Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, P.R. China.
Department of Obstetrics and Gynecology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, P.R. China.
Mol Hum Reprod. 2024 Oct 12;30(10). doi: 10.1093/molehr/gaae036.
Abnormal autophagy and the transforming growth factor-β (TGFβ)-SMAD3/7 signaling pathway play an important role in the development of intrauterine adhesions (IUAs); however, the exact underlying mechanisms remain unclear. In this study, we used IUA patient tissue and SMAD7 conditional knockout mice to detect whether SMAD7 effected IUA via regulation of autophagy and the TGFβ-SMAD3 signaling pathway. We applied a combination of techniques for the detection of p-SMAD3, SMAD7, autophagy and fibrosis-related proteins, autophagic flux, and analysis of the SMAD3 binding site. Endometrial tissue of patients with IUA exhibited lower expression levels of SMAD7. In endometrial stromal cells, silencing of SMAD7 inhibited autophagic flux, whereas overexpressed SMAD7 promoted autophagic flux. This SMAD7-mediated autophagic flux regulates the stromal-myofibroblast transition, and these phenotypes were regulated by the TGFβ-SMAD3 signaling pathway. SMAD3 directly binds to the 3'-untranslated region of transcription factor EB (TFEB) and inhibits its transcription. SMAD7 promoted autophagic flux by inhibiting SMAD3, thereby promoting the expression of TFEB. In SMAD7 conditional knockout mice, the endometria showed a fibrotic phenotype. Simultaneously, autophagic flux was inhibited. On administering the autophagy activator rapamycin, this endometrial fibrosis phenotype was partially reversed. The loss of SMAD7 promotes endometrial fibrosis by inhibiting autophagic flux via the TGFβ-SMAD3 pathway. Therefore, this study reveals a potential therapeutic target for IUA.
异常自噬和转化生长因子-β（TGFβ）-SMAD3/7 信号通路在宫腔粘连（IUA）的发展中起重要作用；然而，确切的潜在机制仍不清楚。在这项研究中，我们使用 IUA 患者组织和 SMAD7 条件性敲除小鼠来检测 SMAD7 是否通过调节自噬和 TGFβ-SMAD3 信号通路影响 IUA。我们应用了一系列技术来检测 p-SMAD3、SMAD7、自噬和纤维化相关蛋白、自噬流以及分析 SMAD3 结合位点。IUA 患者的子宫内膜组织中 SMAD7 的表达水平较低。在子宫内膜基质细胞中，沉默 SMAD7 抑制自噬流，而过表达 SMAD7 则促进自噬流。这种 SMAD7 介导的自噬流调节基质-肌成纤维细胞转化，这些表型受 TGFβ-SMAD3 信号通路调节。SMAD3 直接结合转录因子 EB（TFEB）的 3'-非翻译区并抑制其转录。SMAD7 通过抑制 SMAD3 促进自噬流，从而促进 TFEB 的表达。在 SMAD7 条件性敲除小鼠中，子宫内膜表现出纤维化表型。同时，自噬流受到抑制。在用自噬激活剂雷帕霉素处理后，这种子宫内膜纤维化表型部分得到逆转。SMAD7 的缺失通过 TGFβ-SMAD3 通路抑制自噬流促进子宫内膜纤维化。因此，本研究揭示了 IUA 的一个潜在治疗靶点。
