Research Progress on the Mechanisms of Flavonoids in the Treatment of Endometriosis

doi:10.12280/gjszjk.20260043

Abstract

Abstract:

Endometriosis (EMs) is a gynecological disorder characterized by chronic inflammation and estrogen dependence. Flavonoids, owing to their diverse pharmacological activities including anti-inflammatory, antioxidant, and anti-angiogenic effects, are a group of promising candidates in EMs treatment research. Flavonoids can intervene in the initiation and progression of EMs by targeting key pathological processes, such as chronic inflammation and immune dysregulation, estrogen dependence, angiogenesis, pain sensitization, as well as lesion invasion, migration and fibrosis. Different subclasses of flavonoids (including flavones, flavonols, flavanones, isoflavones, and flavanols) modulate key signaling pathways such as nuclear factor-κB (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1α/vascular endothelial growth factor (HIF-1α/VEGF), and nuclear factor-erythroid 2-related factor 2 (Nrf2). Through these pathways, flavonoids may exert specific effects in suppressing inflammation, regulating estrogen metabolism and signaling, inhibiting angiogenesis, alleviating pain sensitization, suppressing cell invasion and migration, and reducing fibrosis. This review summarizes the mechanisms of multi-target and multi-pathway synergistic actions of flavonoids, to provide a theoretical foundation for promoting the application of flavonoids in the treatment of EMs.

Key words: Endometriosis, Flavonoids, Signal transduction, Therapy, Traditional Chinese drugs

LIU Ya-li, GU Jia-qi. Research Progress on the Mechanisms of Flavonoids in the Treatment of Endometriosis[J]. Journal of International Reproductive Health/Family Planning, 2026, 45(3): 253-258.

References 54

[1]	Bao C, Wang H, Fang H. Genomic Evidence Supports the Recognition of Endometriosis as an Inflammatory Systemic Disease and Reveals Disease-Specific Therapeutic Potentials of Targeting Neutrophil Degranulation[J]. Front Immunol, 2022, 13:758440. doi: 10.3389/fimmu.2022.758440.
[2]	Horne AW, Missmer SA. Pathophysiology, diagnosis, and management of endometriosis[J]. BMJ, 2022, 379:e070750. doi: 10.1136/bmj-2022-070750.
[3]	Zhan L, Cao Y. Personalized therapy in endometriosis - based on ERα or ERβ expression[J]. BMC Med, 2024, 22(1):217. doi: 10.1186/s12916-024-03415-x. pmid: 38816887
[4]	Becker CM, Bokor A, Heikinheimo O, et al. ESHRE guideline: endometriosis[J]. Hum Reprod Open, 2022, 2022(2):hoac009. doi: 10.1093/hropen/hoac009.
[5]	Meresman GF, Götte M, Laschke MW. Plants as source of new therapies for endometriosis: a review of preclinical and clinical studies[J]. Hum Reprod Update, 2021, 27(2):367-392. doi: 10.1093/humupd/dmaa039. pmid: 33124671
[6]	Chen S, Liu Y, Zhong Z, et al. Peritoneal immune microenvironment of endometriosis: Role and therapeutic perspectives[J]. Front Immunol, 2023, 14:1134663. doi: 10.3389/fimmu.2023.1134663.
[7]	Wang X, Wu N, Xue Q. Macrophages in endometriosis: key roles and emerging therapeutic opportunities-a narrative review[J]. Reprod Biol Endocrinol, 2025, 23(1):134. doi: 10.1186/s12958-025-01471-3.
[8]	Marla S, Mortlock S, Heinosalo T, et al. Gene expression profiles separate endometriosis lesion subtypes and indicate a sensitivity of endometrioma to estrogen suppressive treatments through elevated ESR2 expression[J]. BMC Med, 2023, 21(1):460. doi: 10.1186/s12916-023-03166-1. pmid: 37996888
[9]	Zhang P, Wang G. Progesterone Resistance in Endometriosis: Current Evidence and Putative Mechanisms[J]. Int J Mol Sci, 2023, 24(8):6992. doi: 10.3390/ijms24086992.
[10]	Bo C, Wang Y. Angiogenesis signaling in endometriosis: Molecules, diagnosis and treatment (Review)[J]. Mol Med Rep, 2024, 29(3):43. doi: 10.3892/mmr.2024.13167.
[11]	Chen Y, Li T. Unveiling the Mechanisms of Pain in Endometriosis: Comprehensive Analysis of Inflammatory Sensitization and Therapeutic Potential[J]. Int J Mol Sci, 2025, 26(4):1770. doi: 10.3390/ijms26041770.
[12]	Vissers G, Giacomozzi M, Verdurmen W, et al. The role of fibrosis in endometriosis: a systematic review[J]. Hum Reprod Update, 2024, 30(6):706-750. doi: 10.1093/humupd/dmae023.
[13]	Woo JH, Jang DS, Choi JH. Luteolin Promotes Apoptosis of Endometriotic Cells and Inhibits the Alternative Activation of Endometriosis-Associated Macrophages[J]. Biomol Ther (Seoul), 2021, 29(6):678-684. doi: 10.4062/biomolther.2021.045.
[14]	Liu YN, Kang JW, Zhang Y, et al. Vanillin prevents the growth of endometriotic lesions through anti-inflammatory and antioxidant pathways in a mouse model[J]. Food Funct, 2023, 14(14):6730-6744. doi: 10.1039/d3fo00750b.
[15]	Lai N, Fu X, Hei G, et al. The Role of Dendritic Cell Subsets in Recurrent Spontaneous Abortion and the Regulatory Effect of Baicalin on It[J]. J Immunol Res, 2022, 2022:9693064. doi: 10.1155/2022/9693064.
[16]	Park S, Lim W, You S, et al. Ameliorative effects of luteolin against endometriosis progression in vitro and in vivo[J]. J Nutr Biochem, 2019, 67:161-172. doi: 10.1016/j.jnutbio.2019.02.006. pmid: 30925413
[17]	Pourhanifeh MH, Farrokhi-Kebria H, Mostanadi P, et al. Anticancer Properties of Baicalin against Breast Cancer and other Gynecological Cancers: Therapeutic Opportunities based on Underlying Mechanisms[J]. Curr Mol Pharmacol, 2024, 17:e18761429263063. doi: 10.2174/0118761429263063231204095516.
[18]	Park W, Jang H, Kim HS, et al. Therapeutic efficacy and anti-inflammatory mechanism of baicalein on endometriosis progression in patient-derived cell line and mouse model[J]. Phytomedicine, 2024, 130:155469. doi: 10.1016/j.phymed.2024.155469.
[19]	邵艳社, 许雪梅, 杨宝芹, 等. 木犀草素调控HPGD表达抑制子宫内膜间质细胞侵袭和迁移[J]. 安徽医科大学学报, 2023, 58(10):1706-1711. doi: 10.19405/j.cnki.issn1000-1492.2023.10.017.
[20]	Liang YC, Zhong Q, Ma RH, et al. Apigenin inhibits migration and induces apoptosis of human endometrial carcinoma Ishikawa cells via PI3K-AKT-GSK-3β pathway and endoplasmic reticulum stress[J]. J Funct Foods, 2022, 94:105116. doi: 10.1016/j.jff.2022.105116.
[21]	He G, Huang X, Dong Y, et al. Preliminary investigation on the mechanism of baicalein regulating the effects of Nischarin on invasion and apoptosis of human breast cancer cells MCF-7 through Wnt3α/β-catenin pathway[J]. Int Immunopharmacol, 2024, 143(Pt 1):113262. doi: 10.1016/j.intimp.2024.113262.
[22]	王晨曦, 陈中建, 延学军, 等. 汉黄芩苷上调miR-573表达抑制胰腺癌SW1990细胞增殖、迁移及侵袭的研究[J]. 中国临床药理学杂志, 2025, 41(4):482-486. doi: 10.13699/j.cnki.1001-6821.2025.04.007.
[23]	Chen J, Li Z, Chen AY, et al. Inhibitory effect of baicalin and baicalein on ovarian cancer cells[J]. Int J Mol Sci, 2013, 14(3):6012-6025. doi: 10.3390/ijms14036012. pmid: 23502466
[24]	Jamali N, Zal F, Mostafavi-Pour Z, et al. Ameliorative Effects of Quercetin and Metformin and Their Combination Against Experimental Endometriosis in Rats[J]. Reprod Sci, 2021, 28(3):683-692. doi: 10.1007/s43032-020-00377-2. pmid: 33141412
[25]	Shaukat A, Shaukat I, Rajput SA, et al. Icariin Alleviates Escherichia coli Lipopolysaccharide-Mediated Endometritis in Mice by Inhibiting Inflammation and Oxidative Stress[J]. Int J Mol Sci, 2022, 23(18):10219. doi: 10.3390/ijms231810219.
[26]	Huang SQ, Xia L, Xia YQ, et al. Icaritin attenuates recurrent spontaneous abortion in mice by modulating Treg/Th17 imbalance via TGF-β/SMAD signaling pathway[J]. Biochim Biophys Acta Mol Cell Res, 2024, 1871(1): 119574. doi: 10.1016/j.bbamcr.2023.119574.
[27]	李娜, 高磊, 陈兴环. 漆黄素调节AKT/mTOR/4EBP1信号通路对子宫内膜异位症大鼠的保护作用[J]. 中国优生与遗传杂志, 2025, 33(6):1302-1307. doi: 10.13404/j.cnki.cjbhh.2025.06.012.
[28]	Delenko J, Xue X, Chatterjee PK, et al. Quercetin enhances decidualization through AKT-ERK-p53 signaling and supports a role for senescence in endometriosis[J]. Reprod Biol Endocrinol, 2024, 22(1):100. doi: 10.1186/s12958-024-01265-z.
[29]	Han SH, Lee JH, Woo JS, et al. Myricetin induces apoptosis and autophagy in human gastric cancer cells through inhibition of the PI3K/Akt/mTOR pathway[J]. Heliyon, 2022, 8(5):e09309. doi: 10.1016/j.heliyon.2022.e09309.
[30]	Zhang L, Mohankumar K, Martin G, et al. Flavonoids Quercetin and Kaempferol Are NR4A1 Antagonists and Suppress Endometriosis in Female Mice[J]. Endocrinology, 2023, 164(10):bqad133. doi: 10.1210/endocr/bqad133.
[31]	张翼, 吴璐璐, 唐俐, 等. 槲皮素治疗子宫内膜异位症的靶点预测及初步鉴定[J]. 陆军军医大学学报, 2025, 47(16):1913-1922. doi: 10.16016/j.2097-0927.202504113.
[32]	Almatroodi SA, Rahmani AH. Unlocking the Pharmacological Potential of Myricetin Against Various Pathogenesis[J]. Int J Mol Sci, 2025, 26(9):4188. doi: 10.3390/ijms26094188.
[33]	Zhao J, Wang J, Liu J, et al. Effect and mechanisms of kaempferol against endometriosis based on network pharmacology and in vitro experiments[J]. BMC Complement Med Ther, 2022, 22(1):254. doi: 10.1186/s12906-022-03729-4. pmid: 36184634
[34]	李美文, 王红玫, 龙表丽, 等. 槲皮素治疗子宫内膜异位症的药理作用研究进展[J]. 现代药物与临床, 2025, 40(8):2122-2126. doi: 10.7501/j.issn.1674-5515.2025.08.040.
[35]	Wang M, Xu Z, Cai Q, et al. Isorhamnetin inhibits progression of ovarian cancer by targeting ESR1[J]. Ann Transl Med, 2022, 10(22):1216. doi: 10.21037/atm-22-5064. pmid: 36544694
[36]	Lu Z, Peng Q, Hu R, et al. Naringin attenuates inflammatory injury to the bovine endometrium by regulating the endoplasmic reticulum stress-PI3K/AKT-autophagy axis[J]. Front Pharmacol, 2024, 15:1424511. doi: 10.3389/fphar.2024.1424511.
[37]	邵雯琪, 陈芳芳, 王锦浩, 等. 橙皮苷对DEHP引起MAC-T细胞损伤的保护作用[J]. 东北农业大学学报, 2025, 56(6):135-145. doi: 10.19720/j.cnki.issn.1005-9369.2025.06.013.
[38]	Ermiş IS, Deveci E, Aşır F. Effects of Quince Gel and Hesperidin Mixture on Experimental Endometriosis[J]. Molecules, 2023, 28(16):5945.doi: 10.3390/molecules28165945.
[39]	范丽, 陈莉, 杜昊. 川陈皮素调节Shh/Gli1信号通路对子宫内膜异位症大鼠血管生成的影响[J]. 中国医科大学学报, 2025, 54(12):1094-1100. doi: 10.12007/j.issn.0258-4646.2025.12.007.
[40]	李明霞, 汪玲, 刘秀玲, 等. 柚皮苷通过PI3K/Akt/mTOR通路调控宫颈癌细胞活力、侵袭和迁移[J]. 中草药, 2025, 56(6):2017-2024. doi: 10.7501/j.issn.0253-2670.2025.06.015.
[41]	Zhu C, Tian M, Liu N, et al. Analgesic effect of nobiletin against neuropathic pain induced by the chronic constriction injury of the sciatic nerve in mice[J]. Phytother Res, 2022, 36(9):3644-3661. doi: 10.1002/ptr.7532.
[42]	Pinho-Ribeiro FA, Hohmann MS, Borghi SM, et al. Protective effects of the flavonoid hesperidin methyl chalcone in inflammation and pain in mice: role of TRPV1, oxidative stress, cytokines and NF-κB[J]. Chem Biol Interact, 2015, 228:88-99. doi: 10.1016/j.cbi.2015.01.011.
[43]	Hashemi M, Raouf FH, Dogani M, et al. The therapeutic potential of naringenin, a natural citrus flavonoid, on pulpal pain and pain-related cognitive dysfunction[J]. Int Endod J, 2025, 58(10):1644-1658. doi: 10.1111/iej.14267.
[44]	Takaoka O, Mori T, Ito F, et al. Daidzein-rich isoflavone aglycones inhibit cell growth and inflammation in endometriosis[J]. J Steroid Biochem Mol Biol, 2018, 181:125-132. doi: 10.1016/j.jsbmb.2018.04.004.
[45]	Sutrisno S, Wijaya AA, Siregar EM, et al. Genistein Acts as an antiangiogenic and Inflammatory Modulator by Inhibits VEGFR2, TGF-β1, and COX-2 Levels in Peritoneal Endometriosis Lesion of Endometriosis Mice[J]. Asian J Fertil Endocrinol Reprod, 2026, 1(1):5-12.
[46]	Sutrisno S, Destikatari L. Genistein Effect on Estrogen Receptor especially Interleukin-6 and Tumor Necrosis Factor-α in Mice Model of Endometriosis: a Systematic Review and Meta-analysis[J]. Asian J Heal Res, 2023, 2(1):96-104. doi: http://doi.org/10.55561/ajhr.v2i1.90.
[47]	Wardhana AP, Irwanto Y. Effect of Genistein on Proliferating Cell Nuclear Antigen (PCNA) Expression and Vascular Density in The Peritoneum of Endometriosis Mice Model[J]. Asian J Heal Res, 2023, 2(3):5-11. doi: http://doi.org/10.55561/ajhr.v2i3.104.
[48]	Sutrisno S, Maharani M. Genistein Ameliorated Vascular Endothelial Growth Factor-A (VEGF-A) and Estrogen Receptor-Alpha (ER-α) in Endometriosis Mice Model, In Vivo and In Silico[J]. ScientificWorldJournal, 2024, 2024:5338212. doi: 10.1155/2024/5338212.
[49]	Tarumi Y, Takaoka O, Izumi Y, et al. Daidzein-rich isoflavone aglycones inhibit 17β-hydroxysteroid dehydrogenase 1 and increase estrogen sulfotransferase in endometriosis[J]. Gynecol Endocrinol, 2025, 41(1):2516202. doi: 10.1080/09513590.2025.2516202.
[50]	Sutrisno S, Riskianto CR, Rapa Y, et al. The Anti-Inflammatory Effects of Genistein Inhibits Tumor Necrosis Factor-A Receptor 1 (TNF-R1) and IL-8 Receptor (CXCR-1) Levels in Peritoneal Endometriosis Lesion of Mice Model Endometriosis[J]. Asian J Fertil Endocrinol Reprod, 2026, 1(1):13-21.
[51]	Chen X, Man G, Hung SW, et al. Therapeutic effects of green tea on endometriosis[J]. Crit Rev Food Sci Nutr, 2023, 63(18):3222-3235. doi: 10.1080/10408398.2021.1986465.
[52]	Markowska A, Kojs Z, Antoszczak M, et al. Epigallocatechin Gallate as a Potential Therapeutic Agent in Endometriosis: A Narrative Review[J]. Nutrients, 2025, 17(13):2068. doi: 10.3390/nu17132068.
[53]	Sanlier NT, Turkoglu İ, Sacinti KG, et al. Therapeutic potential of epigallocatechin gallate in gynecologic cancer, endometriosis, polycystic ovary syndrome: a mechanistic and translational perspective[J]. Front Nutr, 2025, 12:1746959. doi: 10.3389/fnut.2025.1746959.
[54]	Włodarczyk M, Ciebiera M, Nowicka G, et al. Epigallocatechin Gallate for the Treatment of Benign and Malignant Gynecological Diseases-Focus on Epigenetic Mechanisms[J]. Nutrients, 2024, 16(4):559. doi: 10.3390/nu16040559.