The present study suggests that NR4A1 is involved in the fibrosis of ovarian endometriosis and that Cytosporone B (Csn-B), an agonist of NR4A1, is a potential candidate for the treatment of endometriosis

Endometriosis, which is characterized by the implantation and growth of endometrial glands and stroma on extra-uterine sites, is a common cause of pelvic pain and subfertility in women of reproductive age. Severe symptoms of endometriosis affect 6%–10% of the female population worldwide.

Among them, 50%–60% have pelvic pain and up to 50% have infertility. Histologically, ectopic endometrial glands and stroma are encompassed by dense fibrous tissue.

Excess fibrosis may lead to chronic pain, scarring, and infertility as endometriosis develops and progresses. The pathogenesis of endometriosis has been linked to transforming growth factor-β (TGF-β), the most potent promoter of fibrosis. 

Levels of NR4A1 and P-NR4A1 protein in human endometrial and endometriotic tissue were assessed by western blotting and immunohistochemistry. The expression levels of fibrotic markers in stromal cells were evaluated by real-time PCR. The degree of fibrosis in mouse endometriotic lesions was detected by Masson trichrome and Sirius red staining. 

The level of phosphorylated-NR4A1 was higher in ovarian endometriotic tissue than in normal endometrium, and long-term TGF-β1 stimulation phosphorylated NR4A1 in an AKT-dependent manner and then promoted the expression of fibrotic markers.

Furthermore, inhibition of NR4A1 in stromal cells increased the TGF-β1-dependent elevated expression of fibrotic markers, and loss of NR4A1 stimulated fibrogenesis in mice with endometriosis. Additionally, Cytosporone B (Csn-B), an NR4A1 agonist, effectively decreased the TGF-β1-dependent elevated expression of fibrotic markers in vitro and significantly inhibited fibrogenesis in vivo

The study showed that persistent stimulation of endometriotic tissues with TGF-β1 decreased the activity of NR4A1 through AKT-dependent phosphorylation. The devitalized NR4A1 lost its function as a depressor of TGF-β1 signaling and promoted fibrogenesis in ovarian endometriosis.

Csn-B treatment significantly reduced the expression of fibrotic markers in vitro and inhibited fibrogenesis in mouse endometriosis. This study suggests that NR4A1 is involved in the fibrosis of ovarian endometriosis and that Csn-B, an agonist of NR4A1, is a potential candidate for the treatment of endometriosis.