Blocking GATA6 Alleviates Pyroptosis and Inhibits Abdominal Wall Endometriosis Lesion Growth Through Inactivating the PI3K/AKT Pathway.

Abstract

Endometriosis is a benign gynecological disorder characterized by the abnormal presence of endometrium-like cells, referred to as ectopic tissue, located outside the uterine cavity. Beyond the abnormal proliferation of endometrium-like tissues within and beyond the pelvic cavity, compelling scientific evidence underscores the crucial involvement of the NOD-like receptor NLRP3 inflammasome and pyroptosis in the pathogenesis of EMS. Our investigation has revealed a striking upregulation of the endogenous protein GATA-binding protein 6 (GATA6) in abdominal wall EMS. Notably, the knockdown of GATA6 significantly impaired the viability and migratory potential of primary ectopic endometrial stromal cells (EESCs) while also inhibiting crucial markers of pyroptosis, such as NLRP3, the gasdermin D N-terminal fragment (GSDMD-N), and reactive oxygen species (ROS) levels within these cells. Delving deeper into the underlying mechanisms, we discovered that suppressing GATA6 mitigated the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in EESCs. The administration of 740 Y-P, an agonist of the PI3K/AKT pathway, mitigated the inhibitive actions of GATA6 knockdown on EESCs' growth, migration, and pyroptosis, highlighting the intricate crosstalk between GATA6 and this intricate signaling cascade. In vivo experiments corroborated these findings, demonstrating that reduced GATA6 expression effectively restrained the growth of endometrial lesions and concurrently suppressed pyroptosis, accompanied by a dampening of PI3K/AKT signaling within these lesions. In summary, our study underscores the pivotal role of GATA6 in modulating the growth and pyroptosis of abdominal wall EMS through its regulation of the PI3K/AKT signaling pathway. Silencing GATA6 emerges as a promising approach to alleviate pyroptosis and potentially offers a novel therapeutic angle for managing abdominal wall EMS.