SUN-119 - Mechanistic Crosstalk between Gas6-TAM Receptors and Orphan Nuclear Receptor 4A1 (NR4A1) and NR4A2 in Endometriosis Progression.

Background and

Purpose: Endometriosis is a complex inflammatory disorder characterized by pelvic pain, infertility, and progressive fibrosis, with limited non-hormonal treatment options. Despite recent advances, the precise drivers of endometriotic progression are still under investigation. Recent studies have identified orphan nuclear receptors NR4A1 and NR4A2 as key regulators in endometriosis pathogenesis. This study examines the functional interplay between NR4A1/2 and the Gas6-TAM kinase signaling pathway, aiming to define a novel regulatory axis and evaluate the therapeutic potential of newly developed 1,1-bis(3ʹ-indolyl)-1-(3,5-disubstitutedphenyl)methane (DIM-3,5) analogs in endometriosis progression.

Methods: Several DIM-3,5 analogs were synthesized and evaluated in immortalized human endometriotic epithelial and stromal cell lines. Functional roles of NR4A1, NR4A2, and Gas6-TAM kinases were assessed using siRNA-mediated knockdown. Protein and mRNA expression of Gas6-TAM kinases, EMT, and fibrotic markers were assessed by Western blotting and qRT-PCR. In addition, ongoing chromatin immunoprecipitation (ChIP) and luciferase assays will further delineate NR4A1/2-mediated transcriptional regulation at the promoter regions of the human Gas6 and TAM kinases genes.

Results and

Conclusions: DIM-3,5 analogs and NR4A1/2 silencing significantly reduced Gas6 expression and TAM receptor activity at both transcript and protein levels, correlating with decreased downstream signaling associated with cell proliferation and fibrosis. These findings identify a previously unrecognized NR4A-Gas6-TAM axis as a central mediator of endometriotic progression and suggest that DIM-3,5 analogs are promising non-hormonal therapeutics for endometriosis.

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