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RESEARCH ARTICLE

Therapeutic mechanisms of metformin and Bushen Ditan Decoction in polycystic ovary syndrome: Evidence from a rat model and miRNA sequencing

Jiayi Xu1† ,  Qianchao Shao1† ,  Hanqing Zhang2 ,  Dan Weng1* ,  Wei Lu2*
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1 Department of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China
2 Department of Gynecology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
JBM, e99010095 https://doi.org/10.14440/jbm.0315
Submitted: 25 September 2025 | Revised: 3 November 2025 | Accepted: 18 November 2025 | Published: 2 January 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Background: Polycystic ovary syndrome (PCOS) represents the most common endocrine disorder afflicting women of reproductive age. PCOS is characterized by hormonal imbalances, metabolic abnormalities, and infertility, yet only limited therapeutic options are available. Metformin and Bushen Ditan Decoction (BDD), a traditional Chinese medicine formula, are commonly used in Western and traditional Chinese medicine, respectively, for treating PCOS. Despite their demonstrated clinical efficacy, the mechanisms underlying their therapeutic effects remain incompletely understood. Objective: This study aimed to investigate the therapeutic mechanisms of metformin and BDD in a PCOS rat model. Methods: PCOS was induced in rats by using the Poretsky method. After model induction, the animals were given metformin (150 mg/kg/day) or BDD (8, 16, or 32 mg/kg/day) via intragastric gavage for 4 weeks. Results: Both metformin and BDD significantly reduced testosterone levels and improved lipid metabolism parameters. MicroRNA (miRNA) sequencing of ovarian tissues identified 18 miRNAs commonly regulated by both treatments, and functional enrichment analysis indicated that these differentially expressed miRNAs are involved in autophagy- and metabolism-related pathways implicated in the pathogenesis of PCOS. Conservation analysis across species highlighted the potential clinical relevance of these findings. Conclusion: This study demonstrated how mechanistically metformin and BDD work on PCOS, particularly through the regulation of autophagy- and metabolism-related pathways, providing insights for their future clinical applications.

Keywords
Polycystic ovary syndrome
Metformin
Traditional Chinese medicine
MicroRNAs
Funding
This study was supported by the National Natural Science Foundation of China under grants 31970897 and 22376100, the Open Project Program of Key Laboratory of Metabolic Engineering and Biosynthesis Technology, Ministry of Industry and Information Technology, Nanjing University of Science and Technology and by the sixth Chinese Medicine Clinical Talents Program in China (2025) No. 256, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine.
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References
  1. Hendriks ML, Ket JC, Hompes PG, Homburg R, Lambalk CB. Why does ovarian surgery in PCOS help? Insight into the endocrine implications of ovarian surgery for ovulation induction in polycystic ovary syndrome. Hum Reprod Update. 2007;13(3):249-264. doi: 10.1093/humupd/dml058

 

  1. Rosenfield RL. Clinical review: Adolescent anovulation: Maturational mechanisms and implications. J Clin Endocrinol Metab. 2013;98(9):3572-3583. doi: 10.1210/jc.2013-1770

 

  1. Parker J, O’Brien C, Uppal T, Tremellen K. Molecular impact of metabolic and endocrine disturbance on endometrial function in polycystic ovary syndrome. Int J Mol Sci. 2025;26(20):9926. doi: 10.3390/ijms26209926

 

  1. Garad R, Shorakae S, Teede H. Assessment and Management of Women with Polycystic Ovary Syndrome (PCOS). In: Advanced Practice in Endocrinology Nursing. Berlin: Springer; 2019.

 

  1. Blank SK, McCartney CR, Marshall JC. The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome. Hum Reprod Update. 2006;12(4):351-361. doi: 10.1093/humupd/dml017

 

  1. Pastor CL, Griffin-Korf ML, Aloi JA, Evans WS, Marshall JC. Polycystic ovary syndrome: Evidence for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab. 1997;83(2):582-590. doi: 10.1210/jcem.83.2.4604

 

  1. Chen MJ, Chou CH, Chen SU, Yang WS, Yang YS, Ho HN. The effect of androgens on ovarian follicle maturation: Dihydrotestosterone suppress FSH-stimulated granulosa cell proliferation by upregulating PPARγ-dependent PTEN expression. Sci Rep. 2015;5:18319. doi: 10.1038/srep18319

 

  1. Du L, Wang Y, Li CR, et al. Rat BAT xenotransplantation recovers the fertility and metabolic health of PCOS mice. J Endocrinol. 2021;248(2):249-264. doi: 10.1530/joe-20-0068

 

  1. Prosperi S, Chiarelli F. Insulin resistance, metabolic syndrome and polycystic ovaries: An intriguing conundrum. Front Endocrinol (Lausanne). 2025;16:1669716. doi: 10.3389/fendo.2025.1669716

 

  1. Liu J, Wu Q, Hao Y, et al. Measuring the global disease burden of polycystic ovary syndrome in 194 countries: Global burden of disease study 2017. Hum Reprod. 2021;36(4):1108-1119. doi: 10.1093/humrep/deaa371

 

  1. Manzoor MF, Tariq T, Fatima B, et al. An insight into bisphenol A, food exposure and its adverse effects on health: A review. Front Nutr. 2022;9:1047827. doi: 10.3389/fnut.2022.1047827

 

  1. Twarda-Clapa A, Olczak A, Białkowska AM, Koziołkiewicz M. Advanced glycation end-products (AGEs): Formation, chemistry, classification, receptors, and diseases related to AGEs. Cells. 2022;11(8):1312. doi: 10.3390/cells11081312

 

  1. Dubey P, Reddy S, Sharma K, Johnson S, Hardy G, Dwivedi AK. Polycystic ovary syndrome, insulin resistance, and cardiovascular disease. Curr Cardiol Rep. 2024;26(6):483-495. doi: 10.1007/s11886-024-02050-5

 

  1. Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: An update on mechanisms and implications. Endocr Rev. 2012;33(6):981-1030. doi: 10.1210/er.2011-1034

 

  1. Dadachanji R, Shaikh N, Mukherjee S. Genetic variants associated with hyperandrogenemia in PCOS pathophysiology. Genet Res Int. 2018;2018:7624932. doi: 10.1155/2018/7624932

 

  1. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352(12):1223-1236. doi: 10.1056/nejmra041536

 

  1. Nisenblat V, Norman RJ. Androgens and polycystic ovary syndrome. Curr Opin Endocrinol Diabetes Obes. 2009;16(3):224-321. doi: 10.1097/MED.0b013e32832afd4d

 

  1. Mora M, Manuel LR, María I, Miriam OO, Escobar-Morreale HF. Circulating markers of oxidative stress and polycystic ovary syndrome (PCOS): A systematic review and meta-analysis. Hum Reprod Update. 2013;19(3):268-288. doi: 10.1093/humupd/dms059

 

  1. Zhang J, Fan P, Liu H, Bai H, Wang Y, Zhang F. Apolipoprotein A-I and B levels, dyslipidemia and metabolic syndrome in South-West Chinese women with PCOS. Hum Reprod. 2012;27(8):2484-2493. doi: 10.1093/humrep/des191

 

  1. Ibáñez L, Potau N, Carrascosa A. Insulin resistance, premature adrenarche, and a risk of the polycystic ovary syndrome (PCOS). Trends Endocrinol Metab. 1998;9(2):72-77. doi: 10.1016/s1043-2760(98)00014-9

 

  1. Utriainen P, Laakso S, Liimatta J, Jääskeläinen J, Voutilainen R. Premature adrenarche--a common condition with variable presentation. Horm Res Pdiatr. 2015;83(4):221. doi: 10.1159/000369458

 

  1. Kai Y, Kawano Y, Yamamoto H, Narahara H. A possible role for AMP-activated protein kinase activated by metformin and AICAR in human granulosa cells. Reprod Biol Endocrinol. 2015;13:27. doi: 10.1186/s12958-015-0023-2

 

  1. Patel R, Shah G. Effect of metformin on clinical, metabolic and endocrine outcomes in women with polycystic ovary syndrome: A meta-analysis of randomized controlled trials. Curr Med Res Opin. 2017;33(9):1545-1557. doi: 10.1080/03007995.2017.1279597

 

  1. Ladson G, Dodson WC, Sweet SD, et al. The effects of metformin with lifestyle therapy in polycystic ovary syndrome: A randomized double-blind study. Fertil Steril. 2011;95(3):1059-1066.e1-e7. doi: 10.1016/j.fertnstert.2010.12.002

 

  1. Palomba S, Orio F Jr., Falbo A, et al. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab. Jul 2005;90(7):4068-4074. doi: 10.1210/jc.2005-0110

 

  1. Attia GR, Rainey WE, Carr BR. Metformin directly inhibits androgen production in human thecal cells. Fertil Steril. 2001;76(3):517-524. doi: 10.1016/s0015-0282(01)01975-6

 

  1. Corton JM, Gillespie JG, Hardie DG. Role of the AMP-activated protein kinase in the cellular stress response. Curr Biol CB. 1994;4(4):315-324. doi: 10.1016/s0960-9822(00)00070-1

 

  1. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167-1174. doi: 10.1172/jci13505

 

  1. Xu J, Zuo Y. Efficacy of acupuncture as adjunctive treatment on infertility patients with polycystic ovary syndrome. Zhongguo Zhen Jiu. 2018;38(4):358-361. doi: 10.13703/j.0255-2930.2018.04.004

 

  1. Jing Z, Liang-Zhi X, Tai-Xiang W, Ying T, Yu-Jian J. The effects of Diane-35 and metformin in treatment of polycystic ovary syndrome: An updated systematic review. Gynecol Endocrinol. 2008;24(10):590-600. doi: 10.1080/09513590802288242

 

  1. Tian S, Zhang D. Shen Jin’ao Yi Xue Quan Shu. Vol. 346. Beijing: China Press of Traditional Chinese Medicine; 1998.

 

  1. Liu C, Chen S. Chen Shiduo Yi Xue Quan Shu. Vol. 887-888. Beijing: China Press of Traditional Chinese Medicine; 1999.

 

  1. Poretsky L, Clemons J, Bogovich K. Hyperinsulinemia and human chorionic gonadotropin synergistically promote the growth of ovarian follicular cysts in rats. Metabolism. 1992;41(8):903-910. doi: 10.1016/0026-0495(92)90175-a

 

  1. Cheng Z. The FoxO-autophagy axis in health and disease. Trends Endocrinol Metab. 2019;30(9):658-671. doi: 10.1016/j.tem.2019.07.009

 

  1. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13(2):132-141. doi: 10.1038/ncb2152

 

  1. Karim MR, Fisher CR, Kapphahn RJ, Polanco JR, Ferrington DA. Investigating AKT activation and autophagy in immunoproteasome-deficient retinal cells. PLoS One. 2020;15(4):e0231212. doi: 10.1371/journal.pone.0231212

 

  1. Wang S, Li J, Du Y, et al. The class I PI3K inhibitor S14161 induces autophagy in malignant blood cells by modulating the Beclin 1/Vps34 complex. J Pharmacol Sci. 2017;134(4): 197-202. doi: 10.1016/j.jphs.2017.07.001

 

  1. Furat Rencber S, Kurnaz Ozbek S, Eraldemır C, et al. Effect of resveratrol and metformin on ovarian reserve and ultrastructure in PCOS: An experimental study. J Ovar Res. 2018;11(1):55. doi: 10.1186/s13048-018-0427-7

 

  1. Zhang S, Tu H, Yao J, et al. Combined use of Diane-35 and metformin improves the ovulation in the PCOS rat model possibly via regulating glycolysis pathway. Reprod Biol Endocrinol. 2020;18(1):58. doi: 10.1186/s12958-020-00613-z

 

  1. Feng W, Jia YY, Zhang DY, Shi HR. Management of polycystic ovarian syndrome with Diane-35 or Diane-35 plus metformin. Gynecol Endocrinol. 2016;32(2):147-150. doi: 10.3109/09513590.2015.1101441

 

  1. Wang H, Cheng L, Ding Y, et al. Research progress of Tradition Chinese medicine in treatment of polycystic ovary syndrome. Jilin J Chin Med. 2018;38(12):1483-1487. doi: 10.13463/j.cnki.jlzyy.2018.12.033

 

  1. Deng C. The effffect off TCM plus acupuncture on polycystic ovarian syndrome withinffertility. Clin J Chin Med. 2018;10(13):28-29. doi: 10.3389/fendo.2023.956772

 

  1. Lu W, Ren Q, Liu S, et al. A clinical study on 90 cases of Bushen Ditan decoction in the treatment of adolescent patients with polycystic ovary syndrome with insulin resistance. J Chin Med Mater. 2018;2018(41(3):730-733.

 

  1. Li X, Ullah I, Hou C, Liu Y, Xiao K. Network pharmacology and molecular docking study on the treatment of polycystic ovary syndrome with angelica sinensis- radix rehmanniae drug pair. Medicine (Baltimore). 2023;102(46):e36118. doi: 10.1097/md.0000000000036118

 

  1. Gong W, Zhang N, Cheng G, et al. Rehmannia glutinosa libosch extracts prevent bone loss and architectural deterioration and enhance osteoblastic bone formation by regulating the IGF-1/ PI3K/mTOR pathway in streptozotocin-induced diabetic rats. Int J Mol Sci. 2019;20(16):3964. doi: 10.3390/ijms20163964

 

  1. Wang YY, Feng WS, Wang QH, Kuang HX. Metabolomic profiling reveals blood-tonifying effect of Rehmanniae Radix Praeparata based on theory of activating spleen and generating blood. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China J Chin Mater Med. 2022;47(13):3562-3568.doi: 10.19540/j.cnki.cjcmm.202220220322.401

 

  1. Kakoly NS, Khomami MB, Joham AE, et al. Ethnicity, obesity and the prevalence of impaired glucose tolerance and type 2 diabetes in PCOS: A systematic review and meta-regression. Hum Reprod Update. 2018;24(4):455-467. doi: 10.1093/humupd/dmy007

 

  1. Azziz R. Polycystic ovary syndrome. Obstet Gynecol. 2018;132(2):321-336. doi: 10.1097/aog.0000000000002698

 

  1. Zhu T, Cui J, Goodarzi MO. Polycystic ovary syndrome and Risk of type 2 diabetes, coronary heart disease, and stroke. Diabetes. 2021;70(2):627-637. doi: 10.2337/db20-0800

 

  1. Mizushima N, Komatsu M. Autophagy: Renovation of cells and tissues. Cell. 2011;147(4):728-741. doi: 10.1016/j.cell.2011.10.026

 

  1. Wong YC, Holzbaur EL. Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc Natl Acad Sci U S A. 2014;111(42):E4439-e4448. doi: 10.1073/pnas.1405752111

 

  1. McLendon PM, Ferguson BS, Osinska H, et al. Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy. Proc Natl Acad Sci U S A. 2014;111(48):E5178-E5186. doi: 10.1073/pnas.1415589111

 

  1. Chen M, Hong MJ, Sun H, et al. Essential role for autophagy in the maintenance of immunological memory against influenza infection. Nat Med. 2014;20(5):503-510. doi: 10.1038/nm.3521

 

  1. Sarparanta J, García-Macia M, Singh R. Autophagy and mitochondria in obesity and type 2 diabetes. Curr Diabet Rev. 2017;13(4):352-369. doi: 10.2174/1573399812666160217122530

 

  1. Mao Y, Yu F, Wang J, Guo C, Fan X. Autophagy: A new target for nonalcoholic fatty liver disease therapy. Hepat Med Evid Res. 2016;8:27-37. doi: 10.2147/hmer.S98120

 

  1. Kumariya S, Ubba V, Jha RK, Gayen JR. Autophagy in ovary and polycystic ovary syndrome: Role, dispute and future perspective. Autophagy. 2021;17(10):2706-2733. doi: 10.1080/15548627.2021.1938914

 

  1. Amaravadi RK, Lippincott-Schwartz J, Yin XM, et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin Cancer Res. 2011;17(4):654-666. doi: 10.1158/1078-0432.Ccr-10-2634

 

  1. Park J, Shin H, Song H, Lim HJ. Autophagic regulation in steroid hormone-responsive systems. Steroids. 2016;115: 177-181. doi: 10.1016/j.steroids.2016.09.011

 

  1. Nakashima A, Aoki A, Kusabiraki T, et al. Role of autophagy in oocytogenesis, embryogenesis, implantation, and pathophysiology of pre-eclampsia. J Obstetr Gynaecol Res. 2017;43(4):633-643. doi: 10.1111/jog.13292

 

  1. Ren H, Shao Y, Wu C, Ma X, Lv C, Wang Q. Metformin alleviates oxidative stress and enhances autophagy in diabetic kidney disease via AMPK/SIRT1-FoxO1 pathway. Mol Cell Endocrinol. 2020;500:110628. doi: 10.1016/j.mce.2019.110628
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Journal of Biological Methods, Electronic ISSN: 2326-9901 Print ISSN: TBA, Published by POL Scientific
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