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IGF2BP3/ESM1/KLF10/BECN1 positive feedback loop: a novel therapeutic target in ovarian cancer via lipid metabolism

Anbo Gao1,2, Juan Zou2,3,4, Tian Zeng2,3,4

  • 1Clinical Research Institute, The Second Affiliated Hospital, University of South China, Hengyang, Hunan, China.

Cell Death & Disease
|April 16, 2025
PubMed

Insights

Endothelial cell-specific molecule 1 (ESM1) promotes ovarian cancer (OC) by enhancing cholesterol synthesis and inhibiting lipolysis via a positive feedback loop involving IGF2BP3, KLF10, and BECN1-mediated autophagy. Targeting this pathway offers a promising strategy for OC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Ovarian cancer (OC) frequently presents at advanced stages with high recurrence rates, necessitating novel therapeutic strategies.
  • Understanding the molecular mechanisms driving OC progression, particularly metabolic dysregulation, is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the role of endothelial cell-specific molecule 1 (ESM1) in regulating lipid metabolism and its impact on ovarian cancer (OC) development.
  • To elucidate the molecular pathways through which ESM1 influences cholesterol synthesis and autophagy in OC.

Main Methods:

  • mRNA sequencing to identify genes regulated by ESM1.
  • In vitro assays (Co-IP, dual-luciferase) and autophagy inhibition (chloroquine) to explore mechanisms.
  • Xenograft mouse models and analysis of OC patient samples (microarray, Log-rank test) for in vivo validation.

Main Results:

  • ESM1 silencing decreased cholesterol synthesis and increased lipolysis, linked to Beclin 1 (BECN1) and autophagy suppression.
  • ESM1 inhibits lipolysis by suppressing BECN1-mediated autophagy, with BECN1 regulated by KLF10.
  • A positive feedback loop (IGF2BP3/ESM1/KLF10/BECN1) involving m6A methylation of ESM1 promotes cholesterol synthesis and inhibits lipolysis.
  • High ESM1 expression correlates with poor OC prognosis.

Conclusions:

  • ESM1 plays a critical role in promoting OC by dysregulating lipid metabolism through a novel positive feedback mechanism.
  • The identified ESM1-driven pathway represents a potential therapeutic target for improving ovarian cancer treatment outcomes.

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