Wu Shasha, Chen Qiuhong, Yang Xiao, Zhang Lulu, Huang Xiyue, Huang Jinglin, Wu Jiangling, Sun Congcong, Zhang Wenwen, Wang Jia
Department of Obstetrics and Gynecology, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China.
Medical Sciences Research Center, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China.
Cell Signal. 2025 Jul;131:111730. doi: 10.1016/j.cellsig.2025.111730. Epub 2025 Mar 13.
Kinase suppressor of Ras 1 (KSR1) serves as a scaffold protein within the RAS-RAF pathway and plays a role in tumorigenesis, immune regulation, cell proliferation, and apoptosis. However, the specific role of KSR1 in the formation and progression of fibrotic diseases, such as intrauterine adhesions (IUA), remains unclear. This study aims to investigate KSR1 expression in IUA and the mechanisms underlying its role in promoting IUA progression. KSR1 was found to be significantly overexpressed in the endometrium of both IUA model rats and patients with IUA. KSR1 is positively involved in the regulation of proliferation, migration, and fibrosis (FN1, Collagen I, α-SMA) in immortalized human endometrial stromal cells (THESCs). Furthermore, KSR1 knockdown was observed to inhibit the fibrosis, proliferation, and migration of transforming growth factor-β1 (TGF-β1)-induced THESCs. Further studies demonstrated that the key proteins of the MEK/ERK signaling pathway, p-MEK1 and p-ERK1/2, were significantly overexpressed in the uterus of IUA rats. In vitro rescue experiments confirmed that the MEK/ERK pathway inhibitor U0126 (An ERK inhibitor) effectively suppressed the enhanced fibrosis, proliferation, and migration induced by KSR1 overexpression. In conclusion, this study demonstrates that KSR1 promotes IUA by enhancing proliferation, migration, and fibrosis of endometrial stromal cells via the MEK/ERK signaling pathway.
Ras激酶抑制因子1（KSR1）作为RAS-RAF信号通路中的一种支架蛋白，在肿瘤发生、免疫调节、细胞增殖和凋亡中发挥作用。然而，KSR1在诸如宫腔粘连（IUA）等纤维化疾病的形成和进展中的具体作用仍不清楚。本研究旨在探讨KSR1在IUA中的表达及其促进IUA进展的潜在机制。研究发现，KSR1在IUA模型大鼠和IUA患者的子宫内膜中均显著过表达。KSR1正向参与永生化人子宫内膜基质细胞（THESC）的增殖、迁移和纤维化（纤连蛋白1、I型胶原、α-平滑肌肌动蛋白）调控。此外，观察到敲低KSR1可抑制转化生长因子-β1（TGF-β1）诱导的THESC的纤维化、增殖和迁移。进一步研究表明，MEK/ERK信号通路的关键蛋白p-MEK1和p-ERK1/2在IUA大鼠子宫中显著过表达。体外挽救实验证实，MEK/ERK通路抑制剂U0126（一种ERK抑制剂）有效抑制了KSR1过表达诱导的纤维化、增殖和迁移增强。总之，本研究表明KSR1通过MEK/ERK信号通路增强子宫内膜基质细胞的增殖、迁移和纤维化来促进IUA。
