Endometriosis is a common gynecological disorder characterized by chronic inflammation, defined as abnormal growth of endometrial tissue outside the lining of the uterus and myometrium [1]. Endometriosis causes symptoms such as pain and infertility, which greatly impair the patient's quality of life [[2], [3], [4]]. The incidence of endometriosis is very high, and 10–15% of women of childbearing age are reported to suffer from endometriosis [5]. To date, there is no single very successful treatment option for endometriosis [1]. Therefore, it's critical to develop novel therapeutic strategies for endometriosis. Pyroptosis, also known as cellular inflammatory necrosis, has become a research hotspot recently [6]. As widely described, prominent inflammatory cytokines including interleukin (IL)‐1β and IL-18 are associated with endometriosis [7]. As widely reported, nucleotide-binding domain-like receptor family member pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis accompanied by the elevation of IL‐1β and IL‐18, is the main reason for the occurrence and progression of endometriosis [8,9]. Therefore, new clues about the pathogenic mechanisms of pyroptosis may contribute to the development of novel therapeutic strategies for endometriosis.

Forkhead Box A2 (FoxA2), as a member of the forkhead transcription factor family, functions in regulating various biological processes [[10], [11], [12], [13]]. Recent studies have illustrated that FoxA2 functions in transcriptional regulation of endometrial cells and contributes to the etiology of endometriosis. As proof, Yang et al. identified FoxA2 as a critical factor in the pathology of endometriosis [14]. More importantly, FoxA2 level was significantly reduced in the eutopic endometrium of endometriosis patients, and its knockdown promoted eutopic endometrial stromal cell proliferation and migration [15]. However, biological roles and potential mechanisms of FoxA2 in regulating pyroptosis during endometriosis remain unclear. As well known, FoxA2, as a transcription factor, achieves its biological roles by transcriptional repression of downstream targets [16]. IGF2 mRNA binding protein 1 (IGF2BP1) is only expressed in a limited number of normal adult tissues [17]. However, it was previously observed that IGF2BP1 was high expressed in the serum of endometriosis patients [18], suggesting that IGF2BP1 is a risking factor affecting endometriosis progression. However, the regulatory mechanism of IGF2BP1 involved pyroptosis in endometriosis remains unknown. Herein, it was observed that FoxA2 might be a transcription factor of IGF2BP1 by using AnimalTFDB prediction (http://bioinfo.life.hust.edu.cn/AnimalTFDB/#!/). Therefore, whether FoxA2 affected pyroptosis in endometriosis by transcriptional repression of IGF2BP1 was worthy of further investigation.

As well known, high estrogen production is an endocrine feature of endometriosis [19,20]. The estrogen receptor (ER) has two distinct forms, ERα and ERβ encoded by ESR1 and ESR2, respectively. ERβ expression was significantly higher in endometriotic tissues than in normal uterine endometrium in contrast to ESR1 [21]. In addition, a previous study revealed that ERβ could modulate the inflammasome to promote endometriosis progression, and ERβ inhibition repressed mouse ectopic lesion growth [22]. It's suggesting that ERβ is a risking factor promoting pyroptosis in endometriosis. As widely reported, IGF2BP1, as a RNA‐binding protein, regulates the fate of downstream genes by affecting mRNA stability [23]. In the current work, it was predicted IGF2BP1 had a potential binding site to ERβ through StarBase website (https://starbase.sysu.edu.cn/index.php). Therefore, it was speculated that IGF2BP1 could promote ERβ expression by increasing ERβ mRNA stability, thereby inducing pyroptosis in endometriosis.

Based on the above research, we speculated that FoxA2 transcriptionally inhibited IGF2BP1 expression to repress ERβ expression, thereby suppressing pyroptosis in endometriosis. Our research provided novel perspectives for endometriosis treatment.