Targeting Lipid Metabolism Research Articles

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.

Genetic Polymorphisms in Obesity: How Variants in Lipid Metabolism Genes Contribute to Hyperlipidemia

Obesity is a complex metabolic disorder influenced by both environmental and genetic factors. Among the genetic contributors, polymorphisms in lipid metabolism genes play a significant role in regulating lipid profiles and promoting hyperlipidemia. This review aims to explore the impact of genetic variants on lipid metabolism in individuals with obesity, focusing on genes such as APOE, LPL, FTO, PCSK9, CETP, and FABP. These polymorphisms alter lipid processing, transportation, and storage, leading to aberrant lipid levels, which contribute to hyperlipidemia and subsequent cardiometabolic complications. We will also discuss the gene-environment interactions that modulate these genetic effects and review potential therapeutic interventions targeting lipid metabolism to manage hyperlipidemia in obese individuals. Keywords: Genetic polymorphisms, obesity, lipid metabolism, hyperlipidemia, gene-environment interactions, cardiometabolic disease

MiRNA-148a-3p targets to regulate the lipid metabolism gene SOCS3 to reduce myocardial ischemia/reperfusion injury.

Acute myocardial infarction (AMI) is a major cause of death in cardiovascular patients. SOCS3's protective role in cardiac I/R-I is being explored, and miRNAs, particularly miRNA-148a-3p, are suspected to target SOCS3. To elucidate the role of miRNA-148a-3p targeting lipid metabolism gene SOCS3 in cardiac ischemia-reperfusion injury (I/R-I) in rats. Derived mRNA expression data GSE59867 from GEO, identified 558 lipid metabolism genes from KEGG and GSEA, and screened for differentially expressed genes in acute myocardial infarction (AMI). Predicted miRNA-148a-3p targeting SOCS3 using TargetScanHuman, validated binding via luciferase assay and 3'UTR mutation. Established a rat I/R-I model to assess miRNA-148a-3p and SOCS3 expression, and investigated SOCS3 regulation by miRNA-148a-3p overexpression. Analyzed expression of NF-κB p65, IL-1β, and TNF-α-related proteins, and evaluated cardiac hemodynamics post-SOCS3 regulation by miRNA-148a-3p. In GSE59867, TSPO, SOCS3, LRP1, PLB1, CYP1B1, PPARG, ACSL1, and CYP27A1 were identified as differentially expressed lipid metabolism genes in AMI. The results of immune infiltration showed a close relationship between the differential lipid metabolism genes and the infiltration of immune cells such as macrophages and monocytes. The random forest algorithm identified SOCS3 as the key gene. The luciferase reporter gene demonstrated the participation of miRNA-148a-3p in the regulation of SOCS3 by binding to its 3'UTR. In vivo experiments revealed low expression of miRNA-148a-3p in myocardial I/R, while SOCS3 was highly expressed. Elevated miRNA-148a-3p expression led to a decrease in SOCS3, NF-κB p65, IL-1β, and TNF-α levels during cardiac I/R-I. Overexpression of miRNA-148a-3p enhanced the cardiac performance in rats experiencing cardiac I/R-I. Overexpression of miRNA-148a-3p regulates NF-κB signaling pathway by targeting lipid metabolism gene SOCS3, reduces inflammatory response, and then reduces cardiac I/R-I in rats.

Targeting Lipid Metabolism in Cancer Stem Cells for Anticancer Treatment.

Cancer stem cells (CSCs), or tumor-initiating cells (TICs), are small subpopulations (0.0001-0.1%) of cancer cells that are crucial for cancer relapse and therapy resistance. The elimination of each CSC is essential for achieving long-term remission. Metabolic reprogramming, particularly lipids, has a significant impact on drug efficacy by influencing drug diffusion, altering membrane permeability, modifying mitochondrial function, and adjusting the lipid composition within CSCs. These changes contribute to the development of chemoresistance in various cancers. The intricate relationship between lipid metabolism and drug resistance in CSCs is an emerging area of research, as different lipid species play essential roles in multiple stages of autophagy. However, the link between autophagy and lipid metabolism in the context of CSC regulation remains unclear. Understanding the interplay between autophagy and lipid reprogramming in CSCs could lead to the development of new approaches for enhancing therapies and reducing tumorigenicity in these cells. In this review, we explore the latest findings on lipid metabolism in CSCs, including the role of key regulatory enzymes, inhibitors, and the contribution of autophagy in maintaining lipid homeostasis. These recent findings may provide critical insights for identifying novel pharmacological targets for effective anticancer treatment.

A two‑sample Mendelian randomization study of lipidome and lung cancer

We analyzed the potential relationship between liposomes and lung cancer risk for the first time using MR analysis methods. The results showed that sterol ester, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, sphingomyelin, and triacylglycerol may affect lung cancer risk. However, molecules with different fatty acid compositions also affect lung cancer risk differently. These results may help researchers discover more mechanisms by which lipid metabolism disorders support lung cancer growth and potential targets of lipid metabolism, giving more theoretical support to lung cancer therapeutic approaches that target lipid metabolic pathways.

A Cyclometalated Iridium(III) Complex Exerts High Anticancer Efficacy via Fatty Acid Beta-Oxidation Inhibition and Sphingolipid Metabolism Reprogramming.

Given the extensive role of lipids in cancer development, there is substantial clinical interest in developing therapies that target lipid metabolism. In this study, we identified one cyclometalated iridium complex (Ir2) that exhibits potent antiproliferation activity in MIA PaCa-2 cells by regulating fatty acid metabolism and sphingolipid metabolism simultaneously. Ir2 also efficiently overcomes cisplatin resistance in vitro. Satisfyingly, the generated Ir2@F127 carriers, as a temperature-sensitive in situ gelling system of Ir2, showed effective cancer treatment with minimal side effects in an in vivo xenograft study. To the best of our knowledge, Ir2 is the first reported cyclometalated iridium complex that exerts anticancer activity in MIA PaCa-2 cells by intervening in lipid metabolism, which provides an alternative pathway for the anticancer mechanism of cyclometalated iridium complexes.

Two novel compounds inhibit Flavivirus infection in vitro and in vivo by targeting lipid metabolism.

This study is the inaugural utilization of a lipid compound library in antiviral drug screening. Two lipid compounds, isobavachalcone (IBC) and corosolic acid (CA), emerged from the screening, exhibiting substantial inhibitory effects on the Japanese encephalitis virus (JEV) proliferation in vitro. In vivo experiments underscored their efficacy, with IBC and CA reducing viral loads in the brain and mitigating JEV-induced histopathological changes, effectively shielding mice from fatal JEV infection. Intriguingly, IBC and CA may activate 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) by binding to its active site, curtailing the synthesis of lipid substances, and thus suppressing JEV proliferation. This indicates AMPK as a potential antiviral target. Remarkably, IBC and CA demonstrated suppression of multiple viruses, including Flaviviruses (JEV and Zika virus), porcine herpesvirus (pseudorabies virus), and coronaviruses (porcine deltacoronavirus and porcine epidemic diarrhea virus), suggesting their potential as broad-spectrum antiviral agents. These findings shed new light on the potential applications of these compounds in antiviral research.

Proteomics Analysis Provides Insights into the Role of Lipid Metabolism in T2DM-Related Sarcopenia.

Sarcopenia has been recognized as an emerging complication of type 2 diabetes mellitus (T2DM). Currently, the pathogenesis of T2DM-related sarcopenia remains unclear. The aim of this study was to investigate the molecular mechanisms and potential therapeutic targets for T2DM-related sarcopenia. In this study, a T2DM-related sarcopenia mouse model was established using db/db mice. Proteins extracted from the gastrocnemius muscles of db/db mice and littermate control db/m mice were analyzed by a 4D label-free quantitative proteomics approach. A total of 131 upregulated and 68 downregulated proteins were identified as differentially expressed proteins (DEPs). Bioinformatics analysis revealed that DEPs were significantly enriched in lipid metabolism. Protein-protein interaction network analysis revealed that six hub proteins, including ACOX1, CPT2, ECI2, ACADVL, ACADL, and ECH1, were involved in the fatty acid oxidation. The hub protein-transcription factor-miRNA network was also constructed using the NetworkAnalyst tool. Finally, the hub proteins were validated by Western blotting and immunohistochemistry and further confirmed to be significantly negatively correlated with muscle mass and grip strength. Our study suggested that lipid metabolism, especially excessive fatty acid oxidation, may be a crucial contributor to the progression of T2DM-related sarcopenia and a common cause of the inter-relationship between T2DM and sarcopenia. Targeting lipid metabolism may be a promising therapeutic strategy for T2DM-related sarcopenia.

Alisma Orientalis Extract Ameliorates Hepatic Iron Deregulation in MAFLD Mice via FXR-Mediated Gene Repression.

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.

Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma

BackgroundWhile anti-programmed cell death protein-1 (PD-1) monotherapy has shown effectiveness in treating lung cancer, its response rate is limited to approximately 20%. Recent research suggests that abnormal lipid metabolism in...

Unraveling the intricate relationship between lipid metabolism and oncogenic signaling pathways.

Lipids, the primary constituents of the cell membrane, play essential roles in nearly all cellular functions, such as cell-cell recognition, signaling transduction, and energy provision. Lipid metabolism is necessary for the maintenance of life since it regulates the balance between the processes of synthesis and breakdown. Increasing evidence suggests that cancer cells exhibit abnormal lipid metabolism, significantly affecting their malignant characteristics, including self-renewal, differentiation, invasion, metastasis, and drug sensitivity and resistance. Prominent oncogenic signaling pathways that modulate metabolic gene expression and elevate metabolic enzyme activity include phosphoinositide 3-kinase (PI3K)/AKT, MAPK, NF-kB, Wnt, Notch, and Hippo pathway. Conversely, when metabolic processes are not regulated, they can lead to malfunctions in cellular signal transduction pathways. This, in turn, enables uncontrolled cancer cell growth by providing the necessary energy, building blocks, and redox potentials. Therefore, targeting lipid metabolism-associated oncogenic signaling pathways could be an effective therapeutic approach to decrease cancer incidence and promote survival. This review sheds light on the interactions between lipid reprogramming and signaling pathways in cancer. Exploring lipid metabolism as a target could provide a promising approach for creating anticancer treatments by identifying metabolic inhibitors. Additionally, we have also provided an overview of the drugs targeting lipid metabolism in cancer in this review.

Pharmacological targeting of lipid metabolism by a first-in-class SREBP-targeted degrader to treat glioblastoma.

Pharmacological targeting of lipid metabolism by a first-in-class SREBP-targeted degrader to treat glioblastoma.

Synergistic Steatosis Induction in Mice: Exploring the Interactions and Underlying Mechanisms between PFOA and Tributyltin.

This study explores the impact of environmental pollutants on nuclear receptors (CAR, PXR, PPARα, PPARγ, FXR, and LXR) and their heterodimerization partner, the Retinoid X Receptor (RXR). Such interaction may contribute to the onset of non-alcoholic fatty liver disease (NAFLD), which is initially characterized by steatosis and potentially progresses to steatohepatitis and fibrosis. Epidemiological studies have linked NAFLD occurrence to the exposure to environmental contaminants like PFAS. This study aims to assess the simultaneous activation of nuclear receptors via perfluorooctanoic acid (PFOA) and RXR coactivation via Tributyltin (TBT), examining their combined effects on steatogenic mechanisms. Mice were exposed to PFOA (10 mg/kg/day), TBT (5 mg/kg/day) or a combination of them for three days. Mechanisms underlying hepatic steatosis were explored by measuring nuclear receptor target gene and lipid metabolism key gene expressions, by quantifying plasma lipids and hepatic damage markers. This study elucidated the involvement of the Liver X Receptor (LXR) in the combined effect on steatosis and highlighted the permissive nature of the LXR/RXR heterodimer. Antagonistic effects of TBT on the PFOA-induced activation of the Pregnane X Receptor (PXR) and Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) were also observed. Overall, this study revealed complex interactions between PFOA and TBT, shedding light on their combined impact on liver health.

Drug-Induced Reorganisation of Lipid Metabolism Limits the Therapeutic Efficacy of Ponatinib in Glioma Stem Cells.

The standard of care for glioblastoma (GBM) involves surgery followed by adjuvant radio- and chemotherapy, but often within months, patients relapse, and this has been linked to glioma stem cells (GSCs), self-renewing cells with increased therapy resistance. The identification of the epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) as key players in gliomagenesis inspired the development of inhibitors targeting these tyrosine kinases (TKIs). However, results from clinical trials testing TKIs have been disappointing, and while the role of GSCs in conventional therapy resistance has been extensively studied, less is known about resistance of GSCs to TKIs. In this study, we have used compartmentalised proteomics to analyse the adaptive response of GSCs to ponatinib, a TKI with activity against PDGFR. The analysis of differentially expressed proteins revealed that GSCs respond to ponatinib by broadly rewiring lipid metabolism, involving fatty acid beta-oxidation, cholesterol synthesis, and sphingolipid degradation. Inhibiting each of these metabolic pathways overcame ponatinib adaptation of GSCs, but interrogation of patient data revealed sphingolipid degradation as the most relevant pathway in GBM. Our data highlight that targeting lipid metabolism, and particularly sphingolipid degradation in combinatorial therapies, could improve the outcome of TKI therapies using ponatinib in GBM.

Evaluation of lipid profile in systemic lupus erythematosus and relation with interleukin-10

Objectives: To detect pattern of dyslipidemia in patients of SLE and clarify the correlation between lipid profile with disease activity, inflammatory factors, and cytokines. Materials and Methods: Blood collected from 65 SLE patients and 30 healthy controls measured Th-17, IL-17, IL-10 by flow cytometer. Statistical analysis: The relationship of lipid profile with various parameters was analyzed and stepwise logistic regression was used to assess the predictors of dyslipidemia. Results: The unique pattern of dyslipidemia in high disease activity was a significant decline in high density lipoprotein (HDL) and apolipoprotein A1 when compared to low disease activity. IL-10 was the strongest predictor for HDL (CI: -0.31 to -0.20, p=0.000). This is the first time a relation of IL-10 with HDL has been determined in SLE patients. Conclusions: IL-10 elevation is associated with decline in HDL. Since IL-10 appears to be a potential modulator of dyslipidemia in SLE, it can serve a new target for lipid metabolism to reduce cardiovascular risk in SLE.

Elucidating the Role of Lipid-Metabolism-Related Signal Transduction and Inhibitors in Skin Cancer.

Lipids, as multifunctional molecules, play a crucial role in a variety of cellular processes. These include regulating membrane glycoprotein functions, controlling membrane trafficking, influencing apoptotic pathways, and affecting drug transport. In addition, lipid metabolites can alter the surrounding microenvironment in ways that might encourage tumor progression. The reprogramming of lipid metabolism is pivotal in promoting tumorigenesis and cancer progression, with tumors often displaying significant changes in lipid profiles. This review concentrates on the essential factors that drive lipid metabolic reprogramming, which contributes to the advancement and drug resistance in melanoma. Moreover, we discuss recent advances and current therapeutic strategies that employ small-molecule inhibitors to target lipid metabolism in skin cancers, particularly those associated with inflammation and melanoma.

The switch triggering the invasion process: Lipid metabolism in the metastasis of hepatocellular carcinoma.

In humans, the liver is a central metabolic organ with a complex and unique histological microenvironment. Hepatocellular carcinoma (HCC), which is a highly aggressive disease with a poor prognosis, accounts for most cases of primary liver cancer. As an emerging hallmark of cancers, metabolic reprogramming acts as a runaway mechanism that disrupts homeostasis of the affected organs, including the liver. Specifically, rewiring of the liver metabolic microenvironment, including lipid metabolism, is driven by HCC cells, propelling the phenotypes of HCC cells, including dissemination, invasion, and even metastasis in return. The resulting formation of this vicious loop facilitates various malignant behaviors of HCC further. However, few articles have comprehensively summarized lipid reprogramming in HCC metastasis. Here, we have reviewed the general situation of the liver microenvironment and the physiological lipid metabolism in the liver, and highlighted the effects of different aspects of lipid metabolism on HCC metastasis to explore the underlying mechanisms. In addition, we have recapitulated promising therapeutic strategies targeting lipid metabolism and the effects of lipid metabolic reprogramming on the efficacy of HCC systematical therapy, aiming to offer new perspectives for targeted therapy.

MAPKAP1 orchestrates macrophage polarization and lipid metabolism in fatty liver-enhanced colorectal cancer

Various factors, including fatty liver and macrophage alterations, influence colorectal cancer (CRC). This study explores the mechanistic role of fatty liver in CRC progression, focusing on macrophage polarization and lipid metabolism. A murine fatty liver model was created with a high-fat diet (HFD), and CRC was induced using AOM and DSS. Single-cell transcriptome sequencing (scRNA-seq) identified MAPKAP1 as a critical gene promoting CRC via M2 macrophage polarization and lipid metabolism reprogramming. Prognosis analysis on the TCGA-CRC dataset confirmed MAPKAP1′s significance. In vitro and in vivo experiments demonstrated that EVs from fatty liver cells enhanced MAPKAP1 expression, accelerating CRC development and metastasis. HFD exacerbated CRC, but fatty acid inhibitors delayed progression. Fatty liver upregulates MAPKAP1, driving M2 macrophage polarization and lipid metabolism changes, worsening CRC. These findings suggest potential therapeutic strategies for CRC, particularly targeting lipid metabolism and macrophage-mediated tumor promotion.

Abstract 2087: Targeting lipid metabolism in pancreatic cancer

Abstract Background PIKfyve is a lipid kinase that serves as the sole source of cellular PI(3,5)P2 and PI5P, critical phosphatidylinositols for autophagy and lysosome function. Pancreatic ductal adenocarcinoma (PDAC) is known to upregulate and depend on lysosomal functions such as autophagy to exist in its harsh, nutrient-disrupted microenvironment. Thus, we aimed to establish PIKfyve as a therapeutic target in PDAC. Using a PIKfyve-knockout genetically engineered mouse model of pancreatic cancer (KC and KPC), we determined that PIKfyve was necessary for PDAC development. Given these results, we hypothesized that PIKfyve was critical for maintaining metabolic homeostasis in PDAC and that inhibiting PIKfyve would be an efficacious therapeutic strategy for PDAC. Methods and results We first validated the known role of PIKfyve in regulating autophagy using CRISPRi mediated knockdown, PIKfyve inhibitors Apilimod and ESK981, and a PIKfyve degrader, which all demonstrated that PIKfyve perturbation disrupted autophagic flux and suppressed PDAC cell growth. Little is known about the metabolic impacts of PIKfyve inhibition in PDAC beyond disruption of autophagy. Thus, we paired RNA-seq and a metabolic CRISPR screen to discover that PIKfyve inhibition obligated PDAC cells to upregulate de novo lipid synthesis. Specifically, PDAC cells upregulated fatty acid synthesis genes ACACA and FASN upon PIKfyve inhibition. Additionally, these genes were synthetically critical in the context of PIKfyve inhibition. We further performed metabolomics and lipidomics which revealed accumulation of sphingolipids upon PIKfyve inhibition. Given this, we concluded that PIKfyve regulates lipid homeostasis in PDAC. To further establish PIKfyve as a target in PDAC, we investigated the role of PIKfyve upon inhibition of KRAS, which drives PDAC through MAPK pathway signaling. First, KRAS/MAPK inhibition diminished expression of FASN and ACACA, genes synthetically essential upon PIKfyve inhibition. Additionally, KRAS/MAPK inhibition upregulated autophagy which was attenuated upon concurrent PIKfyve inhibition. Given this metabolic conflict between KRAS/MAPK and PIKfyve, we assessed the effects of dual inhibiting KRAS/MAPK and PIKfyve in a syngeneic orthotopic model. Encouragingly, combination therapy of trametinib (MEK inhibitor) and ESK981 eliminated tumor burden in most of mice, while single treatments only had modest effects. Further, we established a patient-derived xenograft model and showed that while the treatment with individual compounds trametinib, MRTX-1133 (KRASG12D inhibitor), and ESK981 all suppressed tumor growth, the combination of ESK981 and trametinib or ESK981 and MRTX-1133 caused substantial tumor regression in nearly all mice. Taken together, targeting lipid metabolism through inhibition of PIKfyve is a promising therapeutic strategy for PDAC, particularly in combination with the numerous KRAS/MAPK inhibitors in clinical development. Citation Format: Caleb Cheng, Jasmine P. Wisniewski, Ahmet Korkaya, Bailey Jackson, Rahul Mannan, Somnath Mahapatra, Nicholas Rossiter, Rupam Bhattacharyya, Pietro Morlacchi, Sydney Peters, Yuanyuan Qiao, Costas A. Lyssiotis, Arul M. Chinnaiyan. Targeting lipid metabolism in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2087.

Abstract 2077: Exploring the multifaceted efficacy of de novo lipogenesis inhibitor in cancer therapy

Abstract Cancer cells frequently exhibit altered lipid metabolism to sustain their rapid growth and proliferation.Sterol Regulatory Element-Binding Proteins (SREBPs) are key transcription factors that orchestratelipid biosynthesis and uptake in cells. Dysregulation of SREBPs is a common feature of many cancertypes, making them attractive targets for therapeutic intervention. In this study, we present acomprehensive exploration of the potential and rationale for targeting lipid metabolism in cancerthrough the use of a small molecule inhibitor that targets activation of SREBP. We illustrate that oursmall molecule inhibitor (SMI) exhibits potent anticancer activity and effectively targets SREBPsignaling in a variety of prostate cancer models as well as in non-prostate cancer models that arelipogenesis driven. Our novel SMI induces apoptosis and reduces PCa cell proliferation, suppressescell invasion and migration. Furthermore, we illustrate that in addition to suppressing the transcriptionfactor activity of SREBPs, these novel SMIs are highly effective in suppressing both the full length andvariant androgen receptor and their signaling in prostate cancer cells. Notably, in cell and organoidmodels, these novel inhibitors exhibit synergistic anticancer activity in combination with the ARsignaling inhibitor, Enzalutamide. The anticancer activity of these inhibitors extend beyond ARdependent prostate cancer and are also effective in organoid models of neuroendocrine PCa, aparticularly drug-resistant and aggressive PC subtype. Lastly, we illustrate excellent pharmacokineticsand potent anti-tumor effects of these novel SREBP activation inhibitors using in vivo castration-resistant prostate cancer CDX tumors. Given the urgent need for novel targets in PCa, our first-in-class inhibitor represents a promising therapeutic strategy with the potential to effectively targetdysregulated lipogenesis in cancer patients. Citation Format: Dallin Lowder, Jin Na Shin, Maria E. Ruiz-Echartea, Jenny Deng, Aleksandra Rusin, Darlene Skapura, Michael Ittmann, Salma Kaochar. Exploring the multifaceted efficacy of de novo lipogenesis inhibitor in cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2077.