CCN5 negatively regulates TGF-β-induced endometriosis associated fibrosis through Wnt/β-catenin signaling via Smad3-dependent mechanism

作者：Mian Liu, Yi Gong, Hong Cai, Rui Hua, Kai Li, Zhe Wang, Yao Zhou, Yanlin Ma, Song Quan · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-06804-9 · 被引用次数：6 · 研究领域：Connective Tissue Growth Factor Research、Endometriosis Research and Treatment、Lymphatic System and Diseases

BACKGROUND: Fibrogenesis is a common pathological feature of endometriotic lesions and contributes to the development of endometriosis-associated chronic pelvic pain and infertility. TGF-β is a critical factor in the induction of fibrogenesis; however, the underlying regulatory mechanisms of TGF-β-induced fibrosis in endometriosis remain unclear. In this study, we investigated the effects and mechanisms of CCN5 in regulating the progression of TGF-β-induced fibrosis in endometriosis. METHODS: We investigated the role of CCN5 in TGF-β-induced proliferation and pro-fibrotic responses in primary HESCs through CCN5 overexpression and knockdown techniques. We evaluated the impact of CCN5 modulation on the activation of the TGF-β/Smad and Wnt/β-catenin signaling pathways in primary HESCs subjected to TGF-β stimulation. To elucidate the role of Smad3 in CCN5 mediating TGF-β-induced pro-fibrotic response and the activation of TGF-β/Smad and Wnt/β-catenin signaling pathways, we employed SIS3, a specific inhibitor of Smad3. Additionally, we assessed the interaction between CCN5 and Smad3 in primary HESCs. RESULTS: The expression of CCN5 was significantly elevated at both the mRNA and protein levels in patients with endometriosis compared to healthy controls. Overexpression of CCN5 through transfection with LV-CCN5 notably attenuated TGF-β-induced proliferation and pro-fibrotic responses, whereas CCN5 knockdown exhibited the opposite effects in primary HESCs. Additionally, we observed t...