SOAT1

SOAT1 (sterol O-acyltransferase 1) esterifies free cholesterol into inert cholesterol esters, a reaction that prevents unesterified cholesterol from exerting negative feedback on the mevalonate pathway and thereby sustains its flux (PMID:32633781). Through this activity SOAT1 supports cell proliferation and tumor progression, with a selective dependency in p53-mutant pancreatic cancer cells that have undergone p53 loss of heterozygosity, while p53-wild-type organoids are insensitive to its loss (PMID:32633781). Beyond maintaining mevalonate output, SOAT1-driven cholesterol ester synthesis feeds into downstream programs: it regulates the cholesterol metabolism regulators SREBP1 and SREBP2 to upregulate VEGF-C and drive lymphangiogenesis and lymph node metastasis in gastric cancer (PMID:34790132), it elevates plasma membrane cholesterol and cholesterol ester accumulation to promote epithelial-mesenchymal transition in hepatocellular carcinoma (PMID:38724499), and it participates in a double-negative feedback loop with CPT1A that partitions fatty acids between lipid droplet storage and mitochondrial oxidation (PMID:34052835). Pharmacological inhibition of SOAT1 (avasimibe, nootkatone) suppresses these oncogenic outputs, and co-targeting SOAT1 and CPT1A produces synergistic anticancer effects (PMID:34790132, PMID:34052835, PMID:38724499).

1. 2020 High

   Established the core mechanistic logic by which SOAT1 supports tumor growth: cholesterol esterification relieves feedback inhibition of the mevalonate pathway, creating a context-specific dependency tied to p53 status.

   Evidence Genetic knockout/knockdown in organoid and mouse PDAC models with in vitro proliferation and in vivo tumor assays, epistasis with p53 LOH

   PMID:32633781

   Open questions at the time

   • Does not define the molecular sensor linking cholesterol ester levels to mevalonate pathway feedback
   • Mechanism by which p53 LOH specifically confers SOAT1 dependency not resolved
   • No structural or enzymatic characterization of SOAT1 in this context
2. 2021 Medium

   Connected SOAT1's cholesterol ester output to a transcriptional and angiogenic program, showing it acts through SREBP1/2 to induce VEGF-C and lymphangiogenesis driving metastasis.

   Evidence siRNA knockdown, overexpression, avasimibe inhibition, cholesterol ester and lymphangiogenesis assays, and western blot in gastric cancer

   PMID:34790132

   Open questions at the time

   • Mechanism linking cholesterol ester synthesis to SREBP1/2 regulation not defined
   • Single-lab findings without reciprocal validation
   • Direct interaction between SOAT1 and the SREBP machinery not established
3. 2021 Medium

   Defined SOAT1's role in lipid partitioning, revealing a double-negative feedback loop with CPT1A that balances fatty acid storage versus oxidation and exposing a synthetic-lethal co-targeting strategy.

   Evidence Pharmacological inhibition with avasimibe and etomoxir in vitro and in vivo HCC models, western blot, lipid droplet quantification, bioinformatic analysis

   PMID:34052835

   Open questions at the time

   • Molecular basis of the reciprocal SOAT1–CPT1A regulation not mechanistically dissected
   • Single-lab study relying largely on pharmacological inhibitors
   • Direct physical interaction between SOAT1 and CPT1A not demonstrated
4. 2024 Medium

   Linked SOAT1 cholesterol esterification to membrane remodeling, showing that plasma membrane cholesterol enrichment and cholesterol ester accumulation drive EMT in HCC.

   Evidence SOAT1 overexpression/knockdown, cholesterol esterification and plasma membrane cholesterol assays, EMT marker analysis, xenograft and NAFLD-HCC models, nootkatone inhibition

   PMID:38724499

   Open questions at the time

   • Mechanism connecting plasma membrane cholesterol to EMT signaling not defined
   • Single-lab findings with inhibitor specificity not orthogonally confirmed
   • Whether EMT effect is shared across cancer types untested

• How SOAT1's single enzymatic activity is mechanistically routed into distinct downstream programs (mevalonate feedback, SREBP/VEGF-C transcription, CPT1A lipid partitioning, membrane EMT) across tissues remains unresolved.
• No unifying molecular model linking cholesterol esterification to its multiple downstream effects
• Structural and enzymatic mechanism of SOAT1 not addressed in the corpus
• Regulatory inputs controlling SOAT1 activity not characterized