Oral squamous cell carcinoma (OSCC) is an aggressive cancer that poses a substantial threat to human life and quality of life globally. Lipid metabolism reprogramming significantly influences tumor development, affecting not only tumor cells but also tumor-associated macrophages (TAMs) infiltration. SOAT1, a critical enzyme in lipid metabolism, holds high prognostic value in various cancers. This study revealed that SOAT1 is highly expressed in OSCC tissues and positively correlated with M2 TAMs infiltration. Increased SOAT1 expression enhanced the capabilities of cell proliferation, tumor sphere formation, migration, and invasion in OSCC cells, upregulated the SREBP1-regulated adipogenic pathway, activated the PI3K/AKT/mTOR pathway and promoted M2-like polarization of TAMs, thereby contributing to OSCC growth both in vitro and in vivo. Additionally, we explored the upstream transcription factors that regulate SOAT1 and discovered that ETS1 positively regulates SOAT1 expression levels. Knockdown of ETS1 effectively inhibited the malignant phenotype of OSCC cells, whereas restoring SOAT1 expression significantly mitigated this suppression. Based on these findings, we suggest that SOAT1 is regulated by ETS1 and plays a pivotal role in the development of OSCC by facilitating lipid metabolism and M2-like polarization of TAMs. We propose that SOAT1 is a promising target for OSCC therapy with tremendous potential.

Niemann-Pick disease type C1 (NPC1) is a lysosomal disorder due to impaired intracellular cholesterol transport out of the endolysosomal compartment.. Marked heterogeneity has been observed in individuals with the same NPC1 genotype, thus suggesting a significant effect of modifier genes. Prior work demonstrated that decreased SOAT1 activity decreased disease severity in an NPC1 mouse model. Thus, we hypothesized that a polymorphism associated with decreased SOAT1 expression might influence the NPC1 phenotype. Phenotyping and genomic sequencing of 117 individuals with NPC1 was performed as part of a Natural History trial. Phenotyping included determination of disease severity and disease burden. Significant clinical heterogeneity is present in individuals homozygous for the NPC1I1061T variant and in siblings. Analysis of the SOAT1 polymorphism, rs1044925 (A>C), showed a significant association of the C-allele with earlier age of neurological onset. The C-allele may be associated with a higher Annualized Severity Index Score as well as increased frequency of liver disease and seizures. A polymorphism associated with decreased expression of SOAT1 appears to be a genetic modifier of the NPC1 phenotype. This finding is consistent with prior data showing decreased phenotypic severity in Npc1-/-:Soat1-/- mice and supports efforts to investigate the potential of SOAT1 inhibitors as a potential therapy for NPC1.

Sterol o-acyltransferase1 (SOAT1) is an enzyme that regulates lipid metabolism. Nevertheless, the predictive value of SOAT1 regarding immune responses in cancer is not fully understood. Herein, we aimed to expound the predictive value and the potential biological functions of SOAT1 in pan-cancer. Raw data related to SOAT1 expression in 33 different types of cancer were acquired from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. SOAT1 expression was significantly increased in most cancers and showed a distinct correlation with prognosis. This enhanced expression of the SOAT1 gene was confirmed by evaluating SOAT1 protein expression using tissue microarrays. In addition, we found significant positive associations between SOAT1 expression levels and infiltrating immune cells, including T cells, neutrophils, and macrophages. Moreover, the co-expression analysis between SOAT1 and immune genes showed that many immune-related genes were increased with enhanced SOAT1 expression. A gene set enrichment analysis (GSEA) revealed that the expression of SOAT1 correlated with the tumor microenvironment, adaptive immune response, interferon signaling, and cytokine signaling. These findings indicate that SOAT1 is a potential candidate marker for predicting prognosis and a promising target for tumor immunotherapy in cancers.

Endometrial cancer (EC) is the most prevalent gynecological malignancy. Abnormal accumulation of sterol-O-acyl transferase 1 (SOAT1) and SOAT1-mediated cholesterol ester (CE) contributes to cancer progression in various malignancies, including ovarian cancer. Therefore, it was hypothesized that similar molecular changes may occur in EC. The present study aimed to evaluate the diagnostic and/or prognostic potential of SOAT1 and CE in EC by: i) Determining SOAT1 and CE levels in plasma, peritoneal fluid and endometrial tissue from patients with EC and control subjects; ii) performing receiver operating characteristic curve analysis to determine diagnostic performance; iii) comparing SOAT1 and CE expression to that of the tumor proliferation marker Ki67; and iv) assessing the association between SOAT1 expression and survival. Enzyme-linked immunosorbent assay was used to determine the levels of SOAT1 protein in tissue, plasma and peritoneal fluid. The mRNA and protein expression levels of SOAT1 and Ki67 in tissues were detected by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry, respectively. CE levels were determined colorimetrically in plasma and peritoneal fluid. SOAT1-associated survival data from the cBioPortal cancer genomics database were used to assess prognostic relevance. The results revealed that SOAT1 and CE levels were significantly elevated in tumor tissue and peritoneal fluid samples collected from the EC group. By contrast, the plasma levels of SOAT1 and CE in the EC and control groups were similar. Significant positive associations between CE and SOAT1, SOAT1/CE and Ki67, and SOAT1/CE and poor overall survival in patients with EC suggested that SOAT1/CE may be associated with malignancy, aggressiveness and poor prognosis. In conclusion, SOAT1 and CE may serve as potential biomarkers for prognosis and target-specific treatment of EC.

Cholesterol is a key component of all mammalian cell membranes. Disruptions in cholesterol metabolism have been observed in the context of various diseases, including neurodegenerative disorders such as Alzheimer\'s disease (AD). The genetic and pharmacological blockade of acyl-CoA:cholesterol acyltransferase 1/sterol O-acyltransferase 1 (ACAT1/SOAT1), a cholesterol storage enzyme found on the endoplasmic reticulum (ER) and enriched at the mitochondria-associated ER membrane (MAM), has been shown to reduce amyloid pathology and rescue cognitive deficits in mouse models of AD. Additionally, blocking ACAT1/SOAT1 activity stimulates autophagy and lysosomal biogenesis; however, the exact molecular connection between the ACAT1/SOAT1 blockade and these observed benefits remain unknown. Here, using biochemical fractionation techniques, we observe cholesterol accumulation at the MAM which leads to ACAT1/SOAT1 enrichment in this domain. MAM proteomics data suggests that ACAT1/SOAT1 inhibition strengthens the ER-mitochondria connection. Confocal and electron microscopy confirms that ACAT1/SOAT1 inhibition increases the number of ER-mitochondria contact sites and strengthens this connection by shortening the distance between these two organelles. This work demonstrates how directly manipulating local cholesterol levels at the MAM can alter inter-organellar contact sites and suggests that cholesterol buildup at the MAM is the impetus behind the therapeutic benefits of ACAT1/SOAT1 inhibition.

BACKGROUND: Lipid accumulation in tubular cells plays a key role in diabetic kidney disease (DKD). Targeting lipid metabolism disorders has clinical value in delaying the progression of DKD, but the precise mechanism by which molecules mediate lipid-related kidney injury remains unclear. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein that plays a role in lipid metabolism. This study determined the role of PACS-2 in lipid-related kidney injury in DKD.
METHODS: Diabetes was induced by a high-fat diet combined with intraperitoneal injections of streptozotocin (HFD/STZ) in proximal tubule-specific knockout of Pacs-2 mice (PT-Pacs-2-/- mice) and the control mice (Pacs-2fl/fl mice). Transcriptomic analysis was performed between Pacs-2fl/fl mice and PT-Pacs-2-/- mice.
RESULTS: Diabetic PT-Pacs-2-/- mice developed more severe tubule injury and proteinuria compared to diabetic Pacs-2fl/fl mice, which accompanied with increasing lipid synthesis, uptake and decreasing cholesterol efflux as well as lipid accumulation in tubules of the kidney. Furthermore, transcriptome analysis showed that the mRNA level of sterol O-acyltransferase 1 (Soat1) was up-regulated in the kidney of control PT-Pacs-2-/- mice. Transfection of HK2 cells with PACS-2 siRNA under high glucose plus palmitic acid (HGPA) condition aggravated lipid deposition and increased the expression of SOAT1 and sterol regulatory element-binding proteins (SREBPs), while the effect was blocked partially in that of co-transfection of SOAT1 siRNA.
CONCLUSIONS: PACS-2 has a protective role against lipid-related kidney injury in DKD through SOAT1/SREBPs signaling.

Glioblastoma (GBM) is the most lethal primary brain tumor. With limited therapeutic options, novel therapies are desperately needed. Recent studies have shown that GBM acquires large amounts of lipids for rapid growth through activation of sterol regulatory element-binding protein 1 (SREBP-1), a master transcription factor that regulates fatty acid and cholesterol synthesis, and cholesterol uptake. Interestingly, GBM cells divert substantial quantities of lipids into lipid droplets (LDs), a specific storage organelle for neutral lipids, to prevent lipotoxicity by increasing the expression of diacylglycerol acyltransferase 1 (DGAT1) and sterol-O-acyltransferase 1 (SOAT1), which convert excess fatty acids and cholesterol to triacylglycerol and cholesteryl esters, respectively. In this review, we will summarize recent progress on our understanding of lipid metabolism regulation in GBM to promote tumor growth and discuss novel strategies to specifically induce lipotoxicity to tumor cells through disrupting lipid storage, a promising new avenue for treating GBM.

Although cholesterol metabolism is a common pathway for the development of antitumor drugs, there are no specific targets and drugs for clinical use. Here, based on our previous study of sterol O-acyltransferase 1 (SOAT1) in hepatocelluar carcinoma, we sought to screen an effective targeted drug for precise treatment of hepatocelluar carcinoma and, from the perspective of cholesterol metabolism, clarify the relationship between cholesterol regulation and tumorigenesis and development.
In this study, we developed a virtual screening integrated affinity screening technology for target protein drug screening. A series of in vitro and in vivo experiments were used for drug activity verification. Multi-omics analysis and flow cytometry analysis were used to explore antitumor mechanisms. Comparative analysis of proteome and transcriptome combined with survival follow-up information of patients reveals the clinical therapeutic potential of screened drugs.
We screened three compounds, nilotinib, ABT-737, and evacetrapib, that exhibited optimal binding with SOAT1. In particular, nilotinib displayed a high affinity for SOAT1 protein and significantly inhibited tumor activity both in vitro and in vivo. Multi-omics analysis and flow cytometry analysis indicated that SOAT1-targeting compounds reprogrammed the cholesterol metabolism in tumors and enhanced CD8+ T cells and neutrophils to suppress tumor growth.
Taken together, we reported several high-affinity SOAT1 ligands and demonstrated their clinical potential in the precision therapy of liver cancer, and also reveal the potential antitumor mechanism of SOAT1-targeting compounds.

Metabolic reprogramming is a hallmark of glioma, and sterol O-acyltransferase 1 (SOAT1) is an essential target for metabolic therapy. However, the prognostic value of SOAT1 and its association with immune infiltration has not been fully elucidated. Using RNA-seq and clinical data of glioma patients from The Cancer Genome Atlas (TCGA), SOAT1 was found to be correlated with poor prognosis in glioma and the advanced malignancy of clinicopathological characteristics. Next, the correlation between SOAT1 expression and tumor-infiltrating immune cells was performed using the single-sample GSEA algorithm, gene expression profiling interactive analysis (GEPIA), and tumor immune estimation resource version 2 (TIMER2.0); it was found that SOAT1 expression was positively correlated with multiple tumor-infiltrating immune cells. To further verify these results, immunofluorescence was conducted on paraffin-embedded glioma specimens, and a positive trend of the correlation between SOAT1 expression and Treg infiltration was observed in this cohort. Finally, differentially expressed gene analysis, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to explore the biological processes and signaling pathways that SOAT1 may be involved in during glioma pathogenesis. A protein-protein interaction network was established, and co-expression analysis was conducted to investigate the regulatory mechanism of SOAT1 in glioma. To the best of our knowledge, this is the first comprehensive study reporting that SOAT1 may serve as a novel prognostic biomarker associated with immune infiltrates, providing a novel perspective for glioma metabolic therapy.

Targeting molecular alterations as an effective treatment for isocitrate dehydrogenase-wildtype glioblastoma (GBM) patients has not yet been established. Sterol-O-Acyl Transferase 1 (SOAT1), a key enzyme in the conversion of endoplasmic reticulum cholesterol to esters for storage in lipid droplets (LD), serves as a target for the orphan drug mitotane to treat adrenocortical carcinoma. Inhibition of SOAT1 also suppresses GBM growth. Here, we refined SOAT1-expression in GBM and IDH-mutant astrocytoma, CNS WHO grade 4 (HGA), and assessed the distribution of LD in these tumors. Twenty-seven GBM and three HGA specimens were evaluated by multiple GFAP, Iba1, IDH1 R132H, and SOAT1 immunofluorescence labeling as well as Oil Red O staining. To a small extent SOAT1 was expressed by tumor cells in both tumor entities. In contrast, strong expression was observed in glioma-associated macrophages. Triple immunofluorescence labeling revealed, for the first time, evidence for SOAT1 colocalization with Iba1 and IDH1 R132H, respectively. Furthermore, a notable difference in the amount of LD between GBM and HGA was observed. Therefore, SOAT1 suppression might be a therapeutic option to target GBM and HGA growth and invasiveness. In addition, the high expression in cells related to neuroinflammation could be beneficial for a concomitant suppression of protumoral microglia/macrophages.