Flavonoids Quercetin and Kaempferol Are NR4A1 Antagonists and Suppress Endometriosis in Female Mice

Authors

Lei Zhang
Kumaravel Mohankumar
Gregory Martin
Fuada Mariyam
Yuri Park
Sang Jun Han
Stephen Safe

Language

English

Publication Date

8-28-2023

Journal

Endocrinology

DOI

10.1210/endocr/bqad133

PMID

37652054

PMCID

PMC10502789

PubMedCentral® Posted Date

8-31-2023

PubMedCentral® Full Text Version

Post-print

Abstract

Nuclear receptor 4A1 (NR4A1) plays an important role in endometriosis progression; levels of NR4A1 in endometriotic lesions are higher than in normal endometrium, and substituted bis-indole analogs (NR4A1) antagonists suppress endometriosis progression in mice with endometriosis. In addition, the flavonoids kaempferol and quercetin are natural products that directly bind NR4A1 and significantly repress the intrinsic NR4A1-dependent transcriptional activity in human endometriotic epithelial and stromal cells and Ishikawa endometrial cancer cells. NR4A1 knockdown and inhibition of NR4A1 by kaempferol and quercetin suppressed proliferation of human endometriotic epithelial cells and Ishikawa cells by inhibiting epidermal growth factor receptor/c-Myc/survivin-mediated growth-promoting and survival pathways, The mammalian target of rapamycin (mTOR) signaling and αSMA/CTGF/COL1A1/FN-mediated fibrosis signaling but increasing Thioredoxin domain Containing 5/SESN2-mediated oxidative/estrogen receptors stress signaling. In human endometriotic stromal cells, NR4A1 knockdown and inhibition of NR4A1 by kaempferol and quercetin primarily inhibited mTOR signaling by suppressing proliferation of human endometrial stromal cells. In addition, kaempferol and quercetin treatment also effectively suppressed the growth of endometriotic lesions in mice with endometriosis compared with the vehicle without any body weight changes. Therefore, kaempferol and quercetin are NR4A1 antagonists with potential as nutritional therapy for endometriosis.

Keywords

Humans, Female, Animals, Mice, Quercetin, Flavonoids, Endometriosis, Kaempferols, TOR Serine-Threonine Kinases, Mammals, Sestrins, Nuclear Receptor Subfamily 4, Group A, Member 1, quercetin, kaempferol, endometriosis, NR4A1 antagonists

Published Open-Access

yes

Recommended Citation

Zhang, Lei; Mohankumar, Kumaravel; Martin, Gregory; et al., "Flavonoids Quercetin and Kaempferol Are NR4A1 Antagonists and Suppress Endometriosis in Female Mice" (2023). Faculty and Staff Publications. 4870.
https://digitalcommons.library.tmc.edu/baylor_docs/4870