Du Xiufang, Yang Hongjie, Kang Xiaobei, Fu Changna, Yang Tao
Department of Women's Group Health, Shijiazhuang Maternal and Child Health Care Hospital, Shijiazhuang, 050000, Hebei, China.
Shijiazhuang Maternal and Child Health Care Hospital, Shijiazhuang, 050000, Hebei, China.
Cell Biochem Biophys. 2025 Jun;83(2):1757-1770. doi: 10.1007/s12013-024-01583-4. Epub 2024 Oct 4.
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.
子宫内膜异位症是一种良性妇科疾病，其特征是子宫腔外存在类似子宫内膜的细胞，即异位组织。除了盆腔内外类似子宫内膜组织的异常增殖外，有力的科学证据强调了NOD样受体NLRP3炎性小体和细胞焦亡在子宫内膜异位症发病机制中的关键作用。我们的研究发现，腹壁子宫内膜异位症中内源性蛋白GATA结合蛋白6（GATA6）显著上调。值得注意的是，敲低GATA6会显著损害原代异位子宫内膜间质细胞（EESC）的活力和迁移能力，同时还会抑制细胞焦亡的关键标志物，如NLRP3、gasdermin D N端片段（GSDMD-N）以及这些细胞内的活性氧（ROS）水平。深入探究其潜在机制，我们发现抑制GATA6可减轻EESC中磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（AKT）信号通路的激活。给予PI3K/AKT通路激动剂740 Y-P可减轻GATA6敲低对EESC生长、迁移和细胞焦亡的抑制作用，突出了GATA6与这一复杂信号级联之间的复杂相互作用。体内实验证实了这些发现，表明GATA6表达降低可有效抑制子宫内膜病变的生长，同时抑制细胞焦亡，并伴有这些病变内PI3K/AKT信号的减弱。总之，我们的研究强调了GATA6通过调节PI3K/AKT信号通路在调节腹壁子宫内膜异位症的生长和细胞焦亡中的关键作用。沉默GATA6成为减轻细胞焦亡的一种有前景的方法，并可能为腹壁子宫内膜异位症的治疗提供一个新的治疗角度。
