Autophagy can be dynamically induced in response to stresses and is an essential, ubiquitous intracellular recycling system that impacts the fate of damaged resident cells, thereby influencing wound healing. Endometrial fibrosis is a form of abnormal wound healing that causes intrauterine adhesion (IUA) and infertility. We previously demonstrated that overactivated sonic hedgehog (SHH) signaling exacerbated endometrial fibrosis, but the role of autophagy in this process is still unknown. Here, we report that impaired autophagy participates in SHH pathway-induced endometrial fibrosis. Endometrial stroma-myofibroblast transition accompanied by autophagy dysfunction was present in both endometrial biopsies of IUA patients and Amhr2^cre/+ R26-SmoM2^+/− (AM2) transgenic mouse. Mechanistically, SHH pathway negatively regulated autophagy through pAKT-mTORC1 in a human endometrial stromal cell line (T-HESCs). Furthermore, SHH pathway-mediated fibrosis was partly counteracted by autophagy modulation in both T-HESCs and the murine IUA model. Specifically, the impact of SHH pathway inhibition (GANT61) was reversed by the pharmacological autophagy inhibitor chloroquine (CQ) or RNA interference of autophagy-related gene ATG5 or ATG7. Similar results were obtained from the murine IUA model treated with GANT61 and CQ. Moreover, promoting autophagy with rapamycin reduced fibrosis in the AM2 IUA model to baseline levels. In summary, defective autophagy is involved in SHH pathway-driven endometrial fibrosis, suggesting a potential novel molecular target for IUA treatment.

自噬可以响应压力而被动态诱导，并且是一种重要的、无处不在的细胞内循环系统，它影响受损驻留细胞的命运，从而影响伤口愈合。子宫内膜纤维化是伤口愈合异常的一种形式，会导致宫腔粘连 (IUA) 和不孕。我们之前证明过激活的声波刺猬（SHH）信号会加剧子宫内膜纤维化，但自噬在这一过程中的作用仍然未知。在这里，我们报告受损的自噬参与了 SHH 通路诱导的子宫内膜纤维化。IUA 患者的子宫内膜活检和Amhr2 ^cre/+ R26-SmoM2 ^+/- (AM2) 转基因均存在子宫内膜间质-肌成纤维细胞转化并伴有自噬功能障碍鼠标。从机制上讲，SHH 通路通过 pAKT-mTORC1 在人子宫内膜基质细胞系 (T-HESCs) 中负调控自噬。此外，在 T-HESC 和小鼠IUA 模型中，自噬调节部分抵消了 SHH 途径介导的纤维化。具体而言，自噬相关基因ATG5或ATG7的药理学自噬抑制剂氯喹 (CQ) 或 RNA 干扰可逆转 SHH 通路抑制 (GANT61) 的影响。从鼠中也得到了类似的结果用 GANT61 和 CQ 处理的 IUA 模型。此外，用雷帕霉素促进自噬可将 AM2 IUA 模型中的纤维化降低至基线水平。总之，缺陷自噬与 SHH 通路驱动的子宫内膜纤维化有关，提示 IUA 治疗的潜在新分子靶点。