often accompanied by disturbances in iron metabolism. Alisma orientale extract (AOE) has been reported to alleviate MAFLD. However, research on its specific lipid metabolism targets and its potential impact on iron metabolism during the progression of MAFLD remains limited. To establish a model of MAFLD, mice were fed either a standard diet (CON) or a high-fat diet (HFD) for 9 weeks. The mice nourished on the HFD were then randomly assigned to the HF group and the HFA group, with the HFA group receiving AOE by gavage on a daily basis for 13 weeks. Supplementation with AOE remarkably reduced overabundant lipid accumulation in the liver and restored the iron content of the liver. AOE partially but significantly reversed dysregulated lipid metabolizing genes (SCD1, PPAR γ, and CD36) and iron metabolism genes (TFR1, FPN, and HAMP) induced by HFD. Chromatin immunoprecipitation assays indicated that the reduced enrichment of FXR on the promoters of SCD1 and FPN genes induced by HFD was significantly reversed by AOE. These findings suggest that AOE may alleviate HFD-induced disturbances in liver lipid and iron metabolism through FXR-mediated gene repression.

Atherosclerosis refers to a disease characterized by the formation of lipid plaque deposits within arterial walls, leading to reduced blood flow or blockage of blood outflow. The process of endothelial injury induced by oxidized low-density lipoprotein (ox-LDL) is considered the initial stage of atherosclerosis. Ferroptosis is a form of iron-dependent, non-apoptotic cell death, and current research suggests its association with coronary artery disease (CAD). In this study, we observed a correlation between reduced expression of SREBP-1 and the occurrence of stable CAD. Additionally, during the process of endothelial injury induced by ox-LDL, we also noted decreased expression of the SREBP-1/SCD1/FADS2 and involvement in the ferroptosis process. Mechanistically, ox-LDL induced endothelial injury by inhibiting the lipid biosynthesis process mediated by the SREBP-1/SCD1/FADS2, thereby inducing lipid peroxidation and ferroptosis. On the contrary, overexpression of SREBP-1 or supplementation with monounsaturated fatty acids counteracted iron accumulation, mitochondrial damage, and lipid peroxidation-induced ferroptosis, thereby improving endothelial injury. Our study indicated that the decreased expression of peripheral blood SREBP-1 mRNA is an independent risk factor for stable CAD. Furthermore, in endothelial cells, the lipid biosynthesis process mediated by SREBP-1 could ameliorate endothelial injury by resisting ferroptosis. The study has been registered with the Chinese Clinical Trial Registry, which serves as a primary registry in the World Health Organization International Clinical Trials Registry Platform (ChiCTR2300074315, August 3rd, 2023)., (© 2024 Federation of American Societies for Experimental Biology.)

The genetic landscape of cancer cells can lead to specific metabolic dependencies for tumor growth. Dietary interventions represent an attractive strategy to restrict the availability of key nutrients to tumors. In this study, we identified that growth of a subset of melanoma was severely restricted by a rationally designed combination therapy of a stearoyl-CoA desaturase (SCD) inhibitor with an isocaloric low-oleic acid diet. Despite its importance in oncogenesis, SCD underwent monoallelic codeletion along with PTEN on chromosome 10q in approximately 47.5% of melanoma, and the other SCD allele was methylated, resulting in very low-SCD expression. Although this SCD-deficient subset was refractory to SCD inhibitors, the subset of PTEN wild-type melanoma that retained SCD was sensitive. As dietary oleic acid could potentially blunt the effect of SCD inhibitors, a low oleic acid custom diet was combined with an SCD inhibitor. The combination reduced monounsaturated fatty acids and increased saturated fatty acids, inducing robust apoptosis and growth suppression and inhibiting lung metastasis with minimal toxicity in preclinical mouse models of PTEN wild-type melanoma. When combined with anti-PD1 immunotherapy, the SCD inhibitor improved T-cell functionality and further constrained melanoma growth in mice. Collectively, these results suggest that optimizing SCD inhibitors with diets low in oleic acid may offer a viable and efficacious therapeutic approach for improving melanoma treatment. Significance: Blockade of endogenous production of fatty acids essential for melanoma combined with restriction of dietary intake blocks tumor growth and enhances response to immunotherapy, providing a rational drug-diet treatment regimen for melanoma., (©2024 American Association for Cancer Research.)

Ferroptosis is a new form of regulated cell death caused by the iron-dependent peroxidation of phospholipids and is related to cell metabolism, redox homeostasis and various signalling pathways related to cancer. The long non-coding RNA (lncRNA) KB-1460A1.5 acts as a tumour suppressor gene to regulate tumour growth in gliomas, but its molecular network regulatory mechanism is still unclear. In this study, we found that KB-1460A1.5 can induce ferroptosis in glioma and enhance sensitivity to RSL3, a ferroptosis inducer. Tandem mass tag proteomics and nontargeted metabolomics suggest that KB-1460A1.5 affects polyunsaturated fatty acid metabolic processes. Gas chromatography-mass spectrometry-based medium- and long-chain fatty acid-targeted metabolomics confirmed that upregulation of KB-1460A1.5 decreased the levels of monounsaturated fatty acids, oleic acid (OA) and palmitoleic acid (PO) in glioma cells. The addition of OA and PO restored KB-1460A1.5-induced cellular ferroptosis. Molecularly, KB-1460A1.5 inhibited the mammalian target of rapamycin signalling pathway to suppress the expression of downstream sterol regulatory element-binding protein 1 (SREBP-1), thereby attenuating the stearoyl-CoA desaturase-1 (SCD1)-mediated desaturation of polyunsaturated fatty acids. Finally, an animal model of subcutaneous glioma confirmed that KB-1460A1.5 could inhibit tumour progression, SREBP-1/SCD1 expression and ferroptosis. In conclusion, increasing the expression level of KB-1460A1.5 in glioma can promote the induction of oxidative stress and ferroptosis in cancer cells through SREBP-1/SCD1-mediated adipogenesis, demonstrating therapeutic potential in preclinical models., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The extensive application of nuclear technology has increased the potential of uncontrolled radiation exposure to the public. Since skin is the largest organ, radiation-induced skin injury remains a serious medical concern. Organisms evolutionally develop distinct strategies to protect against environment insults and the related research may bring novel insights into therapeutics development. Here, 26 increased peptides are identified in skin tissues of frogs (Pelophylax nigromaculatus) exposed to electron beams, among which four promoted the wound healing of irradiated skin in rats. Specifically, radiation-induced frog skin peptide-2 (RIFSP-2), from histone proteolysis exerted membrane permeability property, maintained cellular homeostasis, and reduced pyroptosis of irradiated cells with decreased TBK1 phosphorylation. Subsequently, stearyl-CoA desaturase 1 (SCD1) is identified, a critical enzyme in biogenesis of monounsaturated fatty acids (MUFAs) as a direct target of RIFSP-2 based on streptavidin-biotin system. The lipidomic analysis further assured the restrain of MUFAs biogenesis by RIFSP-2 following radiation. Moreover, the decreased MUFA limited radiation-induced and STING-mediated inflammation response. In addition, genetic depletion or pharmacological inhibition of STING counteracted the decreased pyroptosis by RIFSP-2 and retarded tissue repair process. Altogether, RIFSP-2 restrains radiation-induced activation of SCD1-MUFA-STING axis. Thus, the stress-induced amphibian peptides can be a bountiful source of novel radiation mitigators., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Background: The prevalence of childhood asthma and obesity is increasing, while obesity increases the risk and severity of asthma. Lipid metabolism has been considered as an important factor in the pathogenesis of obesity-associated asthma. Stearoyl-CoA desaturase 1 (SCD1) is a rate-limiting enzyme that catalyzes the production of monounsaturated fatty acids (MUFA). Methods: In the present study, the microarray data retrieved from the Gene Expression Comprehensive Database (GEO) was analyzed to further clarify the impact of SCD1 on Mast cell activation related lipid mediators and the correlation between SCD1 and obesity asthma in the population. Results: SCD1 was highly expressed in IgE-activated bone marrow-derived mast cells (BMMCs). Meanwhile, SCD1 was also verified expressed highly in dinitrophenyl human serum albumin (DNP-HAS) stimulated RBL-2H3 cells. The expression of SCD1 was up-regulated in peripheral blood leukocytes of asthmatic children, and was positively correlated with skinfold thickness of upper arm, abdominal skinfold and body mass index (BMI). Inhibition of SCD1 expression significantly suppressed the degranulation, lipid mediator production, as well as the migration ability in DNP-HAS-stimulated RBL-2H3 cells. Conclusion: SCD1 is involved in obese-related asthma through regulating mast cells.

Background: Cisplatin (DDP) as the first-line drug has been used in cancer therapy. However, side effects and drug resistance are the challenges of DDP. Disordered lipid metabolism is related to DDP resistance., Study Design: In this study, formosanin C (FC) as the main compound of Rhizoma Paridis saponins (RPS) inhibits pulmonary metastasis by targeting stearyl CoA desaturase-1., Methods and Results: RPS prolonged the survival period of mice, reduced pulmonary metastases and alleviated colon toxicity caused by DDP. FC as the main compound of RPS enhanced the anti-tumor and anti-metastatic effects of DDP. FC decreased the mRNA level of SCD1 and the content of lipid droplets (LDs) in lung cancer cells. Molecular dynamics and isothermal titration calorimetry verified the binding stability and spontaneously between FC and SCD1. SiSCD1 reduced the content of LDs in cell lines and increased mitochondria (mtROS), which was consistent with the results of FC treatment. The combination group decreased DNA repair associated protein as well as DDP resistance markers such as ERCC1 and 53bp1, and increased DNA damage marker like γH2AX, which indirectly confirmed the occurrence of mtROS. In addition, FC combination with DDP also affected epithelial-mesenchymal transition-related protein like VIM and CDH1 in vivo experiments, and thereby inhibited pulmonary metastasis., Conclusion: Our research indicated that the FC as the main compound of RPS targeted the CY2 domain of SCD1, inhibited lipid metabolism in mice, and thereby suppressed cancer metastases. This provided support for use of FC to treat cancer based on lipid metabolism pathway., Competing Interests: Declaration of competing interest We confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Ferroptosis, characterized by iron‑mediated non‑apoptotic cell death and alterations in lipid redox metabolism, has emerged as a critical process implicated in various cellular functions, including cancer. Aurantio‑obtusin (AO), a bioactive compound derived from Cassiae semen (the dried mature seeds of Cassie obtusifolia L. or Cassia toral L.), has anti‑hyperlipidemic and antioxidant properties; however, to the best of our knowledge, the effect of AO on liver cancer cells remains unclear. The Cell Counting Kit‑8, EdU staining and migration assays were employed to assess the anti‑liver cancer activity of AO. Intracellular levels of glutathione peroxidase 4 protein and lipid peroxidation were measured as indicators of ferroptotic status. Immunohistochemical analyses, bioinformatics analyses and western blotting were conducted to evaluate the potential of stearoyl‑CoA desaturase 1 (SCD1) in combination with ferroptosis inducers for the personalized treatment of liver cancer. The present study revealed that AO significantly inhibited the proliferation of liver cancer cells in vitro and in vivo . Mechanistically, AO inhibited AKT/mammalian target of rapamycin (mTOR) signaling, suppressed sterol regulatory element‑binding protein 1 (SREBP1) expression, and downregulated fatty acid synthase expression, thereby inhibiting de novo fatty acid synthesis. Further investigations demonstrated that AO suppressed glutathione peroxidase 4 protein expression through the nuclear factor erythroid 2‑related factor 2/heme oxygenase‑1 pathway, induced ferroptosis in liver cancer cells, and simultaneously inhibited lipogenesis by suppressing SCD1 expression through the AKT/mTOR/SREBP1 pathway. Consequently, this increased the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. Additionally, the enhanced effects of AO and RSL3, which resulted in significant tumor suppression, were confirmed in a xenograft mouse model. In conclusion, the present study demonstrated that AO induced ferroptosis, downregulated the expression of SCD1 and enhanced the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. The synergistic use of AO and a ferroptosis inducer may have promising therapeutic effects in liver cancer cells.

Stearoyl-CoA desaturase-1 (SCD1) is a pivotal enzyme in lipogenesis, which catalyzes the synthesis of monounsaturated fatty acids (MUFA) from saturated fatty acids, whose ablation downregulates lipid synthesis, preventing steatosis and obesity. Yet deletion of SCD1 promotes hepatic inflammation and endoplasmic reticulum stress, raising the question of whether hepatic SCD1 deficiency promotes further liver damage, including fibrosis. To delineate whether SCD1 deficiency predisposes the liver to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), we employed in vivo SCD1 deficient global and liver-specific mouse models fed a high carbohydrate low-fat diet and in vitro established AML12 mouse cells. The absence of liver SCD1 remarkably increased the saturation of liver lipid species, as indicated by lipidomic analysis, and led to hepatic fibrosis. Consistently, SCD1 deficiency promoted hepatic gene expression related to fibrosis, cirrhosis, and HCC. Deletion of SCD1 increased the circulating levels of Osteopontin, known to be increased in fibrosis, and alpha-fetoprotein, often used as an early marker and a prognostic marker for patients with HCC. De novo lipogenesis or dietary supplementation of oleate, an SCD1-generated MUFA, restored the gene expression related to fibrosis, cirrhosis, and HCC. Although SCD1 deficient mice are protected against obesity and fatty liver, our results show that MUFA deprivation results in liver injury, including fibrosis, thus providing novel insights between MUFA insufficiency and pathways leading to fibrosis, cirrhosis, and HCC under lean non-steatotic conditions., Competing Interests: Declaration of competing interest The authors who participated in this study declare no conflicts of interest regarding this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: To investigate the impact of exosomes released by Porphyromonas gingivalis-Lipopolysaccharide activated THP-1 macrophages and human periodontal ligament fibroblasts on hepatocyte fat metabolism., Results: The liver of rats with experimental periodontitis showed obvious steatosis and inflammation compared with control rats. The culture supernatant of macrophages and human periodontal ligament fibroblasts (hPDLFs), when stimulated with Pg-LPS, induced lipogenesis in HepG2 cells. Furthermore, the lipid-promoting effect was effectively inhibited by the addition of the exosome inhibitor GW4869. Subsequently, we isolated exosomes from cells associated with periodontitis. Exosomes released by Pg-LPS-stimulated macrophages and hPDLFs are taken up by hepatocytes, causing mRNA expression related to fat synthesis, promoting triglyceride synthesis, and aggravating NAFLD progression. Finally, two sets of exosomes were injected into mice through the tail vein. In vivo experiments have also demonstrated that periodontitis-associated exosomes promote the development of hepatic injury and steatosis, upregulate SCD-1 expression and inhibit the AMPK signaling pathway., Conclusions: In conclusion, we found that exosomes associated with periodontitis promote hepatocyte adipogenesis by increasing the expression of SCD-1 and suppressing the AMPK pathway, which indicates that close monitoring of the progression of stomatopathy associated extra-oral disorders is important and establishes a theoretical foundation for the prevention and management of fatty liver disease linked to periodontitis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tian Xing reports financial support was provided by National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Overweight, often known as obesity, is the abnormal and excessive accumulation of fat that exposes the health of a person at risk by increasing the likelihood that they may experience many chronic conditions. Consequently, obesity has become a global health threat, presenting serious health issues, and attracting a lot of attention in the healthcare profession and the scientific community., Method: This study aims to explore the anti-adipogenic properties of 7-MEGA™ in an attempt to address obesity, using both in vitro and in vivo research. The effects of 7MEGA™ at three distinct concentrations were investigated in obese mice who were given a high-fat diet (HFD) and 3T3-L1 adipocytes., Results: 7MEGA™ decreased the total fat mass, overall body weight, and the perirenal and subcutaneous white adipose tissue (PWAT and SWAT) contents in HFD mice. Additionally, 7MEGA™ showed promise in improving the metabolic health of individuals with obesity and regulate the levels of insulin hormone, pro-inflammatory cytokines and adipokines. Furthermore, Peroxisome proliferator-activated receptors (PPAR) α and γ, Uncoupling Protein 1 (UCP-1), Sterol Regulatory Element-Binding Protein 1 (SREBP-1), Fatty Acid-Binding Protein 4 (FABP4), Fatty Acid Synthase (FAS), Acetyl-CoA Carboxylase (ACC), Stearoyl-CoA Desaturase-1 (SCD-1) and CCAAT/Enhancer-Binding Protein (C/EBPα) were among the adipogenic regulators that 7MEGA™ could regulate., Conclusion: In summary, this study uncovered that 7MEGA™ demonstrates anti-adipogenic and anti-obesity effects, suggesting its potential in combating obesity., (© 2024. The Author(s).)

Breast invasive carcinoma (BRCA) is one of the most common cancers in women, with its malignant progression significantly influenced by intracellular fatty acid (FA) desaturation. Stearoyl-coenzyme A desaturase (SCD) and fatty acid desaturase 2 (FADS2) are two key rate-limiting enzymes that catalyze the FA desaturation process and cooperate to accelerate lipid metabolic activities. In this study, we investigated the potential functions of SCD and FADS2 in BRCA using bioinformatic analysis and experimental validation. The gene expression profiling interactive analysis database showed that the expression of SCD or FADS2 genes was positively linked to worse overall survival and disease-free survival in the Cancer Genome Atlas database-BRCA. The University of Alabama at Birmingham cancer data analysis portal database indicates that the expression and methylation levels of SCD or FADS2 are associated with various clinicopathological factors in patients with BRCA. Moreover, the tumor immune estimation resource and TISCH databases showed a significant positive correlation between the expression of SCD and the abundance of CD8+ T cells and macrophage cell infiltration, while the expression of FADS2 was positively correlated with the abundance of B cells. Meanwhile, SCD or FADS2 had a higher expression in monocytes/macrophages analyzed the BRCA_GSE143423 and BRCA_GSE114727_inDrop datasets. Mechanistically, the Search Tool for the Retrieval of Distant Genes and CancerSEA databases showed that SCD and FADS2 were upregulated in several cell biology signaling pathways, particularly in inflammation, apoptosis, and DNA repair. Finally, SCD or FADS2 knockdown inhibited the proliferation of MCF-7 and MDA-MB-231 cells. In summary, SCD and FADS2 play significant roles in BRCA development, suggesting that they may serve as potential therapeutic targets for BRCA treatment., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Leptin regulates lipid metabolism, maximizing insulin sensitivity; however, peripheral leptin resistance is not fully understood, and its contribution to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study evaluated the contribution of the leptin axis to MASLD in humans. Forty-three participants, mostly female (86.04%), who underwent cholecystectomy were biopsied. Of the participants, 24 were healthy controls, 8 had MASLD, and 11 had metabolic dysfunction-associated steatohepatitis (MASH). Clinical and biochemical data and the gene expression of leptin, leptin receptor ( LEPR ), suppressor of cytokine signaling 3 ( SOCS3 ), sterol regulatory element-binding transcription factor 1 ( SREBF1 ), stearoyl-CoA desaturase-1 ( SCD1 ), and patatin-like phospholipase domain-containing protein 2 ( PNPLA2 ), were determined from liver and adipose tissue. Higher serum leptin and LEPR levels in the omental adipose tissue (OAT) and liver with MASH were found. In the liver, LEPR was positively correlated with leptin expression in adipose tissue, and SOCS3 was correlated with SREBF1-SCD1 . In OAT, SOCS3 was correlated with insulin resistance and transaminase enzymes ( p < 0.05 for all. In conclusion, we evidenced the correlation between the peripheral leptin resistance axis in OAT-liver crosstalk and the complications of MASLD in humans.

Stearoyl-CoA desaturase 1 (SCD1) is an attractive target for cancer therapy. However, the clinical efficacy of SCD1 inhibitor monotherapy is limited. There is thus a need to elucidate the mechanisms of resistance to SCD1 inhibition and develop new therapeutic strategies for combination therapy. In this study, we investigated the molecular mechanisms by which cancer cells acquire resistance to endoplasmic reticulum (ER) stress-dependent cancer cell death induced by SCD1 inhibition. SCD1 inhibitor-sensitive and -resistant cancer cells were treated with SCD1 inhibitors in vitro, and SCD1 inhibitor-sensitive cancer cells accumulated palmitic acid and underwent ER stress response-induced cell death. Conversely, SCD1-resistant cancer cells did not undergo ER stress response-induced cell death because fatty acid desaturase 2 (FADS2) eliminated the accumulation of palmitic acid. Furthermore, genetic depletion using siRNA showed that FADS2 is a key determinant of sensitivity/resistance of cancer cells to SCD1 inhibitor. A549 cells, an SCD1 inhibitor-resistant cancer cell line, underwent ER stress-dependent cancer cell death upon dual inhibition of SCD1 and FADS2. Thus, combination therapy with SCD1 inhibition and FADS2 inhibition is potentially a new cancer therapeutic strategy targeting fatty acid metabolism., (© 2024. The Author(s).)

SCAP plays a central role in controlling lipid homeostasis by activating SREBP-1, a master transcription factor in controlling fatty acid (FA) synthesis. However, how SCAP expression is regulated in human cancer cells remains unknown. Here, we revealed that STAT3 binds to the promoter of SCAP to activate its expression across multiple cancer cell types. Moreover, we identified that STAT3 also concurrently interacts with the promoter of SREBF1 gene (encoding SREBP-1), amplifying its expression. This dual action by STAT3 collaboratively heightens FA synthesis. Pharmacological inhibition of STAT3 significantly reduces the levels of unsaturated FAs and phospholipids bearing unsaturated FA chains by reducing the SCAP-SREBP-1 signaling axis and its downstream effector SCD1. Examination of clinical samples from patients with glioblastoma, the most lethal brain tumor, demonstrates a substantial co-expression of STAT3, SCAP, SREBP-1, and SCD1. These findings unveil STAT3 directly regulates the expression of SCAP and SREBP-1 to promote FA synthesis, ultimately fueling tumor progression., Competing Interests: Conflict of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Due to soared obesity population worldwide, hepatosteatosis is becoming a major risk factor for hepatocellular carcinoma (HCC). Undertaken molecular events during the progression of steatosis to liver cancer are thus under intensive investigation. In this study, we demonstrated that high-fat diet potentiated mouse liver AKT2. Hepatic AKT2 hyperactivation through gain-of-function mutation of Akt2 (Akt2E17K) caused spontaneous hepatosteatosis, injury, inflammation, fibrosis, and eventually HCC in mice. AKT2 activation also exacerbated lipopolysaccharide and D-galactosamine hydrochloride-induced injury/inflammation and N-Nitrosodiethylamine (DEN)-induced HCC. A positive correlation between AKT2 activity and SCD1 expression was observed in human HCC samples. Activated AKT2 enhanced the production of monounsaturated fatty acid which was dependent on SREBP1 upregulation of SCD1. Blockage of active SREBP1 and ablation of SCD1 reduced steatosis, inflammation, and tumor burden in DEN-treated Akt2 E17K mice. Therefore, AKT2 activation is crucial for the development of steatosis-associated HCC which can be treated with blockage of AKT2-SREBP1-SCD1 signaling cascade., (Copyright © 2024. Published by Elsevier Inc.)

Nuclear hormone receptors exist in dynamic equilibrium between transcriptionally active and inactive complexes dependent on interactions with ligands, proteins, and chromatin. The present studies examined the hypothesis that endogenous ligands activate peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in keratinocytes. The phorbol ester treatment or HRAS infection of primary keratinocytes increased fatty acids that were associated with enhanced PPARβ/δ activity. Fatty acids caused PPARβ/δ-dependent increases in chromatin occupancy and the expression of angiopoietin-like protein 4 ( Angptl4 ) mRNA. Analyses demonstrated that stearoyl Co-A desaturase 1 ( Scd1 ) mediates an increase in intracellular monounsaturated fatty acids in keratinocytes that act as PPARβ/δ ligands. The activation of PPARβ/δ with palmitoleic or oleic acid causes arrest at the G2/M phase of the cell cycle of HRAS-expressing keratinocytes that is not found in similarly treated HRAS-expressing Pparb/d -null keratinocytes. HRAS-expressing Scd1 -null mouse keratinocytes exhibit enhanced cell proliferation, an effect that is mitigated by treatment with palmitoleic or oleic acid. Consistent with these findings, the ligand activation of PPARβ/δ with GW0742 or oleic acid prevented UVB-induced non-melanoma skin carcinogenesis, an effect that required PPARβ/δ. The results from these studies demonstrate that PPARβ/δ has endogenous roles in keratinocytes and can be activated by lipids found in diet and cellular components.

Acetyl-CoA synthetase short-chain family member 1 (ACSS1) uses acetate to generate mitochondrial acetyl-CoA and is regulated by deacetylation by sirtuin 3. We generated an ACSS1-acetylation (Ac) mimic mouse, where lysine-635 was mutated to glutamine (K635Q). Male Acss1 K635Q/K635Q mice were smaller with higher metabolic rate and blood acetate and decreased liver/serum ATP and lactate levels. After a 48-hour fast, Acss1 K635Q/K635Q mice presented hypothermia and liver aberrations, including enlargement, discoloration, lipid droplet accumulation, and microsteatosis, consistent with nonalcoholic fatty liver disease (NAFLD). RNA sequencing analysis suggested dysregulation of fatty acid metabolism, cellular senescence, and hepatic steatosis networks, consistent with NAFLD. Fasted Acss1 K635Q/K635Q mouse livers showed increased fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1), both associated with NAFLD, and increased carbohydrate response element-binding protein binding to Fasn and Scd1 enhancer regions. Last, liver lipidomics showed elevated ceramide, lysophosphatidylethanolamine, and lysophosphatidylcholine, all associated with NAFLD. Thus, we propose that ACSS1-K635-Ac dysregulation leads to aberrant lipid metabolism, cellular senescence, and NAFLD.

Protein pathology spreading within the nervous system, accompanies neurodegeneration and a spectrum of motor and cognitive dysfunctions. Currently available therapies against Parkinson's disease and other synucleinopathies are mostly symptomatic and fail to slow the disease progression in the long term. Modification of α-synuclein (αS) aggregation and toxicity of its pathogenic forms is one of the main goals in neuroprotective approach. Since the discovery of lipid component of Lewy bodies, fatty acids became a crucial, yet little explored target for research. MUFAs (monounsaturated fatty acids) are substrates for lipids, such as phospholipids, triglycerides and cholesteryl esters. They regulate membrane fluidity, take part in signal transduction, cellular differentiation and other fundamental processes. αS and MUFA interactions are essential for Lewy body pathology. αS increases levels of MUFAs, mainly oleic acid, which in turn can enhance αS toxicity and aggregation. Thus, reduction of MUFAs synthesis by inhibition of stearoyl-CoA desaturase (SCD) activity could be the new way to prevent aggravation of αS pathology. Due to the limited distribution in peripheral tissues, SCD5 is a potential target in novel therapies and therefore could be an important starting point in search for disease-modifying neuroprotective therapy. Here we summarize facts about physiology and pathology of αS, explain recently discovered lipid-αS interactions, review SCD function and involved mechanisms, present available SCD inhibitors and discuss their pharmacological potential in disease management. Modulation of MUFA synthesis, decreasing αS and lipid toxicity is clearly essential, but unexplored avenue in pharmacotherapy of Parkinson's disease and synucleinopathies., Competing Interests: Declaration of competing interest None, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Transcriptional response to changes in oxygen concentration is mainly controlled by hypoxia-inducible transcription factors (HIFs). Besides regulation of hypoxia-responsible gene expression, HIF-3α has recently been shown to be involved in lung development and in the metabolic process of fat tissue. However, the precise mechanism for such properties of HIF-3α is still largely unknown. To this end, we generated HIF3A gene-disrupted mice by means of genome editing technology to explore the pleiotropic role of HIF-3α in development and physiology. We obtained adult mice carrying homozygous HIF3A gene mutations with comparable body weight and height to wild-type mice. However, the number of litters and ratio of homozygous mutation carriers born from the mating between homozygous mutant mice was lower than expected due to sporadic deaths on postnatal day 1. HIF3A gene-disrupted mice exhibited abnormal configuration of the lung such as a reduced number of alveoli and thickened alveolar walls. Transcriptome analysis showed, as well as genes associated with lung development, an upregulation of stearoyl-Coenzyme A desaturase 1, a pivotal enzyme for fatty acid metabolism. Analysis of fatty acid composition in the lung employing gas chromatography indicated an elevation in palmitoleic acid and a reduction in oleic acid, suggesting an imbalance in distribution of fatty acid, a constituent of lung surfactant. Accordingly, administration of glucocorticoid injections during pregnancy resulted in a restoration of normal alveolar counts and a decrease in neonatal mortality. In conclusion, these observations provide novel insights into a pivotal role of HIF-3α in the preservation of critically important structure and function of alveoli beyond the regulation of hypoxia-mediated gene expression., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kawahata et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Plasmodium is an obligate intracellular parasite that requires intense lipid synthesis for membrane biogenesis and survival. One of the principal membrane components is oleic acid, which is needed to maintain the membrane's biophysical properties and fluidity. The malaria parasite can modify fatty acids, and stearoyl-CoA Δ9-desaturase (Scd) is an enzyme that catalyzes the synthesis of oleic acid by desaturation of stearic acid. Scd is dispensable in P. falciparum blood stages; however, its role in mosquito and liver stages remains unknown. We show that P. berghei Scd localizes to the ER in the blood and liver stages. Disruption of Scd in the rodent malaria parasite P. berghei did not affect parasite blood stage propagation, mosquito stage development, or early liver-stage development. However, when Scd KO sporozoites were inoculated intravenously or by mosquito bite into mice, they failed to initiate blood-stage infection. Immunofluorescence analysis revealed that organelle biogenesis was impaired and merozoite formation was abolished, which initiates blood-stage infections. Genetic complementation of the KO parasites restored merozoite formation to a level similar to that of WT parasites. Mice immunized with Scd KO sporozoites confer long-lasting sterile protection against infectious sporozoite challenge. Thus, the Scd KO parasite is an appealing candidate for inducing protective pre-erythrocytic immunity and hence its utility as a GAP., (© 2024 John Wiley & Sons Ltd.)

Non-alcoholic fatty liver disease (NAFLD) is a major health problem. However, no effective treatments are currently available. Thus, there is a critical need to develop novel drugs that can prevent and treat NAFLD with few side effects. In this study, Tussilagone (TUS), a natural sesquiterpene isolated from Tussilago farfara L, was explored in vitro and in vivo for its potential to treat NAFLD. Our results showed that in vitro TUS reduced oleic acid palmitate acid-induced triglyceride and cholesterol synthesis in HepG 2 cells, reduced intracellular lipid droplet accumulation, improved glucose metabolism disorders and increased energy metabolism and reduced oxidative stress levels. In vivo, TUS significantly reduced fat accumulation and improved liver injury in high-fat diet (HFD)-induced mice. TUS treatment significantly increased liver mitochondrial counts and antioxidant levels compared to the HFD group of mice. In addition, TUS was found to reduce the expression of genes involved in lipid synthesis sterol regulatory element binding protein-1 (SREBP1), fatty acid synthase (FASN), and stearoy-CoA desaturase 1 (SCD1) in vitro and in vivo. Our results suggest that TUS may be helpful in the treatment of NAFLD, suggesting that TUS is a promising compound for the treatment of NAFLD. Our findings provided novel insights into the application of TUS in regulating lipid metabolism., (© 2023 John Wiley & Sons, Ltd.)

Gastric cancer (GC) presents a formidable global health challenge, and conventional therapies face efficacy limitations. Ubiquitin-specific protease 7 (USP7) plays pivotal roles in GC development, immune response, and chemo-resistance, making it a promising target. Various USP7 inhibitors have shown selectivity and efficacy in preclinical studies. However, the mechanistic role of USP7 has not been fully elucidated, and currently, no USP7 inhibitors have been approved for clinical use. In this study, DHPO is identified as a potent USP7 inhibitor for GC treatment through in silico screening. DHPO demonstrates significant anti-tumor activity in vitro, inhibiting cell viability and clonogenic ability, and preventing tumor migration and invasion. In vivo studies using orthotopic gastric tumor mouse models validate DHPO's efficacy in suppressing tumor growth and metastasis without significant toxicity. Mechanistically, DHPO inhibition triggers ferroptosis, evidenced by mitochondrial alterations, lipid Reactive Oxygen Species (ROS), Malondialdehyde (MDA) accumulation, and iron overload. Further investigations unveil USP7's regulation of Stearoyl-CoA Desaturase (SCD) through deubiquitination, linking USP7 inhibition to SCD degradation and ferroptosis induction. Overall, this study identifies USP7 as a key player in ferroptosis of GC, elucidates DHPO's inhibitory mechanisms, and highlights its potential for GC treatment by inducing ferroptosis through SCD regulation., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Objective: Exposure of adipocytes to 'cool' temperatures often found in the periphery of the body induces expression of Stearoyl-CoA Desaturase-1 (Scd1), an enzyme that converts saturated fatty acids to monounsaturated fatty acids. The goal of this study is to further investigate the roles of Scd in adipocytes., Method: In this study, we employed Scd1 knockout cells and mouse models, along with pharmacological Scd1 inhibition to dissect the enzyme's function in adipocyte physiology., Results: Our study reveals that production of monounsaturated lipids by Scd1 is necessary for fusion of autophagosomes to lysosomes and that with a Scd1-deficiency, autophagosomes accumulate. In addition, Scd1-deficiency impairs lysosomal and autolysosomal acidification resulting in vacuole accumulation and eventual cell death. Blocking autophagosome formation or supplementation with monounsaturated fatty acids maintains vitality of Scd1-deficient adipocytes., Conclusion: This study demonstrates the indispensable role of Scd1 in adipocyte survival, with its inhibition in vivo triggering autophagy-dependent cell death and its depletion in vivo leading to the loss of bone marrow adipocytes., Competing Interests: Declaration of competing interest JC is a consultant for Thermo Fisher Scientific, Seer, and 908 Devices., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Ovarian cancer is a leading cause of death among gynecologic tumors, often detected at advanced stages. Metabolic reprogramming and increased lipid biosynthesis are key factors driving cancer cell growth. Stearoyl-CoA desaturase 1 (SCD1) is a crucial enzyme involved in de novo lipid synthesis, producing mono-unsaturated fatty acids (MUFAs). Here, we aimed to investigate the expression and significance of SCD1 in epithelial ovarian cancer (EOC). Comparative analysis of normal ovarian surface epithelial (NOSE) tissues and cell lines revealed elevated SCD1 expression in EOC tissues and cells. Inhibition of SCD1 significantly reduced the proliferation of EOC cells and patient-derived organoids and induced apoptotic cell death. Interestingly, SCD1 inhibition did not affect the viability of non-cancer cells, indicating selective cytotoxicity against EOC cells. SCD1 inhibition on EOC cells induced endoplasmic reticulum (ER) stress by activating the unfolded protein response (UPR) sensors and resulted in apoptosis. The addition of exogenous oleic acid, a product of SCD1, rescued EOC cells from ER stress-mediated apoptosis induced by SCD1 inhibition, underscoring the importance of lipid desaturation for cancer cell survival. Taken together, our findings suggest that the inhibition of SCD1 is a promising biomarker as well as a novel therapeutic target for ovarian cancer by regulating ER stress and inducing cancer cell apoptosis., (© 2024. The Author(s).)

Evidence from genetic and epidemiological studies point to lipid metabolism defects in both the brain and periphery being at the core of Alzheimer's disease (AD) pathogenesis. Previously, we reported that central inhibition of the rate-limiting enzyme in monounsaturated fatty acid synthesis, stearoyl-CoA desaturase (SCD), improves brain structure and function in the 3xTg mouse model of AD (3xTg-AD). Here, we tested whether these beneficial central effects involve recovery of peripheral metabolic defects, such as fat accumulation and glucose and insulin handling. As early as 3 months of age, 3xTg-AD mice exhibited peripheral phenotypes including increased body weight and visceral and subcutaneous white adipose tissue as well as diabetic-like peripheral gluco-regulatory abnormalities. We found that intracerebral infusion of an SCD inhibitor that normalizes brain fatty acid desaturation, synapse loss and learning and memory deficits in middle-aged memory-impaired 3xTg-AD mice did not affect these peripheral phenotypes. This suggests that the beneficial effects of central SCD inhibition on cognitive function are not mediated by recovery of peripheral metabolic abnormalities. Given the widespread side-effects of systemically administered SCD inhibitors, these data suggest that selective inhibition of SCD in the brain may represent a clinically safer and more effective strategy for AD., (© 2024. The Author(s).)

Background: Yeast is often used to build cell factories to produce various chemicals or nutrient substances, which means the yeast has to encounter stressful environments. Previous research reported that unsaturated fatty acids were closely related to yeast stress resistance. Engineering unsaturated fatty acids may be a viable strategy for enhancing the stress resistance of cells., Results: In this study, two desaturase genes, OLE1 and FAD2 from Z. rouxii, were overexpressed in S. cerevisiae to determine how unsaturated fatty acids affect cellular stress tolerance of cells. After cloning and plasmid recombination, the recombinant S. cerevisiae cells were constructed. Analysis of membrane fatty acid contents revealed that the recombinant S. cerevisiae with overexpression of OLE1 and FAD2 genes contained higher levels of fatty acids C16:1 (2.77 times), C18:1 (1.51 times) and C18:2 (4.15 times) than the wild-type S. cerevisiae pY15TEF1. In addition, recombinant S. cerevisiae cells were more resistant to multiple stresses, and exhibited improved membrane functionality, including membrane fluidity and integrity., Conclusion: These findings demonstrated that strengthening the expression of desaturases was beneficial to stress tolerance. Overall, this study may provide a suitable means to build a cell factory of industrial yeast cells with high tolerance during biological manufacturing. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Background: Lung cancer is the leading cause of cancer-related death worldwide. The sex differences in the occurrence and fatality rates of non-small cell lung cancer (NSCLC), along with its association with estrogen dependence, suggest that estrogen receptors (ERs) contribute to the development of NSCLC. However, the influence of G protein-coupled estrogen receptor (GPER1) on NSCLC remains to be determined. Escape from ferroptosis is one of the hallmarks of tumor discovered in recent years. In this context, the present study evaluated whether GPER1 promotes NSCLC progression by preventing ferroptosis, and the underlying mechanism through which GPER1 protects against ferroptosis was also explored., Methods: The effects of GPER1 on the cytotoxicity of H 2 O 2 , the ferroptosis inducer RSL3, and Erastin were assessed using the CCK8 assay and plate cloning. Lipid peroxidation levels were measured based on the levels of MDA and BODIPY™581/591C11. GPER1 overexpression and knockdown were performed and G1 was used, and the expression of SCD1 and PI3K/AKT/mTOR signaling factors was measured. Immunofluorescence analysis and immunohistochemistry were performed on paired specimens to measure the correlation between the expression of GPER1 and SCD1 in NSCLC tissues. The effect of GPER1 on the cytotoxicity of cisplatin was measured in vitro using the CCK8 assay and in vivo using xenograft tumor models., Results: GPER1 and G1 alleviated the cytotoxicity of H 2 O 2 , reduced sensitivity to RSL3, and impaired lipid peroxidation in NSCLC tissues. In addition, GPER1 and G1 promoted the protein and mRNA expression of SCD1 and the activation of PI3K/AKT/mTOR signaling. GPER1 and SCD1 expression were elevated and positively correlated in NSCLC tissues, and high GPER1 expression predicted a poor prognosis. GPER1 knockdown enhanced the antitumor activity of cisplatin in vitro and in vivo., Conclusion: GPER1 prevents ferroptosis in NSCLC by promoting the activation of PI3K/AKT/mTOR signaling, thereby inducing SCD1 expression. Therefore, treatments targeting GPER1 combined with cisplatin would exhibit better antitumor effects., (© 2024. The Author(s).)

Exercise promotes pulsatile shear stress in the arterial circulation and ameliorates cardiometabolic diseases. However, exercise-mediated metabolic transducers for vascular protection remain under-investigated. Untargeted metabolomic analysis demonstrated that wild-type mice undergoing voluntary wheel running exercise expressed increased endothelial stearoyl-CoA desaturase 1 (SCD1) that catalyzes anti-inflammatory lipid metabolites, namely, oleic (OA) and palmitoleic acids (PA), to mitigate NF-κB-mediated inflammatory responses. In silico analysis revealed that exercise augmented time-averaged wall shear stress but mitigated flow recirculation and oscillatory shear index in the lesser curvature of the mouse aortic arch. Following exercise, endothelial Scd1 -deleted mice ( Ldlr -/- Scd1 EC-/- ) on high-fat diet developed persistent VCAM1-positive endothelium in the lesser curvature and the descending aorta, whereas SCD1 overexpression via adenovirus transfection mitigated endoplasmic reticulum stress and inflammatory biomarkers. Single-cell transcriptomics of the aorta identified Scd1 -positive and Vcam1 -negative endothelial subclusters interacting with other candidate genes. Thus, exercise mitigates flow recirculation and activates endothelial SCD1 to catalyze OA and PA for vascular endothelial protection.

Papillary thyroid carcinoma (PTC) stands as the leading cancer type among endocrine malignancies, and there exists a strong correlation between thyroid cancer and obesity. However, the clinical significance and molecular mechanism of lipid metabolism in the development of PTC remain unclear. In this study, it was demonstrated that the downregulation of METTL16 enhanced lipid metabolism and promoted the malignant progression of PTC. METTL16 was expressed at lower levels in PTC tissues because of DNMT1-mediated hypermethylation of its promoter. Loss- and gain-of-function studies clarified the effects of METTL16 on PTC progression. METTL16 overexpression increased the abundance of m 6 A in SCD1 cells, increasing RNA decay via the m 6 A reader YTHDC2. The SCD1 inhibitor A939572 inhibited growth and slowed down lipid metabolism in PTC cells. These results confirm the crucial role of METTL16 in restraining PTC progression through SCD1-activated lipid metabolism in cooperation with YTHDC2. This suggests that the combination of METTL16 and anti-SCD1 blockade might constitute an effective therapy for PTC., (© 2024. The Author(s).)

Circular RNAs (circRNAs) are covalently closed noncoding RNA molecules that play multiple roles in tumorigenesis and metastasis. Ferroptosis is an iron-dependent, regulated form of cell death and has emerged as a promising target for cancer treatment. However, whether and how circRNAs regulate ferroptotic cell death in colorectal cancer (CRC) remains largely unknown. Three circRNA microarrays were used to screen differentially expressed circRNAs in CRC tissues. A series of functional experiments were conducted to investigate the effects of circRNA on CRC cell proliferation, migration and ferroptosis. We found that hsa&#95;circ&#95;0058495 (circRHBDD1), a novel circRNA, was significantly upregulated in colorectal cancer tissues and cells. The expression levels of circRHBDD1 in serum samples were strongly associated with the advancement of CRC. Silencing of circRHBDD1 remarkably suppressed the proliferation and migration of CRC cells in vitro. Moreover, the depletion of circRHBDD1 notably increased ferroptotic cell death and enhanced RSL3-induced ferroptosis in CRC cells. Mechanistically, circRHBDD1 upregulated the expression of stearoyl-CoA desaturase (SCD), a ferroptosis suppressor mediating lipid remodelling, by enhancing the ELAVL1/SCD mRNA interaction. Finally, circRHBDD1 knockdown repressed the tumorigenesis and ferroptosis of CRC cells in vivo. In conclusion, circRHBDD1 facilitates tumour progression and obstructs ferroptosis in CRC by regulating SCD expression in an ELAVL1-dependent manner., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

In pre-disposed individuals, a reprogramming of the hepatic lipid metabolism may support liver cancer initiation. We conducted a high-resolution mass spectrometry based untargeted lipidomics analysis of pre-diagnostic serum samples from a nested case-control study (219 liver cancer cases and 219 controls) within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Out of 462 annotated lipids, 158 (34.2%) were associated with liver cancer risk in a conditional logistic regression analysis at a false discovery rate (FDR) <0.05. A chemical set enrichment analysis (ChemRICH) and co-regulatory set analysis suggested that 22/28 lipid classes and 47/83 correlation modules were significantly associated with liver cancer risk (FDR <0.05). Strong positive associations were observed for monounsaturated fatty acids (MUFA), triacylglycerols (TAGs) and phosphatidylcholines (PCs) having MUFA acyl chains. Negative associations were observed for sphingolipids (ceramides and sphingomyelins), lysophosphatidylcholines, cholesterol esters and polyunsaturated fatty acids (PUFA) containing TAGs and PCs. Stearoyl-CoA desaturase enzyme 1 (SCD1), a rate limiting enzyme in fatty acid metabolism and ceramidases seems to be critical in this reprogramming. In conclusion, our study reports pre-diagnostic lipid changes that provide novel insights into hepatic lipid metabolism reprogramming may contribute to a pro-cell growth and anti-apoptotic tissue environment and, in turn, support liver cancer initiation., (© 2023 UICC.)

Metastasis is responsible for at least 90% of colon cancer (CC)-related deaths. Lipid metabolism is a critical factor in cancer metastasis, yet the underlying mechanism requires further investigation. Herein, through the utilisation of single-cell sequencing and proteomics, we identified sulfotransferase SULT2B1 as a novel metastatic tumour marker of CC, which was associated with poor prognosis. CC orthotopic model and in vitro assays showed that SULT2B1 promoted lipid metabolism and metastasis. Moreover, SULT2B1 directly interacted with SCD1 to facilitate lipid metabolism and promoted metastasis of CC cells. And the combined application of SCD1 inhibitor CAY with SULT2B1- konockout (KO) demonstrated a more robust inhibitory effect on lipid metabolism and metastasis of CC cells in comparison to sole application of SULT2B1-KO. Notably, we revealed that lovastatin can block the SULT2B1-induced promotion of lipid metabolism and distant metastasis in vivo. Further evidence showed that SMC1A transcriptionally upregulated the expression of SULT2B1. Our findings unveiled the critical role of SULT2B1 in CC metastasis and provided a new perspective for the treatment of CC patients with distant metastasis., (© 2024 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Non-alcoholic fatty liver disease (NAFLD) is associated with mutations in lipopolysaccharide-binding protein ( LBP ), but the underlying epigenetic mechanisms remain understudied. Herein, LBP -/- rats with NAFLD were established and used to conduct integrative targeting-active enhancer histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation coupled with high-throughput and transcriptomic sequencing analysis to explore the potential epigenetic pathomechanisms of active enhancers of NAFLD exacerbation upon LBP deficiency. Notably, LBP -/- reduced the inflammatory response but markedly aggravated high-fat diet (HFD)-induced NAFLD in rats, with pronounced alterations in the histone acetylome and regulatory transcriptome. In total, 1 128 differential enhancer-target genes significantly enriched in cholesterol and fatty acid metabolism were identified between wild-type (WT) and LBP -/- NAFLD rats. Based on integrative analysis, CCAAT/enhancer-binding protein β (C/EBPβ) was identified as a pivotal transcription factor (TF) and contributor to dysregulated histone acetylome H3K27ac, and the lipid metabolism gene SCD was identified as a downstream effector exacerbating NAFLD. This study not only broadens our understanding of the essential role of LBP in the pathogenesis of NAFLD from an epigenetics perspective but also identifies key TF C/EBPβ and functional gene SCD as potential regulators and therapeutic targets.

Osteosarcoma (OS) is the most common malignant bone tumor. Fatty acid reprogramming plays an essential role in OS progression. However, new fatty acid related therapeutic targets of OS have not been completely elucidated. Therefore, we firstly identified 113 differentially expressed fatty acid metabolism genes using bioinformatic analysis, 19 of which were found to be associated with OS prognosis. Then, 7 hub genes were screened out and yielded a strong prediction accuracy (AUC value = 0.88, at 3 years) for predicting the survival status of OS patients. Furthermore, we confirmed that SCD was highly expressed in OS cells and patients. And Knock-down of SCD impaired proliferation and migration of OS cells. Moreover, SCD was transcriptionally activated by c-Myc to promote proliferation and migration of OS cells. Finally, SCD inhibitor could significantly induce OS ferroptosis in vitro and in vivo. In conclusion, we identified that SCD was a reliable risk factor for OS patients. And SCD was activated by c-Myc. The inhibitor of SCD could significantly impaired OS growth and induce OS ferroptosis, which indicated that SCD was a potential drug target for OS treatment., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Overnutrition and genetic predisposition are major risk factors for various metabolic disorders. Stearoyl-CoA desaturase-1 (SCD1) plays a key role in these conditions by synthesizing unsaturated fatty acids (FAs), thereby promoting fat storage and alleviating lipotoxicity. Expression of SCD1 is influenced by various saturated and cis-unsaturated FAs, but the possible role of dietary trans FAs (TFAs) and SCD1 promoter polymorphisms in its regulations has not been addressed. Therefore, we aimed to investigate the impact of the two main TFAs, vaccenate and elaidate, and four common promoter polymorphisms (rs1054411, rs670213, rs2275657, rs2275656) on SCD1 expression in HEK293T and HepG2 cell cultures using luciferase reporter assay, qPCR and immunoblotting. We found that SCD1 protein and mRNA levels as well as SCD1 promoter activity are markedly elevated by elaidate, but not altered by vaccenate. The promoter polymorphisms did not affect the basal transcriptional activity of SCD1. However, the minor allele of rs1054411 increased SCD1 expression in the presence of various FAs. Moreover, this variant was predicted in silico and verified in vitro to reduce the binding of ETS1 transcription factor to SCD1 promoter. Although we could not confirm an association with type 2 diabetes mellitus, the FA-dependent and ETS1-mediated effect of rs1054411 polymorphism deserves further investigation as it may modulate the development of lipid metabolism-related conditions., (© 2024. The Author(s).)

Metabolic diseases, featured with dysregulated energy homeostasis, have become major global health challenges. Patients with metabolic diseases have high probability to manifest multiple complications in lipid metabolism, e.g. obesity, insulin resistance and fatty liver. Therefore, targeting the hub genes in lipid metabolism may systemically ameliorate the metabolic diseases, along with the complications. Stearoyl-CoA desaturase 1(SCD1) is a key enzyme that desaturates the saturated fatty acids (SFAs) derived from de novo lipogenesis or diet to generate monounsaturated fatty acids (MUFAs). SCD1 maintains the metabolic and tissue homeostasis by responding to, and integrating the multiple layers of endogenous stimuli, which is mediated by the synthesized MUFAs. It critically regulates a myriad of physiological processes, including energy homeostasis, development, autophagy, tumorigenesis and inflammation. Aberrant transcriptional and epigenetic activation of SCD1 regulates AMPK/ACC, SIRT1/PGC1α, NcDase/Wnt, etc, and causes aberrant lipid accumulation, thereby promoting the progression of obesity, non-alcoholic fatty liver, diabetes and cancer. This review critically assesses the integrative mechanisms of the (patho)physiological functions of SCD1 in metabolic homeostasis, inflammation and autophagy. For translational perspective, potent SCD1 inhibitors have been developed to treat various types of cancer. We thus discuss the multidisciplinary advances that greatly accelerate the development of SCD1 new inhibitors. In conclusion, besides cancer treatment, SCD1 may serve as the promising target to combat multiple metabolic complications simultaneously., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The synthesis rates of n-3 and n-6 polyunsaturated fatty acids (PUFAs) in rodents and humans are not agreed upon and depend on substrate availability independently of the capacity for synthesis. Therefore, we aimed to assess the activities of the enzymes for n-3 and n-6 PUFA synthesis pathways in liver, brain, testicle, kidney, heart, and lung, in relation to their protein concentration levels. Eight-week-old Balb/c mice (n = 8) were fed a standard chow diet (6.2% fat, 18.6% protein, and 44.2% carbohydrates) until 14 weeks of age, anesthetized with isoflurane and tissue samples were collected (previously perfused) and stored at -80°C. The protein concentration of the enzymes (Δ-6D, Δ-5D, Elovl2, and Elovl5) were assessed by ELISA kits; their activities were assayed using specific PUFA precursors and measuring the respective PUFA products as fatty acid methyl esters by gas chromatographic analysis. The liver had the highest capacity for PUFA biosynthesis, with limited activity in the brain, testicles, and kidney, while we failed to detect activity in the heart and lung. The protein concentration and activity of the enzymes were significantly correlated. Furthermore, Δ-6D, Δ-5D, and Elovl2 have a higher affinity for n-3 PUFA precursors compared to n-6 PUFA. The capacity for PUFA synthesis in mice mainly resides in the liver, with enzymes having preference for n-3 PUFAs., (© 2023 International Union of Biochemistry and Molecular Biology.)

Environmental chemicals, such as plasticizers, have been linked to increased rates of obesity, according to epidemiological studies. Acetyl triethyl citrate (ATEC) is a plasticizer that is commonly utilized in pharmaceutical products and food packaging as a non-phthalate alternative. Due to its direct contact with the human body and high leakage rate from the polymers, assessment of the potential risk of ATEC exposure at environmentally relevant low doses to human health is needed. Male C57BL/6 J mice were fed diets containing ATEC at doses of either 0.1 or 10 μg/kg per day in a period of 12 weeks to mimic the real exposure environment. The findings suggest that in C57BL/6 J mice, ATEC exposure resulted in increased body weight gain, body fat percentage, and benign hepatocytes, as well as adipocyte size. Consistent with in vivo models, ATEC treatment obviously stimulated the increase of intracellular lipid load in both mouse and human hepatocytes. Mechanically, ATEC induced the transcriptional expression of genes involved in de novo lipogenesis and lipid uptake. Using both enzyme inhibitor and small interfering RNA (siRNA) transfection, we found that stearoyl-coenzyme A desaturase 1 (SCD1) played a significant role in ATEC-induced intracellular lipid accumulation. This study for the first time provided initial evidence suggesting the obesogenic and fatty liver-inducing effect of ATEC at low doses near human exposure levels, and ATEC might be a potential environmental obesogen and its effect on human health need to be further evaluated., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Stearoyl-CoA desaturase 1 (SCD1) converts saturated fatty acids to monounsaturated fatty acids. The expression of SCD1 is increased in many cancers, and the altered expression contributes to the proliferation, invasion, sternness and chemoresistance of cancer cells. Recently, more evidence has been reported to further support the important role of SCD1 in cancer, and the regulation mechanism of SCD1 has also been focused. Multiple factors are involved in the regulation of SCD1, including metabolism, diet, tumor microenvironment, transcription factors, non-coding RNAs, and epigenetics modification. Moreover, SCD1 is found to be involved in regulating ferroptosis resistance. Based on these findings, SCD1 has been considered as a potential target for cancer treatment. However, the resistance of SCD1 inhibition may occur in certain tumors due to tumor heterogeneity and metabolic plasticity. This review summarizes recent advances in the regulation and function of SCD1 in tumors and discusses the potential clinical application of targeting SCD1 for cancer treatment., (© 2023. Science China Press.)

Increases in fatty acid (FA) biosynthesis meet the higher lipid demand by intensely proliferating cancer cells and promoting their progression. Stearoyl-CoA desaturase 1 (SCD1) is the key enzyme in FA biosynthesis, converting saturated FA (SFA) into monounsaturated FA (MUFA). Increases in the MUFA/SFA ratio and SCD1 expression have been observed in cancers of various origins and correlate with their aggressiveness. However, much is still unknown about the SCD1-dependent molecular mechanisms that promote specific changes in metabolic pathways of cancer cells. The present study investigated the involvement of SCD1 in shaping glucose and lipid metabolism in colorectal cancer (CRC) cells. Excess FAs that derive from de novo lipogenesis are stored in organelles, called lipid droplets (LDs), mainly in the form of triacylglycerol (TAG) and cholesteryl esters. LD accumulation is associated with key features of cancer development and progression. Consistent with our findings, the pharmacological inhibition of SCD1 activity affects CRC cell viability and impairs TAG accumulation and LD formation in these cells through the activation of lipolytic and lipophagic pathways. We showed that SCD1 suppression affects crucial lipogenic processes that promote lipid accumulation in CRC cells but in a sterol regulatory element-binding protein 1-independent manner. We propose that adenosine monophosphate-activated protein kinase contributes to these changes through the activation of lipolysis and inhibition of TAG synthesis. We also provide evidence of the involvement of SCD1 in the regulation of glucose uptake and utilization in CRC cells. These findings underscore the importance of SCD1 in regulating cellular processes that promote cancer development and progression., (© 2023 Wiley Periodicals LLC.)

Chronic hepatitis B virus (HBV) infection remains a significant public health concern worldwide. Several metabolic processes regulate HBV DNA replication, including autophagy and lipid metabolism. In this study, we clarified the effect of lipids on HBV replication and elucidated possible mechanisms. We discovered that lipid metabolic gene expression levels were negatively correlated with the HBV DNA in plasma. Our data showed that fatty acid stimulation significantly reduced HBV DNA, hepatitis B surface antigen (HBsAg), and hepatitis B e antigen (HBeAg) levels in HepG2.2.15 cells, which are human hepatoma cell cultures transfected with HBV DNA. The Stearoyl coenzyme A desaturase 1 (SCD1)-autophagy pathway has also been implicated in inhibiting HBV replication by fatty acids stimulation. SCD1 knockdown deregulates the inhibitory effect of fatty acids on HBV by enhancing autophagy. When 3 methyladenine (3MA) was added, the inhibitory effects of specific autophagy inhibitors eliminated the positive effects of SCD1 knockdown on HBV replication. Our results indicate that SCD1 participates in the regulation of inhibition of HBV replication by fatty acids stimulation through regulating autophagy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)