{"paper_id":"87d87b3b-4b6d-4fe3-9e2e-46e73a88ec19","body_text":"Abstract\nObjective\nTo investigate the therapeutic effects and mechanisms of curcumin (Cur) in adenomyosis (AM).\nMethods\nA mouse uterine AM model was established by exposing ICR neonatal mice to tamoxifen (TAM). Female neonatal mice (day 1, n=24) were numbered and randomly divided into control, model (TAM 1 mg/kg per day, day 2 to 5), low- and high-doses Cur groups (TAM 1 mg/kg per day, day 2 to 5; Cur 50 and 200 mg/kg per day, respectively, week 13 to 15), by a random number table, with 6 mice in each group. The effect of Cur was assessed by a hot-plate test on mice and uterine sections for hematoxylin and eosin (HE), Masson staining, and immunohistochemistry staining of E-cadherin, N-cadherin, matrix metalloproteinases (MMP) 9 and MMP 11. Ishikawa (IK) cell phenotypic transformation was induced by transforming growth factor beta 1 (TGF-β1), and the mRNA and protein expressions of E-cadherin, N-cadherin, MMP 9, MMP 11 and p-Smad3/Smad3 were detected by quantitative real-time PCR and Western blot after Cur treatment.\nResults\nIn vivo study results showed that Cur significantly improved pain tolerance (P<0.01). The degrees of lesion fibrosis and invasion of ectopic glands in model mice were significantly higher than those in control mice, and the degrees were significantly reduced after high-dose Cur treatment (P<0.01). High-dose Cur reversed the decrease of E-cadherin and the increase of the levels of N-cadherin, MMP 9 and MMP11 by inhibiting the production of TGF-β1 in the uterine tissue (P<0.01). In vitro study, Cur increased the protein expression of E-cadherin and reduced the protein expressions of N-cadherin, MMP 9 and MMP 11 (P<0.01). Cur effectively inhibited the phosphorylation of p-Smad3/Smad3 in IK cells induced by TGF-β1 (P<0.01).\nConclusion\nCur effectively alleviates AM and inhibits fibroblast differentiation and epithelial-mesenchymal transition by TGF-β1/Smad3 pathway, which provides a new approach for treating AM by non-hormonal drugs.\nSimilar content being viewed by others\nAvailability of Data and Materials\nData may be made available from the corresponding author upon reasonable request.\nReferences\nGuo SW. Cracking the enigma of adenomyosis: an update on its pathogenesis and pathophysiology. Reproduction 2022;164:R101–R121.\nChapron C, Vannuccini S, Santulli P, Abrão MS, Carmona F, Fraser IS, et al. Diagnosing adenomyosis: an integrated clinical and imaging approach. Hum Reprod Update 2020;26:392–411.\nWang X, Benagiano G, Liu X, Guo SW. Unveiling the pathogenesis of adenomyosis through animal models. J Clin Med 2022;11:1744.\nSolares JG, Donnez J, Donnez O, Dolmans MM. Pathogenesis of uterine adenomyosis: invagination or metaplasia? Fertil Steril 2018;109:371–379.\nLaganà AS, Salmeri FM, Frangež HB, Ghezzi F, Bokal EV, Granese R. Evaluation of M1 and M2 macrophages in ovarian endometriomas from women affected by endometriosis at different stages of the disease. Gynecol Endocrinol 2019;36:441–444.\nKhan KN, Fujishita A, Mori T. Pathogenesis of human adenomyosis: current understanding and its association with infertility. J Clin Med 2022;11:4057.\nYoo JY, Ku BJ, Kim TH, Ahn IJ, Ahn JY, Yang WS, et al. β-Catenin activates TGF-β-induced epithelial-mesenchymal transition in adenomyosis. Exp Mol Med 2020;52:1754–1765.\nChen D, Qiao H, Wang Y, Zhou L, Yin N, Fang LQ, et al. Adenomyosis-derived extracellular vesicles endow endometrial epithelial cells with an invasive phenotype through epithelial-mesenchymal transition. Genes Dis 2020;7:636–648.\nThiery JP, Acloque H, Huang RYJ, Nieto MA. Epithelial mesenchymal transition in tumor metastasis. Annu Rev Pathol 2018;13:395–412.\nLamouille S, Xu J, Derynck R. Molecular mechanisms of epithelialmesenchymal transition. Nat Rev Mol Cell Biol 2014;15:178–196.\nLee JH, Massagué J. TGF-β in developmental and fibrogenic EMTs. Semin Cancer Biol 2022;86:136–145.\nPontis A, D’Alterio MN, Pirarba S, Angelis CD, Tinelli R, Angioni S. Adenomyosis: a systematic review of medical treatment. Gynecol Endocrinol 2016;32:696–700.\nYaikwawong M, Kamdee K, Chuengsamarn S. Curcumin attenuates liver steatosis via antioxidant and anti-inflammatory pathways in obese patients with type 2 diabetes mellitus: a randomized controlled trial. Int J Mol Sci 2025;26:9286.\nNicoliche T, Bartolomeo CS, Lemes RMR, Pereira GC, Nunes TA, Oliveira RB, et al. Antiviral, anti-inflammatory and antioxidant effects of curcumin and curcuminoids in SH-SY5Y cells infected by SARS-CoV-2. Sci Rep 2024;14:10696.\nMiao L, Huang F, Sun YY, Jiang W, Chen YJ, Zhang M. Curcumin plays a local anti-inflammatory and antioxidant role via the HMGB1/TLR4/NF-κB pathway in rat masseter muscle under psychological stress. J Oral Rehabil 2022;49:249–257.\nZhang L, Cheng X, Xu SC, Bao JD, Yu HX. Curcumin induces endoplasmic reticulum stress-associated apoptosis in human papillary thyroid carcinoma BCPAP cells via disruption of intracellular calcium homeostasis. Medicine 2018;97:e1109597.\nWang T, Wu X, Rudaisat MA, Song YJ, Cheng H. Curcumin induces G2/M arrest and triggers autophagy, ROS generation and cell senescence in cervical cancer cells. J Cancer 2020;11:6704–6715.\nKunihiro AG, Brickey JA, Frye JB, Luis PB, Schneider C, Funk JL, et al. Curcumin, but not curcumin-glucuronide, inhibits Smad signaling in TGFβ-dependent bone metastatic breast cancer cells and is enriched in bone compared to other tissues. J Nutr Biochem 2019;63:150–156.\nElzoheiry A, Ayad E, Omar N, Elbakry K, Hyder A. Anti-liver fibrosis activity of curcumin/chitosan-coated green silver nanoparticles. Sci Rep 2022;12:18403.\nKay N, Huang CY, Shiu LY, Yu YC, Chang Y, Suen JL, et al. The effects of anti-TGF-β1 on epithelial-mesenchymal transition in the pathogenesis of adenomyosis. Reprod Sci 2020;27:1698–1706.\nZhu B, Zhang C, Shen X, Chen C, Chen X, Lu Y et al. Protective effects of resveratrol against adenomyosis in a mouse model. Dose Response 2023;21:15593258231164055.\nEtrusco A, Barra F, Chiantera V, Ferrero S, Bogliolo S, Evangelisti G, et al. Current medical therapy for adenomyosis: from bench to bedside. Drugs 2023;83:1595–1611.\nMantzorou M, Pavlidou E, Vasios G, Tsagalioti E, Giaginis C. Effects of curcumin consumption on human chronic diseases: a narrative review of the most recent clinical data. Phytother Res 2018;32:957–975.\nXu B, Zhang JE, Ye L, Yuan CW. Curcumin interferes with TGF-β1-induced fibrosis in NRK-49F cells by reversing ADAMTS18 gene methylation. Chin J Integr Med 2024;30:600–607.\nMa J, Ma SY, Ding CH. Curcumin reduces cardiac fibrosis by inhibiting myofibroblast differentiation and decreasing transforming growth factor β1 and matrix metalloproteinase 9/tissue inhibitor of metalloproteinase 1. Chin J Integr Med 2017;23:362–369.\nGuo SW. The role of platelets in the pathogenesis and pathophysiology of adenomyosis. J Clin Med 2023;12:842.\nTie Y, Tang F, Peng D, Zhang Y, Shi H. TGF-beta signal transduction: biology, function and therapy for diseases. Mol Biomed 2022;3:45.\nXin X, Cheng X, Zeng F, Xu Q, Hou L. The role of TGF-β/Smad signaling in hepatocellular carcinoma: from mechanism to therapy and prognosis. Int J Biol Sci 2024;20:1436–1451.\nAuthor information\nAuthors and Affiliations\nContributions\nYang QM: conceptualization, methodology, software, data curation, and writing-original draft. Chen Y: methodology and formal analysis. Xia LH: writing-review, editing and visualization. Xu H: investigation and validation. Jin XF: funding acquisition. Wu Q: conceptualization, methodology, writing-review and editing, visualization, project administration, and funding acquisition. All authors have read and approved the final manuscript for publication.\nCorresponding author\nEthics declarations\nThe authors declare no competing interests.\nAdditional information\nSupported by Zhejiang Province Medical and Health Technology Plan Project (Nos. 2021KY504, 2023KY054 and 2025KY553), Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital, Zhejiang University School of Medicine (No. ZDFY2022-CD-8)\nElectronic Supplementary Material\nRights and permissions\nAbout this article\nCite this article\nYang, Qm., Chen, Y., Xia, Lh. et al. Curcumin Inhibits Fibroblast Differentiation and Epithelial-Mesenchymal Transition to Alleviate Adenomyosis through TGF-β1/Smad3 Pathway. Chin. J. Integr. Med. 32, 407–414 (2026). https://doi.org/10.1007/s11655-025-4215-0\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s11655-025-4215-0","source_license":"CC0","license_restricted":false}