Fatty Acid Synthase Inhibitor Research Articles

P-1858. Exploring the Role of Fatty acid synthase (FASN) Inhibition in Interferon Gamma Mediated Killing of Histoplasma capsulatum

Abstract Background Histoplasma capsulatum (Hc) is the leading cause of fungal respiratory infections in the US. Most cases are mild but 20% require hospitalization. Immunosuppression is a major risk factor for disseminated histoplasmosis. The cytokine Interferon gamma (IFN)-γ is crucial for host resistance to Hc. The absence of IFN-γ or its failure to signal affects the host immune response. Activated CD4+ T cells release IFN-γ to arm macrophages(MΦ) to kill intracellular yeasts. Immunometabolism is a key element in the function of MΦ and fatty acid synthase (FASN) regulates inflammatory responses by these cells. FASN is a large multi-enzyme complex comprised of 6 separate enzymatic grooves that work together to produce 16-carbon chain saturated fatty acid (FA), palmitate, from acetyl-coenzyme A (CoA) and malonyl-CoA(Figure 1). The influence of FASN in the IFN-γ-mediated activation of MΦ remains unclear. Key inhibitor targets in FASN complex Methods Figure 1 shows key inhibitor targets in FASN complex. Bone marrow derived Mφ were used in all experiments with a 2 to 1 yeast to Mφ ratio. IFN-γ induced killing of Hc in mouse Mφ require 48h. We used the tetrazolium salt XTT to assess the Hc viability as this correlates with the colony counts. Controls (Hc in Mφ) are set to 100 %. Toxicity of each inhibitor to Hc and Mφ was studied first. Mφ were treated with IFN-γ 4hrs before infection and then treated with graded amounts of FASN inhibitors C 75 (inhibits ketoacyl synthase), orlistat (inhibits thioesterase), and TVB-3166 or GSK2194069 (both inhibit ketoacyl synthase) 2hrs before infection with 2x Hc for 48hrs. Intracellular yeast survival at 48hrs was assessed. Effect of FASN inhibitors on IFN- γ mediated killing of Hc at 48 hrs. n= 3-10 , mean ±SEM Results Pretreatment with the FASN inhibitor C75 reversed the killing activity of IFN- γ. Neither orlistat or inhibitors of ketoacyl reductase modified the impact of IFN-γ. (Figure 2) Conclusion The FASN inhibitor C75 reversed the activity of IFN-γ in killing Hc. These results suggest that cholesterol synthesis may be involved in the action of IFN- γ. Disclosures All Authors: No reported disclosures

Metabolic Reprogramming in Prostate Cancer: The Roles of HOXB13 and FASN in Tumor Progression and Therapy

Metabolic reprogramming, particularly lipid metabolism, is a hallmark of cancer progression and a critical vulnerability in prostate cancer (PCa). Two pivotal studies, one by Lu et al. and the other by Dairo et al., have illuminated the roles of HOXB13, a transcriptional regulator, and fatty acid synthase (FASN), a key enzyme in lipid biosynthesis, in the metabolic dysregulation of PCa. The Lu et al. study highlights HOXB13’s role in androgen receptor (AR)-independent PCa, where it regulates lipid metabolism via epigenetic mechanisms involving histone deacetylase HDAC3. A G84E mutation in HOXB13 disrupts this regulation, leading to increased lipid synthesis and a pro-metastatic phenotype. The Dairo et al. study demonstrates that FASN hypomethylation, coupled with increased expression, drives lipid biosynthesis critical for tumor growth. Both studies establish a link between HOXB13 mutations and FASN dysregulation, underscoring their interplay in PCa biology. Therapeutically, pharmacological inhibition of FASN mitigates the aggressive features of HOXB13-deficient or mutant PCa, highlighting lipid metabolism as a promising target. Despite their strengths, including robust methodologies, limitations include reliance on preclinical models and the need for broader patient diversity. These studies collectively emphasize the potential of metabolic and epigenetic interventions for precision medicine in PCa, paving the way for novel therapies targeting lipid metabolism in patients with specific genetic and epigenetic profiles.

Fatty acid synthase inhibition improves hypertension-induced erectile dysfunction by suppressing oxidative stress and NLRP3 inflammasome-dependent pyroptosis through activating the Nrf2/HO-1 pathway.

Erectile dysfunction (ED) is a prevalent male sexual disorder, commonly associated with hypertension, though the underlying mechanisms remain poorly understood. This study aims to explore the role of Fatty acid synthase (Fasn) in hypertension-induced ED and evaluate the therapeutic potential of the Fasn inhibitor C75. Erectile function was assessed by determining the intracavernous pressure/mean arterial pressure (ICP/MAP) ratio, followed by the collection of cavernous tissue for transcriptomic and non-targeted metabolomic analyses. In vitro, a concentration of 10-6 M angiotensin II (Ang II) was applied to rat aortic endothelial cells (RAOECs) to establish a model of hypertension. In vivo, spontaneously hypertensive rats (SHR) were randomly divided into two groups. The SHR+C75 group received intraperitoneal injections of C75 at a dose of 2 mg/kg once a week. After five weeks of treatment, the erectile function of the rats was assessed, and penile tissues were harvested for further analysis. Molecular and protein expression were assessed using Western blotting, qRT-PCR, immunofluorescence staining, and immunohistochemistry. The SHR exhibited ED, indicated by reduced maximum ICP/MAP ratios. Histologically, corpus cavernosum tissue of SHR showed elevated fibrosis and endothelial dysfunction. Additionally, increased expression of the NLRP3 inflammasome, Caspase-1, GSDMD, and the pro-inflammatory cytokines IL-1β and IL-18 was observed. Multi-omics analysis revealed significant enrichment in lipid metabolic pathways, with Fasn identified as a hub gene. In vitro, siFasn and C75 enhanced antioxidant markers Nrf2 and HO-1, reduced ROS accumulation, and suppressed NLRP3 and GSDMD levels. In vivo, C75 treatment restored endothelial function and reversed erectile dysfunction, accompanied by decreased oxidative stress and pyroptosis in the penile corpus cavernosum. These findings suggest that Fasn inhibition may offer a promising therapeutic strategy for hypertension-induced ED by alleviating oxidative stress and suppressing NLRP3 inflammasome-dependent endothelial cell pyroptosis via activation of the Nrf2/HO-1 pathway.

FASN inhibition shows the potential for enhancing radiotherapy outcomes by targeting glycolysis, AKT, and ERK pathways in breast cancer

Purpose Breast cancer ranks as the most prevalent cancer in women, characterized by heightened fatty acid synthesis and glycolytic activity. Fatty acid synthase (FASN) is prominently expressed in breast cancer cells, regulating fatty acid synthesis, thereby enhancing tumor growth and migration, and leading to radioresistance. This study aims to investigate how FASN inhibition affects cell proliferation, migration, and radioresistance in breast cancer, as well as the mechanisms involved. Materials and methods We used lentiviruses carrying shFASN to create FASN-knockdown cell lines called MCF-7-shFASN and MDA-MB-231-shFASN. We conducted Western blot analysis to determine the expression levels of FASN and other proteins of interest. Furthermore, we evaluated cellular glucose uptake and migration using the 18F-FDG assay, wound healing, and transwell assays. We also employed the MTT assay to assess the short-term survival of the negative control and FASN-knockdown cells after irradiation. Results FASN knockdown led to a decrease in the expressions of proteins related to fatty acid synthesis and glycolysis in both MCF-7-shFASN and MDA-MB-231-shFASN cells when compared to their counterparts. Moreover, reduced 18F-FDG uptake and lactate production were also detected after FASN knockdown. FASN knockdown inhibited cell proliferation and survival by downregulating the AKT, ERK, and AMPK pathways and promoted apoptosis by increasing the BAX/p-Bcl-2 ratio. In addition, FASN knockdown impaired cell migration while enhancing radiosensitivity. Conclusions FASN knockdown disrupts fatty acid synthesis and glycolysis, inhibits cell proliferation and induces apoptosis. The increased radiosensitivity after FASN inhibition suggests that it could potentially complement radiotherapy in treating breast cancer.

Lipid metabolic reprogramming drives triglyceride storage and variable sensitivity to FASN inhibition in endocrine-resistant breast cancer cells.

Lipid metabolic reprogramming is increasingly recognized as a hallmark of endocrine resistance in estrogen receptor-positive (ER+) breast cancer. In this study, we investigated alterations in lipid metabolism in ER+ breast cancer cell lines with acquired resistance to common endocrine therapies and evaluated the efficacy of a clinically relevant fatty acid synthase (FASN) inhibitor. ER+ breast cancer cell lines resistant to Tamoxifen (TamR), Fulvestrant (FulvR), and long-term estrogen withdrawal (EWD) were derived. Global gene expression and lipidomic profiling were performed to compare parental and endocrine resistant cells. Lipid storage was assessed using Oil Red O (ORO) staining. The FASN inhibitor TVB-2640 was tested for its impact on lipid storage and cell growth. 13 C 2 -acetate tracing was used to evaluate FASN activity and the efficacy of TVB-2640. Endocrine resistant cells showed significant enrichment in lipid metabolism pathways and distinct lipidomic profiles, characterized by elevated triglyceride levels and enhanced cytoplasmic lipid droplets. 13 C 2 -acetate tracing revealed increased FASN activity in endocrine resistant cells, which was effectively reduced by TVB-2640. While TVB-2640 reduced lipid storage in most but not all cell lines, this did not correlate with decreased cell growth. Polyunsaturated fatty acids (PUFAs) containing 6 or more double bonds were elevated in endocrine resistant cells and remained unaffected or increased with TVB-2640. Endocrine resistant breast cancer cells undergo a metabolic shift toward increased triglyceride storage and PUFAs with high degrees of desaturation. While TVB-2640 reduced lipid storage in most conditions, it had limited effects on the growth of endocrine resistant breast cancer cells. Targeting specific lipid metabolic dependencies, particularly pathways that produce PUFAs, represents a potential therapeutic strategy in endocrine resistant breast cancer.

Targeting Fatty Acid Synthase to Halt Tumor Progression and Enhance Radiosensitivity in Breast Cancer Cells

PurposeBreast cancer, the most prevalent cancer among women, is closely linked to abnormal glucose and lipid metabolism, leading to radioresistance by upregulating survival-signaling pathways. Overexpression of fatty acid synthase (FASN), a key enzyme in lipogenesis, results in excessive lipid synthesis in breast cancer. This study evaluated whether FASN inhibition enhanced the radiosensitivity of breast cancer cells and inhibited their progression, potentially uncovering mechanisms for new therapeutic strategies.MethodsMCF-7 breast cancer cells were treated with the FASN inhibitors orlistat and TVB-3166, and cytotoxicity was assessed using the MTT assay. Protein expression changes, migratory ability, and responses to radiotherapy were analyzed by the Western blotting, Transwell, and MTT assays, respectively. To confirm FASN dependence, MCF-7 cells were infected with shFASN lentivirus to verify the specificity of the observed effects to FASN inhibition.ResultsBoth orlistat and TVB-3166 treatments induced significant cell death. Reduced FASN, HKII, pERK, and pAKT expression levels, along with an increased BAX/p-BCL2 ratio, indicate that FASN inhibition disrupted cell proliferation and promoted apoptosis by altering tumor metabolism. Furthermore, decreased MMP9 expression correlated with reduced cell migration after FASN inhibition. Importantly, FASN inhibition significantly and dose-dependently enhanced the radiosensitivity of MCF-7 cells. These findings were validated using shFASN lentivirus, confirming that the observed effects were FASN-dependent.ConclusionFASN inhibition limited survival and migration and enhanced radiosensitivity in MCF-7 cells. These findings indicate the potential efficacy of FASN inhibitors as standalone therapies or as adjuncts to radiotherapy for breast cancer.

Fatty Acid Synthase (FASN) Inhibitors Suppress Metformin-Induced Fat Accumulation and Apoptosis in H4IIE Hepatocellular Carcinoma Cells.

We previously reported that metformin, a widely prescribed antidiabetic drug, induces the accumulation of triglyceride (TG) together with the apoptotic death of H4IIE via AMP-activated protein kinase (AMPK) in hepatocellular carcinoma (HCC) cells. However, the effect of cytoplasmic fat accumulation on the growth of HCCs remains controversial. Herein, we investigated the effect of fatty acid synthase (FASN) inhibitors on the basal- or metformin-induced changes including the content of cytoplasmic TG and the viability of HCC cells. Cerulenin and C75, inhibitors of FASN, did not significantly affect the basal TG content but dose-dependently suppressed the metformin-induced increase in the cytoplasmic TG content. Metformin-induced apoptosis of H4IIE cells was also significantly reduced by cerulenin and C75. Metformin enhanced the generation of reactive oxygen species which was suppressed by adding cerulenin or T75. Cerulenin also stimulated cell migration, which was suppressed by metformin. However, the degree of suppressive effect of metformin on TG synthesis, apoptosis, and cell migration was much more prominent by the inhibition of AMPK by compound C than cerulenin. In conclusion, our study found that excess fat accumulation is responsible for the apoptosis of H4IIE HCC cells and is informative for designing anti-tumor reagents, especially in HCC.

TFAP2A activates CTHRC1 to influence the migration of lung adenocarcinoma cells by modulating fatty acid metabolism.

Tumor metastasis is the main cause of death in lung adenocarcinoma (LAC) patients. It is known that the collagen triple helix repeats containing 1 (CTHRC1) protein is implicated in tissue remodeling and is tightly linked to the carcinogenesis and metastasis of solid tumors. However, the functional role of CTHRC1 and its potential mechanisms in LAC cell metastasis have not been fully explored. The expression level of CTHRC1 in LAC was measured by using bioinformatics analysis combined with quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB). Small interfering RNA and overexpression methods were employed to investigate the function and molecular mechanisms of CTHRC1 in LAC cells. Through bioinformatics analysis, qRT-PCR, WB, scratch healing assay, Transwell, assay kits, and flow cytometry, the downstream pathways and upstream regulatory genes of CTHRC1 in LAC cells were investigated. The binding sites were verified by using chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene experiments. In this project, CTHRC1 was found to be abnormally upregulated in LAC tissues and cells. CTHRC1 promoted the migration and invasion of LAC cells. The promoting effect of CTHRC1 overexpression on LAC cell migration was weakened after the addition of orlistat (a fatty acid synthase inhibitor). Mechanistically, TF AP-2α (TFAP2A) was directly bound to the upstream sequence of the CTHRC1 promoter and promoted CTHRC1 expression. The TFAP2A-CTHRC1 axis induced the migration of LAC cells by activating fatty acid metabolism. Our results indicated that TFAP2A activates fatty acid metabolism by positively modulating the expression of CTHRC1, thereby facilitating tumor cells' migration and invasion. These findings provided novel insights into LAC treatment and future research.

Computational Studies on Diospyros Ebenum and Oldenlandia Umbellata Phytochemicals as Novel Fatty Acid Synthase Inhibitors

Computational Studies on Diospyros Ebenum and Oldenlandia Umbellata Phytochemicals as Novel Fatty Acid Synthase Inhibitors

Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH).

Metabolic dysfunction-associated steatotic liver disease (MASLD)and its severe subgroup metabolic dysfunction-associated steatohepatitis (MASH) have become a global epidemic and are driven by chronic overnutrition and multiple genetic susceptibility factors. The physiological outcomes include hepatocyte death, liver inflammation and cirrhosis. The first therapeutic for MASLD and MASH, resmetirom, has recently been approved for clinical use and has energized this therapeutic space. However, there is still much to learn in clinical studies of MASH, such as the scale of placebo responses, optimal trial end points, the time required for fibrosis reversal and side effect profiles. This Review introduces aspects of disease pathogenesis related to drug development and discusses two main therapeutic approaches. Thyroid hormone receptor-β agonists, such as resmetirom, as well as fatty acid synthase inhibitors, target the liver and enable it to function within a toxic metabolic environment. In parallel, incretin analogues such as semaglutide improve metabolism, allowing the liver to self-regulate and reversing many aspects of MASH. We also discuss how combinations of therapeutics could potentially be used to treat patients.

Fatty acid synthase inhibition alleviates lung fibrosis via β-catenin signal in fibroblasts.

Idiopathic pulmonary fibrosis is a progressive and lethal interstitial lung disease with an unclear etiology and limited treatment options. Fatty acid synthase (FASN) plays various roles in metabolic-related diseases. This study demonstrates that FASN expression is increased in fibroblasts from the lung tissues of patients with idiopathic pulmonary fibrosis and in bleomycin-treated mice. In MRC-5 cells, the inhibition of FASN using shRNA or the pharmacological inhibitor C75 resulted in the increased mRNA and protein expression of glycogen synthase kinase 3β and Axin1, both negative regulators of the Wnt/β-catenin signaling pathway, and promoted autophagy. This outcome led to a decrease in β-catenin protein and mRNA levels, effectively inhibiting the proliferation, migration, and differentiation of lung fibroblasts into myofibroblasts, while inducing the differentiation of fibroblasts into adipofibroblasts. In vivo experiments showed that C75 alleviated bleomycin-induced lung fibrosis in mice by inhibiting β-catenin. In conclusion, these findings suggest that inhibiting FASN in fibroblasts may diminish the activity of the Wnt/β-catenin signaling pathway, providing a potential therapeutic avenue for pulmonary fibrosis.

High mobility group A1 (HMGA1) promotes the tumorigenesis of colorectal cancer by increasing lipid synthesis

Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to meet the high energy and biosynthetic demands required for their proliferation. High mobility group A1 (HMGA1) is a structural transcription factor and frequently overexpressed in human colorectal cancer (CRC). Here, we show that HMGA1 promotes CRC progression by driving lipid synthesis in a AOM/DSS-induced CRC mouse model. Using conditional knockout (Hmga1△IEC) and knock-in (Hmga1IEC-OE/+) mouse models, we demonstrate that HMGA1 enhances CRC cell proliferation and accelerates tumor development by upregulating fatty acid synthase (FASN). Mechanistically, HMGA1 increases the transcriptional activity of sterol regulatory element-binding protein 1 (SREBP1) on the FASN promoter, leading to increased lipid accumulation in intestinal epithelial cells. Moreover, a high-fat diet exacerbates CRC progression in Hmga1△IEC mice, while pharmacological inhibition of FASN by orlistat reduces tumor growth in Hmga1IEC-OE/+ mice. Our findings suggest that targeting lipid metabolism could offer a promising therapeutic strategy for CRC.

VCP enhances autophagy-related osteosarcoma progression by recruiting USP2 to inhibit ubiquitination and degradation of FASN

Osteosarcoma (OS) is a highly aggressive malignant tumor with a high rate of disability and mortality rates, and dysregulated autophagy is a crucial factor in cancer. However, the molecular mechanisms that regulate autophagy in OS remain unclear. This study aimed to explore key molecules that affect autophagy in OS and their regulatory mechanisms. We found that fatty acid synthase (FASN) was significantly increased in activated autophagy models of OS and promoted OS proliferation in an autophagy-dependent manner, as detected by LC3 double-labeled fluorescence confocal microscopy, western blotting, transmission electron microscopy (TEM), and cell functional experiments. Furthermore, co-immunoprecipitation combined with mass spectrometry (Co-IP/MS), ubiquitination modification, molecular docking, and protein truncation methods were used to identify FASN-interacting proteins and analyze their effects on OS. Valosin-containing protein (VCP) enhanced the FASN stability by recruiting ubiquitin specific peptidase-2 (USP2) to remove the K48-linked ubiquitin chains from FASN; domain 2 of VCP and the amino acid sequence () of USP2 were critical for their interactions. Gain- and loss-of-function experiments showed that the inhibition of FASN or USP2 attenuated the stimulatory effect of VCP overexpression on autophagy and the malignant phenotypes of OS cells in vitro and in vivo. Notably, micro-CT indicated that VCP induced severe bone destruction in nude mice, which was abrogated by FASN or USP2 downregulation. In summary, VCP recruits USP2 to stabilize FASN by deubiquitylation, thereby activating autophagy and promoting OS progression. The identification of the VCP/USP2/FASN axis, which mediates autophagy regulation, provides important insights into the underlying mechanisms of OS and offers potential diagnostic and therapeutic strategies for patients with OS.

Interaction mechanism of lipid metabolism remodeling, oxidative stress, and immune response mediated by Epinephelus coioides SRECII

Scavenger receptors (SRs), a category of pattern recognition receptors primarily expressed on the surface of myeloid cells, play pivotal roles in oxidation response and lipid metabolism. However, current research on Scavenger Receptor class F type II (SRECⅡ) revolves around Van Den Ende-Gupta Syndrome (VDEG), the potential function of SRECII, particularly in regulating lipid metabolism and oxidative stress processes, remains elusive. Herein, we elucidate that SRECII from Epinephelus coioides (EcSRECII) may modulate fatty acid oxidation and oxidative stress levels via interactions with lipoprotein particles. EcSRECII mediates the internalization of oxidized Low-Density Lipoprotein (oxLDL), thereby inducing lipid accumulation. This process upregulates the expression of genes associated with lipid synthesis and concurrently suppresses those involved in lipolysis. Additionally, EcSRECII exacerbates the production of Reactive Oxygen Species (ROS) following oxLDL exposure, evidenced by significantly heightened activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), increased accumulation of malondialdehyde (MDA), and enhanced total antioxidant capacity (T-AOC). Furthermore, we reveal that EcSRECII-mediated oxLDL internalization culminates in apoptosis and necrosis in GS cells. Ultimately, we demonstrate that EcSRECII augments oxLDL-induced cellular oxidative stress and inflammatory responses, effects that are notably mitigated by EcSRECII knockdown or pretreatment with the fatty acid synthase (FAS) inhibitor C75. Collectively, our study underscores the role of EcSRECII in facilitating oxLDL internalization and subsequent lipid metabolism remodeling, thereby participating in the intricate regulation of intracellular oxidative stress and immune responses.

Denifanstat for the treatment of metabolic dysfunction-associated steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2b trial

Denifanstat, an oral fatty acid synthase (FASN) inhibitor, blocks de-novo lipogenesis, a key pathway driving progressive lipotoxicity, inflammation, and fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). This study aimed to examine the safety and efficacy of denifanstat for improving liver histology in individuals with MASH and moderate to advanced fibrosis. This multicentre, double-blind, randomised, placebo-controlled, phase 2b trial was conducted at 100 clinical sites in the USA, Canada, and Poland. After a screening period of up to 90 days, participants aged 18 years and older with biopsy-confirmed MASH and stage F2 or F3 fibrosis were randomly assigned (2:1) to receive either 50 mg oral denifanstat or placebo once per day for 52 weeks. Participants were dynamically allocated to treatment groups via a centrally administered interactive web-based response system and stratified by type 2 diabetes, region, and fibrosis stage. Investigators, patients, and the sponsor were masked to group allocation until database lock. The primary efficacy endpoints were a 2-point or greater improvement in non-alcoholic fatty liver disease activity score (NAS) without a worsening of fibrosis or MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis at week 52, assessed by intention to treat. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04906421, and is closed for enrolment. Of the 1087 individuals screened between June 2, 2021, and June 28, 2022, 168 eligible participants were randomly assigned to receive a dose of 50 mg denifanstat once per day (n=112) or placebo (n=56). All 168 participants (100 female, 68 male) received at least one dose of study treatment. In the ITT population, 42 (38%) of 112 participants in the denifanstat group had a 2-point or greater improvement in NAS without a worsening of fibrosis versus nine (16%) of 56 participants in the placebo group (common risk difference 21·0%, 95% CI 8·1-33·9; p=0·0035). 29 (26%) of 112 participants in the denifanstat group showed MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis compared with six (11%) of 56 participants in the placebo group (common risk difference 13·0%, 0·7-25·3; p=0·0173). The most common treatment-emergent adverse events were COVID-19 (19 [17%] of 112 in the denifanstat group vs six [11%] of 56) in the placebo group, dry eye symptoms (ten [9%] of 112 vs eight [14%] of 56), and alopecia (21 [19%] of 112 vs two [4%] of 56). All adverse events considered to be related to the study drug were of grade 1 or grade 2. None of the serious adverse events (13 [12%] of 112 participants in the denifanstat group vs three [5%] of 56 in the placebo group) were considered drug-related. Treatment with denifanstat resulted in statistically significant and clinically meaningful improvements in disease activity, MASH resolution, and fibrosis. The results of this phase 2b trial support the advancement of denifanstat to phase 3 development. Sagimet Biosciences.

Self-Resistance Gene-Guided Discovery of the Molecular Basis for Biosynthesis of the Fatty Acid Synthase Inhibitor Cerulenin.

Cerulenin (1) is the first reported natural fatty acid synthase inhibitor and has been intensively researched for its antifungal, anticancer and anti-obesity properties. However, the molecular basis for its biosynthesis has remained a mystery for six decades. Here, we have identified the polyketide biosynthetic gene cluster (cer) responsible for the biosynthesis of 1 from two Sarocladium species using a self-resistance gene mining approach, which we validated via heterologous reconstitution of cer cluster in an Aspergillus nidulans host. Expression of various combinations of cer genes uncovered key pathway intermediates, electrocyclisation products derived from PKS-encoded polyenoic acids, and a suite of 13 new analogues of 1. This enabled us to establish a biosynthetic pathway to 1 that starts with a C12 polyketide precursor containing both E and Z double bonds and involves a complex series of epoxidations, double bond shifts, E/Z isomerisation and epoxide reduction. Using in vitro assays, we further validated the roles of amidotransferase CerD in amidation, and oxidase CerF and reductase CerE in the final two-electron oxidation and enone reduction steps towards 1. These findings expand our understanding of complex tailoring modifications in highly reducing PKS pathways and pave the way for the engineered biosynthesis of cerulenin analogues.

Self‐Resistance Gene‐Guided Discovery of the Molecular Basis for Biosynthesis of the Fatty Acid Synthase Inhibitor Cerulenin

Self‐Resistance Gene‐Guided Discovery of the Molecular Basis for Biosynthesis of the Fatty Acid Synthase Inhibitor Cerulenin

Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategies

Hepatocellular carcinoma (HCC) poses significant treatment challenges due to high postoperative recurrence rates and the limited effectiveness of targeted medications. Researchers have identified the unique metabolic profiles of cancer stem cells (CSCs) as the primary drivers of cancer recurrence, metastasis, and drug resistance. Therefore, to address the therapeutic conundrum, this study focused on rewinding metabolic reprogramming of CSCs as a novel therapeutic strategy. HCC CSCs exhibited elevated fatty acid (FA) metabolism compared with parental cells. To specifically target FA metabolism in CSCs, we utilized cerulenin, a fatty acid synthase (FASN) inhibitor. Surprisingly, cerulenin can diminish CSC-like characteristics, including stemness gene expression, spherogenicity, tumorigenicity, and metastatic potential. In addition, sorafenib, a multikinase inhibitor used as targeted therapy for advanced HCC, was employed in combination with cerulenin, demonstrating a great synergistic effect, particularly in CSCs. Importantly, our RNA sequencing analysis disclosed that the amyloid protein precursor (APP) is a crucial downstream effector of FASN in regulating CSC properties. We found that APP plays a crucial role in CSCs’ characteristics that can be inhibited by cerulenin. By focusing on FA metabolism, this study identified the FASN/APP axis as a viable target to develop a more potent therapy strategy for advanced HCC.

Virtual Screening Bioactive Compounds of Rheum Genus in Inhibiting Steatohepatitis: In silico studies

The fatty liver disease known as steatohepatitis is characterized by liver inflammation. De novo lipogenesis and mevalonate pathway have been identified as contributing to the development of fatty liver. Rheum genus has pharmacological properties such as antioxidant, anti-inflammatory, hepatoprotective, and hypolipidemic. Consequently, the current study investigated bioactive compounds from Rheum genus using in-silico method. The 109 compounds and their natural inhibitors against the enzyme targets ATP-citrate lyase (ACLY), Acetyl-CoA carboxylase (ACC), Fatty Acid Synthase (FASN), Stearoyl-CoA desaturase (SCD1), and HMG-CoA reductase (HMGCR) were performed. The results obtained are in the form of a re-rank score, with the best compound results for each enzyme is Catechin 7,3'-di-O-β-D-glucopyranoside (A1) (-148.73), 4' - Methoxy - 3, 3',5 - trihydroxystilbene' - O - β – D (2"-O-p-coumaryl) - glucopyranoside (A2) (-136,808), 2-Cinnamoyl-1,6-digalloyl glucose (A3) (-149,589), 3-O-Galloyl Epicatechin (A4) (-160,018), and 6-C-Glucopyranosyl Procyanidin B2 (A5) (-84,843) as ACLY, ACC, FASN, SCD1 and HMGCR inhibitors, respectively. Analyses using the ADMET and Lipinski rules revealed that A4 has the potential to be a lead compound for oral drug use, but more research is required.

Exploring Genetic Drug Targets in Acne Vulgaris: A Comprehensive Proteome-Wide Mendelian Randomization Study.

Acne vulgaris presents a substantial clinical challenge due to its complex pathophysiology and significant impact on quality of life. Identification of novel therapeutic targets for acne using genetic tools can guide the development of more effective treatments. Utilizing a dataset comprising 35 559 Icelandic individuals, we performed proteomic analyses to quantify 4709 circulating proteins. We integrated these data with acne-specific genome-wide association studies (GWAS) encompassing 34 422 acne patients and 364 991 controls. Mendelian randomization (MR) analyses employed the TwoSampleMR tool and Summary-data-based Mendelian Randomization (SMR) to estimate the causal effects of identified proteins on acne risk. Colocalization analyses assessed the likelihood of shared genetic etiology between protein levels and acne using the "coloc" R package. Our proteome-wide MR analysis initially identified 128 proteins potentially associated with acne risk. Following multiple testing corrections using the Benjamini-Hochberg method, fatty acid synthase (FASN) and tissue inhibitor of metalloproteinases 4 (TIMP4) remained significantly associated with acne risk. FASN exhibited a protective effect against acne (OR = 0.768, 95% CI: 0.676-0.872, p = 4.685E-05), while TIMP4 was associated with an increased risk (OR = 1.169, 95% CI: 1.103-1.241, p = 1.956E-07). Colocalization analysis supported a shared genetic basis for these protein-acne associations, with posterior probabilities indicating strong evidence of shared causal variants. Our findings highlight the utility of integrative genomic approaches in identifying potential therapeutic targets for acne. FASN and TIMP4, in particular, demonstrate strong potential as targets for therapeutic intervention, pending further validation through clinical research. These results offer a foundation for targeted acne treatment development, aligning with personalized medicine principles.