Farnesoid X Receptor Agonist GW4064 Inhibits Aromatase and ERβ Expression in Human Endometriotic Stromal Cells

Area of Science:

• Endocrinology
• Molecular Biology
• Gynecology

Background:

• Endometriosis is an estrogen-dependent condition where the role of Farnesoid X receptor (FXR) is unclear.
• FXR activation inhibits estrogen signaling in other cancers, but its effect on endometriosis requires investigation.

Purpose of the Study:

• To explore the therapeutic potential of FXR activation using the synthetic agonist GW4064 in endometriosis.
• To elucidate the molecular mechanisms underlying FXR's action in endometriosis.

Main Methods:

• Investigated FXR expression in endometriotic tissues and stromal cells (ESCs).
• Treated ESCs with GW4064 and assessed changes in aromatase, estrogen receptor β (ERβ), and signaling pathways (ERK1/2, p38, AMPK, Stat3).
• Utilized inhibitors and small interfering RNAs to confirm pathway involvement and performed coimmunoprecipitation and chromatin immunoprecipitation assays. Evaluated GW4064 in endometriosis xenografts.

Main Results:

• FXR expression was higher in endometriotic tissues than eutopic tissues.
• GW4064 treatment dose-dependently decreased aromatase and ERβ expression in ESCs.
• GW4064 activated ERK1/2, p38, AMPK, and Stat3; pathway inhibitors reversed GW4064 effects on aromatase and ERβ.
• GW4064 increased Stat3 phosphorylation, enhancing its binding to the ESR2 promoter, downregulating ERβ.
• FXR competed with CREB for binding to the aromatase promoter. GW4064 treatment suppressed aromatase and ERβ in vivo.

Conclusions:

• FXR activation by GW4064 demonstrates therapeutic potential for endometriosis by reducing key estrogen-related factors.
• FXR influences endometriosis via modulation of aromatase and ERβ expression through distinct signaling pathways.
• FXR represents a promising therapeutic target for endometriosis management.