A novel mechanism regulating pyroptosis-induced fibrosis in endometriosis via lnc-MALAT1/miR-141-3p/NLRP3 pathway†

Endometriosis is a chronic inflammatory disease distinguished by ectopic endometrium and fibrosis. NLRP3 inflammasome and pyroptosis are present in endometriosis. Aberrant increase of Long noncoding (Lnc)-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a vital role in endometriosis. However, the relationship between lnc-MALAT1, pyroptosis, and fibrosis is not completely known. In the present study, we found that the pyroptosis levels in ectopic endometrium of patients with endometriosis were significantly increased, consistent with fibrosis levels. Lipopolysaccharide (LPS) + ATP could induce pyroptosis of primary endometrial stromal cells (ESCs), thereby releasing interleukin (IL)-1 beta and stimulating transforming growth factor (TGF)-beta 1-mediated fibrosis. NLRP3 inhibitor MCC950 had the same effect as TGF-beta 1 inhibitor SB-431542 in suppressing the fibrosis-inducing effect of LPS + ATP in vivo and in vitro. The abnormal increase of lnc-MALAT1 in ectopic endometrium was connected with NLRP3-mediated pyroptosis and fibrosis. Leveraging bioinformatic prediction and luciferase assays combined with western blotting and quantitative reverse transcriptase-polymerase chain reaction, we validated that lnc-MALAT1 sponges miR-141-3p to promote NLRP3 expression. Silencing lnc-MALAT1 in HESCs ameliorated NLRP3-mediated pyroptosis and IL-1 beta release, thereby relieving TGF-beta 1-mediated fibrosis. Consequently, our findings suggest that lnc-MALAT1 is critical for NLRP3-induced pyroptosis and fibrosis in endometriosis through sponging miR-141-3p, which may indicate a new therapeutic target of endometriosis treatment. Lnc-MALAT1 sponges miR-141-3p to deregulate its inhibitory effect on NLRP3, thus promoting endometrial stromal cell pyroptosis and exacerbating the progressive fibrosis of ectopic lesions.