TMEM119 links to ovarian endometriosis progression via MAPK-mediated suppression of ectopic endometrial stromal cell senescence

Transmembrane protein TMEM119 has been implicated in tumor progression (e.g., ovarian cancer), but its role and underlying mechanism in ovarian endometriosis (EM) remain elusive. Thus, this study aimed to investigate the expression pattern and functional role of TMEM119 in ovarian EM. To this end, TMEM119 expression was first analyzed using the GSE141549 dataset, and further detected in ovarian EM tissues and ovarian ectopic endometrial stromal cells (ESCs). After TMEM119 overexpression in ectopic ESCs, gene ontology/Kyoto Encyclopedia of Genes and Genomes enrichment analyses of differentially expressed genes (DEGs) were conducted. For ectopic ESCs with TMEM119 knockdown or overexpression [divided into four groups: negative control (NC)-short hairpin (sh) RNA, TMEM119-shRNA, NC-overexpression (OE), and TMEM119-OE], we detected cell cycle distribution, positive rates of p16, p21, and p53, senescence-associated β-galactosidase positivity, cell proliferation, and the expression of p53 and mitogen-activated protein kinase (MAPK) pathway-related proteins. Molecular docking was performed to evaluate the binding affinity between TMEM119 and therapeutic drugs for ovarian EM. Results showed that TMEM119 was significantly upregulated in ovarian EM tissues and ovarian ectopic ESCs. TMEM119 knockdown induced senescence in ectopic ESCs-evidenced by increased positive rates of p16 and p21, G0/G1 phase arrest, and accumulated senescence-associated β-galactosidase positivity-accompanied by decreased cell proliferation and MAPK phosphorylation. In contrast, TMEM119 overexpression exerted the opposite effects. However, the change in p53 protein expression was not obvious. Molecular docking showed that TMEM119 exhibited strong binding affinity for danazol, drospirenone, and sufugolix. Collectively, TMEM119 is significantly upregulated in ovarian EM, where it blocks ectopic ESC senescence via MAPK signaling and consequently accelerates lesion expansion. Inducing cellular senescence may therefore constitute a tractable therapeutic avenue for ovarian EM.