Baicalein inhibits FURIN‐MT1‐MMP‐mediated invasion of ectopic endometrial stromal cells in endometriosis possibly by reducing the secretion of TGFB1

Abstract

Problem: Endometriosis (EMs) is characterized by the presence of endometrial stroma and glands outside the uterus. Our previous study showed that baicalein inhibited proliferation and induced apoptosis in EMs. However, the effects of baicalein on the invasiveness of ectopic endometrial stromal cells (EcESCs) remain unclear. The aim of this study was to assess the potential anti-invasive effect of baicalein and determine the underlying mechanism. Methods: The invasive and migratory properties of EcESCs were assessed in vitro using Transwell and wound healing assays. The expression of functional markers of EcESCs, including matrix metalloproteases (MMPs), FURIN, and TGFB1, was analyzed using WB and ELISA. Additionally, a mouse model of EMs was treated with baicalein (10 mg/kg/d and 35 mg/kg/d) for 4 weeks. The weight and number of ectopic lesions were determined, and the expression of markers was assessed using immunohistochemistry. Results: Baicalein inhibited the invasion of EcESCs and the expression of certain invasion-related proteins, including MMP9, MMP2, and MT1-MMP. Exposure to baicalein reduced the extracellular levels of TGFB1 in EcESCs and the reduced expression of TGFB1, resulting in decreased expression of FURIN in EcESCs, which serves a pivotal role in the transformation of pro-MT1-MMP to activated MT1-MMP. In the mouse model of EMs, intraperitoneal injection of baicalein inhibited the growth of ectopic lesions and reduced MT1-MMP, FURIN, and TGFB1 expression. Conclusions: Baicalein reduced the invasion of EMs, potentially by restricting the FURIN-MT1-MMP-mediated cell invasion of EcESCs maybe through reduction of the autocrine of TGFB1.

Baicalein Relieves Ferroptosis-Mediated Phagocytosis Inhibition of Macrophages in Ovarian Endometriosis

“…Our previous studies have shown that baicalein induces EcESCs apoptosis and inhibits invasion [ 19 , 20 ]. We intended to explore more mechanisms of baicalein as a potential anti-ferroptosis drug in Ems.…”

“…Baicalein also inhibits erastin-induced ferrous iron production, glutathione depletion, and lipid peroxidation in pancreatic cancer cells [ 16 ]. Our previous studies had shown that baicalein induced EcESCs apoptosis through the NF-kB signaling pathway [ 19 ] and inhibited the invasion of EcESCs by invasion-related proteins, including MT1-MMP, MMP2, and MMP9 [ 20 ].…”

The possible role furin and furin inhibitors in endometrial adenocarcinoma: A narrative review

“…Total furin activity in cervical swabs and uterine lavage correlated with the severity and progression of atypical endometrial hyperplasia and endometriosis 10,30 . An experimental study illustrated that inhibition growth of endometriosis by baicalein reduced furin level 52 . The results imply the possible function of PC furin in the propagation of atypical endometrial hyperplasia and endometriosis.…”

Polyphenols as a Diet Therapy Concept for Endometriosis—Current Opinion and Future Perspectives

“…The number of cells in the G1 phase increased with a simultaneous decline in the number of cells in the S and G2/M phases compared with non-treated control cells [ 95 ]. More recent findings indicate that baicalein reduces ectopic endometrial stromal cell invasiveness, as demonstrated by analysis of invasion-related proteins, including MMP-9, MMP-2 and membrane type 1-matrix metalloproteinase (MT1-MMP) [ 96 ]. In a mouse model of endometriosis, intraperitoneal administration of baicalein inhibited ectopic lesions’ growth, reduced MT1-MMP, proprotein convertase of MMPs (FURIN) and TGFB1 expression.…”

“…In a mouse model of endometriosis, intraperitoneal administration of baicalein inhibited ectopic lesions’ growth, reduced MT1-MMP, proprotein convertase of MMPs (FURIN) and TGFB1 expression. Thus, baicalein with a potent pro-apoptotic and anti-invasive activity may provide a novel treatment strategy for endometriosis, as the authors suggested [ 96 ]. Promising preclinical research results indicate that undertaking clinical studies on endometriosis treatment with baicalein is warranted and recommended to obtain strong evidence for therapeutic baicalein potential.…”