SpringerLink
Log in

Insights on the NF-κB system in polycystic ovary syndrome, attractive therapeutic targets

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The nuclear factor κappa B (NF-κB) signaling plays a well-known function in inflammation and regulates a wide variety of biological processes. Low-grade chronic inflammation is gradually considered to be closely related to the pathogenesis of Polycystic ovary syndrome (PCOS). In this review, we provide an overview on the involvement of NF-κB in the progression of PCOS particularly, such as hyperandrogenemia, insulin resistance, cardiovascular diseases, and endometrial dysfunction. From a clinical perspective, progressive recognition of NF-κB pathway provides opportunities for therapeutic interventions aimed at inhibiting pathway-specific mechanisms. With the accumulation of basic experimental and clinical data, NF-κB signaling pathway was recognized as a therapeutic target. Although there have been no specific small molecule NF-κB inhibitors in PCOS, a plethora of natural and synthetic compound have emerged for the pharmacologic intervention of the pathway. The traditional herbs developed for NF-κB pathway have become increasingly popular in recent years. Abundant evidence elucidated that NF-κB inhibitors can significantly improve the symptoms of PCOS. Herein, we summarized evidence relating to how NF-κB pathway is involved in the development and progression of PCOS. Furthermore, we present an in-depth overview of NF-κB inhibitors for therapy interventions of PCOS. Taken together, the NF-κB signaling may be a futuristic treatment strategy for PCOS.

Graphical abstract

NF-κB affects various aspects of polycystic ovary syndrome, such as hyperandrogenemia, insulin resistance, cardiovascular diseases, endometrial dysfunction, and hypothalamic endocrine gonadal axis disorder.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

Not applicable.

Abbreviations

PCOS:

Polycystic ovary syndrome

NF-κB:

Nuclear factor-κappa B

IκB:

Inhibitory κappa B

IKK:

IκB kinase

TBK1:

TANK-binding kinase 1

TNF:

Tumor necrosis factor

NIK:

NF-κB inducing kinase

NEMO:

NF-κB essential modulator

PRRs:

Pattern-recognition receptors

TCR:

T-cell receptor

BCR:

B-cell receptor

TLR:

Toll-like receptors

IL-1:

Interleukin-1

TIRAP:

Toll/interleukin receptor adaptor protein

TRAM:

TRIF-related adaptor molecule

MyD88:

Myeloid differentiation primary response gene 88

IRAK:

Interleukin-1 receptor-associated kinase

TRAF6:

Tumor Necrosis Factor receptor-associated factor 6

TAK1:

Transforming growth factor-β activated kinase 1

TNFR1:

Tumor necrosis factor receptor 1

TRADD:

TNFR-associated death domain

cIAP:

Cellular inhibitor of apoptosis

AR:

Androgen receptor

MCP-1:

Macrophage chemotactic protein-1

GnRH:

Gonadotropin-releasing hormone

LDL:

Low-density lipoprotein

ICAM-1:

Intercellular adhesion molecule-1

VCAM-1:

Vascular adhesion molecule-1

eNOS:

Endothelial nitric oxide synthase

FSH:

Follicle-stimulating hormones

LH:

Luteinizing hormone

IFN:

Interferon

T:

Testosterone

EC:

Endothelial cell

References

  1. Joham AE, Norman RJ, Stener-Victorin E, Legro RS, Franks S, Moran LJ, Boyle J, Teede HJ (2022) Polycystic ovary syndrome. Lancet Diabetes Endocrinol 10(9):668–680. https://doi.org/10.1016/S2213-8587(22)00163-2

    Article  CAS  PubMed  Google Scholar 

  2. Alesi S, Ee C, Moran LJ, Rao V, Mousa A (2022) Nutritional supplements and complementary therapies in polycystic ovary syndrome. Adv Nutr 13(4):1243–1266. https://doi.org/10.1093/advances/nmab141

    Article  CAS  PubMed  Google Scholar 

  3. Cooney LG, Lee I, Sammel MD, Dokras A (2017) High prevalence of moderate and severe depressive and anxiety symptoms in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod 32(5):1075–1091. https://doi.org/10.1093/humrep/dex044

    Article  PubMed  Google Scholar 

  4. Kakoly NS, Earnest A, Teede HJ, Moran LJ, Joham AE (2019) The impact of obesity on the incidence of type 2 diabetes among women with polycystic ovary syndrome. Diabetes Care 42(4):560–567. https://doi.org/10.2337/dc18-1738

    Article  PubMed  Google Scholar 

  5. Joham AE, Piltonen T, Lujan ME, Kiconco S, Tay CT (2022) Challenges in diagnosis and understanding of natural history of polycystic ovary syndrome. Clin Endocrinol (Oxf) 97(2):165–173. https://doi.org/10.1111/cen.14757

    Article  PubMed  Google Scholar 

  6. Hoeger KM, Dokras A, Piltonen T (2021) Update on PCOS: consequences, challenges, and guiding treatment. J Clin Endocrinol Metab 106(3):e1071–e1083. https://doi.org/10.1210/clinem/dgaa839

    Article  PubMed  Google Scholar 

  7. Defrere S, Gonzalez-Ramos R, Lousse JC, Colette S, Donnez O, Donnez J, Van Langendonckt A (2011) Insights into iron and nuclear factor-kappa B (NF-kappaB) involvement in chronic inflammatory processes in peritoneal endometriosis. Histol Histopathol 26(8):1083–1092. https://doi.org/10.14670/HH-26.1083

    Article  CAS  PubMed  Google Scholar 

  8. Huang Z, Du G, Huang X, Han L, Han X, Xu B, Zhang Y, Yu M, Qin Y, **a Y et al (2018) The enhancer RNA lnc-SLC4A1-1 epigenetically regulates unexplained recurrent pregnancy loss (URPL) by activating CXCL8 and NF-kB pathway. EBioMedicine 38:162–170. https://doi.org/10.1016/j.ebiom.2018.11.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gou Y, Li X, Li P, Zhang H, Xu T, Wang H, Wang B, Ma X, Jiang X, Zhang Z (2019) Estrogen receptor beta upregulates CCL2 via NF-kappaB signaling in endometriotic stromal cells and recruits macrophages to promote the pathogenesis of endometriosis. Hum Reprod 34(4):646–658. https://doi.org/10.1093/humrep/dez019

    Article  CAS  PubMed  Google Scholar 

  10. Harrington BS, Annunziata CM (2019) NF-kappaB signaling in ovarian cancer. Cancers (Basel) 11(8):1182. https://doi.org/10.3390/cancers11081182

    Article  CAS  PubMed  Google Scholar 

  11. Liu M, Gao J, Zhang Y, Li P, Wang H, Ren X, Li C (2015) Serum levels of TSP-1, NF-kappaB and TGF-beta1 in polycystic ovarian syndrome (PCOS) patients in northern China suggest PCOS is associated with chronic inflammation. Clin Endocrinol (Oxf) 83(6):913–922. https://doi.org/10.1111/cen.12951

    Article  CAS  PubMed  Google Scholar 

  12. Diamanti-Kandarakis E, Piperi C, Patsouris E, Korkolopoulou P, Panidis D, Pawelczyk L, Papavassiliou AG, Duleba AJ (2007) Immunohistochemical localization of advanced glycation end-products (AGEs) and their receptor (RAGE) in polycystic and normal ovaries. Histochem Cell Biol 127(6):581–589. https://doi.org/10.1007/s00418-006-0265-3

    Article  CAS  PubMed  Google Scholar 

  13. Hu M, Zhang Y, Li X, Cui P, Sferruzzi-Perri AN, Brannstrom M, Shao LR, Billig H (2021) TLR4-Associated IRF-7 and NFkappaB signaling act as a molecular link between androgen and metformin activities and cytokine synthesis in the PCOS endometrium. J Clin Endocrinol Metab 106(4):1022–1040. https://doi.org/10.1210/clinem/dgaa951

    Article  PubMed  Google Scholar 

  14. Tan BK, Adya R, Chen J, Lehnert H, Sant Cassia LJ, Randeva HS (2011) Metformin treatment exerts antiinvasive and antimetastatic effects in human endometrial carcinoma cells. J Clin Endocrinol Metab 96(3):808–816. https://doi.org/10.1210/jc.2010-1803

    Article  CAS  PubMed  Google Scholar 

  15. Malin SK, Kirwan JP, Sia CL, Gonzalez F (2015) Pancreatic beta-cell dysfunction in polycystic ovary syndrome: role of hyperglycemia-induced nuclear factor-kappaB activation and systemic inflammation. Am J Physiol Endocrinol Metab 308(9):E770-777. https://doi.org/10.1152/ajpendo.00510.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pahl HL (1999) Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18(49):6853–6866. https://doi.org/10.1038/sj.onc.1203239

    Article  CAS  PubMed  Google Scholar 

  17. Mitchell S, Vargas J, Hoffmann A (2016) Signaling via the NFkappaB system. Wiley Interdiscip Rev Syst Biol Med 8(3):227–241. https://doi.org/10.1002/wsbm.1331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Prescott JA, Mitchell JP, Cook SJ (2021) Inhibitory feedback control of NF-kappaB signalling in health and disease. Biochem J 478(13):2619–2664. https://doi.org/10.1042/BCJ20210139

    Article  CAS  PubMed  Google Scholar 

  19. Mulero MC, Huxford T, Ghosh G (2019) NF-kappaB, IkappaB, and IKK: integral components of immune system signaling. Adv Exp Med Biol 1172:207–226. https://doi.org/10.1007/978-981-13-9367-9_10

    Article  CAS  PubMed  Google Scholar 

  20. MaruYama T (2015) The nuclear IkappaB family of proteins controls gene regulation and immune homeostasis. Int Immunopharmacol 28(2):836–840. https://doi.org/10.1016/j.intimp.2015.03.053

    Article  CAS  PubMed  Google Scholar 

  21. Annemann M, Plaza-Sirvent C, Schuster M, Katsoulis-Dimitriou K, Kliche S, Schraven B, Schmitz I (2016) Atypical IkappaB proteins in immune cell differentiation and function. Immunol Lett 171:26–35. https://doi.org/10.1016/j.imlet.2016.01.006

    Article  CAS  PubMed  Google Scholar 

  22. Wang X, Peng H, Huang Y, Kong W, Cui Q, Du J, ** H (2020) Post-translational Modifications of IkappaBalpha: the state of the art. Front Cell Dev Biol 8:574706. https://doi.org/10.3389/fcell.2020.574706

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hinz M, Arslan SC, Scheidereit C (2012) It takes two to tango: IkappaBs, the multifunctional partners of NF-kappaB. Immunol Rev 246(1):59–76. https://doi.org/10.1111/j.1600-065X.2012.01102.x

    Article  CAS  PubMed  Google Scholar 

  24. Chiba T, Inoko H, Kimura M, Sato T (2013) Role of nuclear IkappaBs in inflammation regulation. Biomol Concepts 4(2):187–196. https://doi.org/10.1515/bmc-2012-0039

    Article  CAS  PubMed  Google Scholar 

  25. Prescott JA, Cook SJ (2018) Targeting IKKbeta in cancer: challenges and opportunities for the therapeutic utilisation of IKKbeta inhibitors. Cells 7(9):115. https://doi.org/10.3390/cells7090115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Goktuna SI, Diamanti MA, Chau TL (2018) IKKs and tumor cell plasticity. FEBS J 285(12):2161–2181. https://doi.org/10.1111/febs.14444

    Article  CAS  PubMed  Google Scholar 

  27. Antonia RJ, Hagan RS, Baldwin AS (2021) Expanding the view of IKK: new substrates and new biology. Trends Cell Biol 31(3):166–178. https://doi.org/10.1016/j.tcb.2020.12.003

    Article  CAS  PubMed  Google Scholar 

  28. Li X, Hu Y (2021) Attribution of NF-kappaB activity to CHUK/IKKalpha-involved carcinogenesis. Cancers (Basel) 13(6):1411. https://doi.org/10.3390/cancers13061411

    Article  CAS  PubMed  Google Scholar 

  29. Awasthee N, Rai V, Chava S, Nallasamy P, Kunnumakkara AB, Bishayee A, Chauhan SC, Challagundla KB, Gupta SC (2019) Targeting IkappaappaB kinases for cancer therapy. Semin Cancer Biol 56:12–24. https://doi.org/10.1016/j.semcancer.2018.02.007

    Article  CAS  PubMed  Google Scholar 

  30. ** J, **ao Y, Chang JH, Yu J, Hu H, Starr R, Brittain GC, Chang M, Cheng X, Sun SC (2020) Author correction: the kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-kappaB signaling. Nat Immunol 21(9):1134. https://doi.org/10.1038/s41590-020-0748-8

    Article  CAS  PubMed  Google Scholar 

  31. Sun SC (2017) The non-canonical NF-kappaB pathway in immunity and inflammation. Nat Rev Immunol 17(9):545–558. https://doi.org/10.1038/nri.2017.52

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yu H, Lin L, Zhang Z, Zhang H, Hu H (2020) Targeting NF-kappaB pathway for the therapy of diseases: mechanism and clinical study. Signal Transduct Target Ther 5(1):209. https://doi.org/10.1038/s41392-020-00312-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34(5):637–650. https://doi.org/10.1016/j.immuni.2011.05.006

    Article  CAS  PubMed  Google Scholar 

  34. Walsh MC, Lee J, Choi Y (2015) Tumor necrosis factor receptor- associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system. Immunol Rev 266(1):72–92. https://doi.org/10.1111/imr.12302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang W, Gao W, Zhu Q, Alasbahi A, Seki E, Yang L (2021) TAK1: a molecular link between liver inflammation, fibrosis, steatosis, and carcinogenesis. Front Cell Dev Biol. 9:734749. https://doi.org/10.3389/fcell.2021.734749

    Article  PubMed  PubMed Central  Google Scholar 

  36. Kracht M, Muller-Ladner U, Schmitz ML (2020) Mutual regulation of metabolic processes and proinflammatory NF-kappaB signaling. J Allergy Clin Immunol 146(4):694–705. https://doi.org/10.1016/j.jaci.2020.07.027

    Article  CAS  PubMed  Google Scholar 

  37. Napetschnig J, Wu H (2013) Molecular basis of NF-kappaB signaling. Annu Rev Biophys 42:443–468. https://doi.org/10.1146/annurev-biophys-083012-130338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gaud G, Lesourne R, Love PE (2018) Regulatory mechanisms in T cell receptor signalling. Nat Rev Immunol 18(8):485–497. https://doi.org/10.1038/s41577-018-0020-8

    Article  CAS  PubMed  Google Scholar 

  39. Kwak K, Akkaya M, Pierce SK (2019) B cell signaling in context. Nat Immunol 20(8):963–969. https://doi.org/10.1038/s41590-019-0427-9

    Article  CAS  PubMed  Google Scholar 

  40. O’Neill LA (2008) The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol Rev 226:10–18. https://doi.org/10.1111/j.1600-065X.2008.00701.x

    Article  CAS  PubMed  Google Scholar 

  41. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11(10):700–714. https://doi.org/10.1038/nrm2970

    Article  CAS  PubMed  Google Scholar 

  42. Liu Y, Liu T, Lei T, Zhang D, Du S, Girani L, Qi D, Lin C, Tong R, Wang Y (2019) RIP1/RIP3-regulated necroptosis as a target for multifaceted disease therapy (Review). Int J Mol Med 44(3):771–786. https://doi.org/10.3892/ijmm.2019.4244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tegowski M, Baldwin A (2018) Noncanonical NF-kappaB in Cancer. Biomedicines 6(2):66. https://doi.org/10.3390/biomedicines6020066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ramakrishnan P, Wang W, Wallach D (2004) Receptor-specific signaling for both the alternative and the canonical NF-kappaB activation pathways by NF-kappaB-inducing kinase. Immunity 21(4):477–489. https://doi.org/10.1016/j.immuni.2004.08.009

    Article  CAS  PubMed  Google Scholar 

  45. McPherson AJ, Snell LM, Mak TW, Watts TH (2012) Opposing roles for TRAF1 in the alternative versus classical NF-kappaB pathway in T cells. J Biol Chem 287(27):23010–23019. https://doi.org/10.1074/jbc.M112.350538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. ** J, Hu H, Li HS, Yu J, **ao Y, Brittain GC, Zou Q, Cheng X, Mallette FA, Watowich SS et al (2014) Noncanonical NF-kappaB pathway controls the production of type I interferons in antiviral innate immunity. Immunity 40(3):342–354. https://doi.org/10.1016/j.immuni.2014.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nishikori M, Ohno H, Haga H, Uchiyama T (2005) Stimulation of CD30 in anaplastic large cell lymphoma leads to production of nuclear factor-kappaB p52, which is associated with hyperphosphorylated Bcl-3. Cancer Sci 96(8):487–497. https://doi.org/10.1111/j.1349-7006.2005.00078.x

    Article  CAS  PubMed  Google Scholar 

  48. **ao G, Harhaj EW, Sun SC (2001) NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell 7(2):401–409. https://doi.org/10.1016/s1097-2765(01)00187-3

    Article  CAS  PubMed  Google Scholar 

  49. Tilborghs S, Corthouts J, Verhoeven Y, Arias D, Rolfo C, Trinh XB, van Dam PA (2017) The role of nuclear factor-kappa B signaling in human cervical cancer. Crit Rev Oncol Hematol 120:141–150. https://doi.org/10.1016/j.critrevonc.2017.11.001

    Article  PubMed  Google Scholar 

  50. Zhou YY, He CH, Lan H, Dong ZW, Wu YQ, Song JL (2022) Rhamnocitrin decreases fibrosis of ovarian granulosa cells by regulating the activation of the PPARgamma/NF-kappaB/TGF-beta1/Smad2/3 signaling pathway mediated by Wisp2. Ann Transl Med 10(14):789. https://doi.org/10.21037/atm-22-2496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lizneva D, Gavrilova-Jordan L, Walker W, Azziz R (2016) Androgen excess: Investigations and management. Best Pract Res Clin Obstet Gynaecol 37:98–118. https://doi.org/10.1016/j.bpobgyn.2016.05.003

    Article  PubMed  Google Scholar 

  52. Lang Q, Yidong X, Xueguang Z, Sixian W, Wenming X, Tao Z (2019) ETA-mediated anti-TNF-alpha therapy ameliorates the phenotype of PCOS model induced by letrozole. PLoS ONE 14(6):e0217495. https://doi.org/10.1371/journal.pone.0217495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. He Z, Wang Y, Zhuan L, Li Y, Tang ZO, Wu Z, Ma Y (2021) MIF-mediated NF-kappaB signaling pathway regulates the pathogenesis of polycystic ovary syndrome in rats. Cytokine 146:155632. https://doi.org/10.1016/j.cyto.2021.155632

    Article  CAS  PubMed  Google Scholar 

  54. Su C, Chen M, Huang H, Lin J (2015) Testosterone enhances lipopolysaccharide-induced interleukin-6 and macrophage chemotactic protein-1 expression by activating the extracellular signal-regulated kinase 1/2/nuclear factor-kappaB signalling pathways in 3T3-L1 adipocytes. Mol Med Rep 12(1):696–704. https://doi.org/10.3892/mmr.2015.3401

    Article  CAS  PubMed  Google Scholar 

  55. Sumaiya K, Langford D, Natarajaseenivasan K, Shanmughapriya S (2022) Macrophage migration inhibitory factor (MIF): A multifaceted cytokine regulated by genetic and physiological strategies. Pharmacol Ther 233:108024. https://doi.org/10.1016/j.pharmthera.2021.108024

    Article  CAS  PubMed  Google Scholar 

  56. Bernhagen J, Krohn R, Lue H, Gregory JL, Zernecke A, Koenen RR, Dewor M, Georgiev I, Schober A, Leng L et al (2007) MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med 13(5):587–596. https://doi.org/10.1038/nm1567

    Article  CAS  PubMed  Google Scholar 

  57. Takahashi K, Mizuarai S, Araki H, Mashiko S, Ishihara A, Kanatani A, Itadani H, Kotani H (2003) Adiposity elevates plasma MCP-1 levels leading to the increased CD11b-positive monocytes in mice. J Biol Chem 278(47):46654–46660. https://doi.org/10.1074/jbc.M309895200

    Article  CAS  PubMed  Google Scholar 

  58. Gonzalez F, Rote NS, Minium J, Kirwan JP (2006) Increased activation of nuclear factor kappaB triggers inflammation and insulin resistance in polycystic ovary syndrome. J Clin Endocrinol Metab 91(4):1508–1512. https://doi.org/10.1210/jc.2005-2327

    Article  CAS  PubMed  Google Scholar 

  59. Gonzalez F, Rote NS, Minium J, Kirwan JP (2009) Evidence of proatherogenic inflammation in polycystic ovary syndrome. Metabolism 58(7):954–962. https://doi.org/10.1016/j.metabol.2009.02.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang D, Weng Y, Zhang Y, Wang R, Wang T, Zhou J, Shen S, Wang H, Wang Y (2020) Exposure to hyperandrogen drives ovarian dysfunction and fibrosis by activating the NLRP3 inflammasome in mice. Sci Total Environ 745:141049. https://doi.org/10.1016/j.scitotenv.2020.141049

    Article  CAS  PubMed  Google Scholar 

  61. Meakin AS, Gough M, Saif Z, Clifton VL (2022) An ex vivo approach to understanding sex-specific differences in placental androgen signalling in the presence and absence of inflammation. Placenta 120:49–58. https://doi.org/10.1016/j.placenta.2022.02.010

    Article  CAS  PubMed  Google Scholar 

  62. Fox CW, Zhang L, Sohni A, Doblado M, Wilkinson MF, Chang RJ, Duleba AJ (2019) Inflammatory stimuli trigger increased androgen production and shifts in gene expression in theca-interstitial cells. Endocrinology 160(12):2946–2958. https://doi.org/10.1210/en.2019-00588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhao J, Tan Y, Feng Z, Zhou Y, Wang F, Zhou G, Yan J, Nie X (2022) Catalpol attenuates polycystic ovarian syndrome by regulating sirtuin 1 mediated NF-kappaB signaling pathway. Reprod Biol 22(3):100671. https://doi.org/10.1016/j.repbio.2022.100671

    Article  CAS  PubMed  Google Scholar 

  64. Tosi F, Bonora E, Moghetti P (2017) Insulin resistance in a large cohort of women with polycystic ovary syndrome: a comparison between euglycaemic-hyperinsulinaemic clamp and surrogate indexes. Hum Reprod 32(12):2515–2521. https://doi.org/10.1093/humrep/dex308

    Article  CAS  PubMed  Google Scholar 

  65. Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11(2):191–198. https://doi.org/10.1038/nm1185

    Article  CAS  PubMed  Google Scholar 

  66. Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11(2):183–190. https://doi.org/10.1038/nm1166

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. He F, Huang Y, Song Z, Zhou HJ, Zhang H, Perry RJ, Shulman GI, Min W (2021) Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance. J Exp Med 218(3):e20201416. https://doi.org/10.1084/jem.20201416

    Article  CAS  PubMed  Google Scholar 

  68. Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11(2):98–107. https://doi.org/10.1038/nri2925

    Article  CAS  PubMed  Google Scholar 

  69. Kleinridders A, Schenten D, Konner AC, Belgardt BF, Mauer J, Okamura T, Wunderlich FT, Medzhitov R, Bruning JC (2009) MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab 10(4):249–259. https://doi.org/10.1016/j.cmet.2009.08.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Davis JE, Gabler NK, Walker-Daniels J, Spurlock ME (2008) Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Obesity (Silver Spring) 16(6):1248–1255. https://doi.org/10.1038/oby.2008.210

    Article  CAS  PubMed  Google Scholar 

  71. Guo Z, Zhang Y, Liu C, Youn JY, Cai H (2021) Toll-Like Receptor 2 (TLR2) Knockout Abrogates Diabetic and Obese Phenotypes While Restoring Endothelial Function via Inhibition of NOX1. Diabetes 70(9):2107–2119. https://doi.org/10.2337/db20-0591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D (2008) Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135(1):61–73. https://doi.org/10.1016/j.cell.2008.07.043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wunderlich FT, Luedde T, Singer S, Schmidt-Supprian M, Baumgartl J, Schirmacher P, Pasparakis M, Bruning JC (2008) Hepatic NF-kappa B essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proc Natl Acad Sci U S A 105(4):1297–1302. https://doi.org/10.1073/pnas.0707849104

    Article  PubMed  PubMed Central  Google Scholar 

  74. Chiang SH, Bazuine M, Lumeng CN, Geletka LM, Mowers J, White NM, Ma JT, Zhou J, Qi N, Westcott D et al (2009) The protein kinase IKKepsilon regulates energy balance in obese mice. Cell 138(5):961–975. https://doi.org/10.1016/j.cell.2009.06.046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhao P, Wong KI, Sun X, Reilly SM, Uhm M, Liao Z, Skorobogatko Y, Saltiel AR (2018) TBK1 at the crossroads of inflammation and energy homeostasis in adipose tissue. Cell 172(4):731–743. https://doi.org/10.1016/j.cell.2018.01.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Aguayo-Mazzucato C, Andle J, Lee TB Jr, Midha A, Talemal L, Chipashvili V, Hollister-Lock J, van Deursen J, Weir G, Bonner-Weir S (2019) Acceleration of beta cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab 30(1):129–142. https://doi.org/10.1016/j.cmet.2019.05.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hudish LI, Reusch JE, Sussel L (2019) beta Cell dysfunction during progression of metabolic syndrome to type 2 diabetes. J Clin Invest 129(10):4001–4008. https://doi.org/10.1172/JCI129188

    Article  PubMed  PubMed Central  Google Scholar 

  78. Gonzalez F, Nair KS, Daniels JK, Basal E, Schimke JM, Blair HE (2012) Hyperandrogenism sensitizes leukocytes to hyperglycemia to promote oxidative stress in lean reproductive-age women. J Clin Endocrinol Metab 97(8):2836–2843. https://doi.org/10.1210/jc.2012-1259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Gonzalez F, Nair KS, Daniels JK, Basal E, Schimke JM (2012) Hyperandrogenism sensitizes mononuclear cells to promote glucose-induced inflammation in lean reproductive-age women. Am J Physiol Endocrinol Metab 302(3):E297-306. https://doi.org/10.1152/ajpendo.00416.2011

    Article  CAS  PubMed  Google Scholar 

  80. Gonzalez F, Rote NS, Minium J, Kirwan JP (2006) Reactive oxygen species-induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome. J Clin Endocrinol Metab 91(1):336–340. https://doi.org/10.1210/jc.2005-1696

    Article  CAS  PubMed  Google Scholar 

  81. Westwell-Roper C, Nackiewicz D, Dan M, Ehses JA (2014) Toll-like receptors and NLRP3 as central regulators of pancreatic islet inflammation in type 2 diabetes. Immunol Cell Biol 92(4):314–323. https://doi.org/10.1038/icb.2014.4

    Article  CAS  PubMed  Google Scholar 

  82. Palomba S, Piltonen TT, Giudice LC (2021) Endometrial function in women with polycystic ovary syndrome: a comprehensive review. Hum Reprod Update 27(3):584–618. https://doi.org/10.1093/humupd/dmaa051

    Article  CAS  PubMed  Google Scholar 

  83. Xue Z, Li J, Feng J, Han H, Zhao J, Zhang J, Han Y, Wu X, Zhang Y (2021) Research progress on the mechanism between polycystic ovary syndrome and abnormal endometrium. Front Physiol 12:788772. https://doi.org/10.3389/fphys.2021.788772

    Article  PubMed  PubMed Central  Google Scholar 

  84. Eisman LE, Pisarska MD, Wertheimer S, Chan JL, Akopians AL, Surrey MW, Danzer HC, Ghadir S, Chang WY, Alexander CJ et al (2021) Clinical utility of the endometrial receptivity analysis in women with prior failed transfers. J Assist Reprod Genet 38(3):645–650. https://doi.org/10.1007/s10815-020-02041-9

    Article  PubMed  PubMed Central  Google Scholar 

  85. Meczekalski B, Perez-Roncero GR, Lopez-Baena MT, Chedraui P, Perez-Lopez FR (2020) The polycystic ovary syndrome and gynecological cancer risk. Gynecol Endocrinol 36(4):289–293. https://doi.org/10.1080/09513590.2020.1730794

    Article  CAS  PubMed  Google Scholar 

  86. Amjadi F, Mehdizadeh M, Ashrafi M, Nasrabadi D, Taleahmad S, Mirzaei M, Gupta V, Salekdeh GH, Aflatoonian R (2018) Distinct changes in the proteome profile of endometrial tissues in polycystic ovary syndrome compared with healthy fertile women. Reprod Biomed Online 37(2):184–200. https://doi.org/10.1016/j.rbmo.2018.04.043

    Article  CAS  PubMed  Google Scholar 

  87. Hu M, Zhang Y, Guo X, Jia W, Liu G, Zhang J, Cui P, Li J, Li W, Wu X et al (2019) Perturbed ovarian and uterine glucocorticoid receptor signaling accompanies the balanced regulation of mitochondrial function and NFkappaB-mediated inflammation under conditions of hyperandrogenism and insulin resistance. Life Sci 232:116681. https://doi.org/10.1016/j.lfs.2019.116681

    Article  CAS  PubMed  Google Scholar 

  88. Zhang Y, Hu M, Meng F, Sun X, Xu H, Zhang J, Cui P, Morina N, Li X, Li W et al (2017) Metformin ameliorates uterine defects in a rat model of polycystic ovary syndrome. EBioMedicine 18:157–170. https://doi.org/10.1016/j.ebiom.2017.03.023

    Article  PubMed  PubMed Central  Google Scholar 

  89. Koc O, Ozdemirici S, Acet M, Soyturk U, Aydin S (2017) Nuclear factor-kappaB expression in the endometrium of normal and overweight women with polycystic ovary syndrome. J Obstet Gynaecol 37(7):924–930. https://doi.org/10.1080/01443615.2017.1315563

    Article  CAS  PubMed  Google Scholar 

  90. Paravati R, De Mello N, Onyido EK, Francis LW, Brusehafer K, Younas K, Spencer-Harty S, Conlan RS, Gonzalez D, Margarit L (2020) Differential regulation of osteopontin and CD44 correlates with infertility status in PCOS patients. J Mol Med (Berl) 98(12):1713–1725. https://doi.org/10.1007/s00109-020-01985-w

    Article  CAS  PubMed  Google Scholar 

  91. Ha LX, Wu YY, Yin T, Yuan YY, Du YD (2021) Effect of TNF-alpha on endometrial glucose transporter-4 expression in patients with polycystic ovary syndrome through nuclear factor-kappa B signaling pathway activation. J Physiol Pharmacol 72(6):1. https://doi.org/10.26402/jpp.2021.6.13

    Article  CAS  Google Scholar 

  92. Ibanez L, Oberfield SE, Witchel S, Auchus RJ, Chang RJ, Codner E, Dabadghao P, Darendeliler F, Elbarbary NS, Gambineri A et al (2017) An International consortium update: pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Horm Res Paediatr 88(6):371–395. https://doi.org/10.1159/000479371

    Article  CAS  PubMed  Google Scholar 

  93. Harter CJL, Kavanagh GS, Smith JT (2018) The role of kisspeptin neurons in reproduction and metabolism. J Endocrinol 238(3):R173–R183. https://doi.org/10.1530/JOE-18-0108

    Article  CAS  PubMed  Google Scholar 

  94. Patel R, Smith JT (2020) Novel actions of kisspeptin signaling outside of GnRH-mediated fertility: a potential role in energy balance. Domest Anim Endocrinol 73:106467. https://doi.org/10.1016/j.domaniend.2020.106467

    Article  CAS  PubMed  Google Scholar 

  95. Olaniyi KS, Areloegbe SE, Oyeleke MB (2022) Acetate restores hypothalamic-adipose kisspeptin status in a rat model of PCOS by suppression of NLRP3 immunoreactivity. Endocrine 78(3):628–640. https://doi.org/10.1007/s12020-022-03191-9

    Article  CAS  PubMed  Google Scholar 

  96. Liu H, **e J, Fan L, **a Y, Peng X, Zhou J, Ni X (2022) Cryptotanshinone protects against PCOS-induced damage of ovarian tissue via regulating oxidative stress, mitochondrial membrane potential, inflammation, and apoptosis via regulating ferroptosis. Oxid Med Cell Longev 2022:8011850. https://doi.org/10.1155/2022/8011850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yang Y, Yang L, Qi C, Hu G, Wang L, Sun Z, Ni X (2020) Cryptotanshinone alleviates polycystic ovary syndrome in rats by regulating the HMGB1/TLR4/NFkappaB signaling pathway. Mol Med Rep 22(5):3851–3861. https://doi.org/10.3892/mmr.2020.11469

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Brenjian S, Moini A, Yamini N, Kashani L, Faridmojtahedi M, Bahramrezaie M, Khodarahmian M, Amidi F (2020) Resveratrol treatment in patients with polycystic ovary syndrome decreased pro-inflammatory and endoplasmic reticulum stress markers. Am J Reprod Immunol 83(1):e13186. https://doi.org/10.1111/aji.13186

    Article  PubMed  Google Scholar 

  99. Okoth K, Chandan JS, Marshall T, Thangaratinam S, Thomas GN, Nirantharakumar K, Adderley NJ (2020) Association between the reproductive health of young women and cardiovascular disease in later life: umbrella review. BMJ 371:m3502. https://doi.org/10.1136/bmj.m3502

    Article  PubMed  PubMed Central  Google Scholar 

  100. Oliver-Williams C, Vassard D, Pinborg A, Schmidt L (2020) Risk of cardiovascular disease for women with polycystic ovary syndrome: results from a national Danish registry cohort study. Eur J Prev Cardiol 2020:2047487320939674. https://doi.org/10.1177/2047487320939674

    Article  Google Scholar 

  101. Glintborg D, Rubin KH, Nybo M, Abrahamsen B, Andersen M (2018) Cardiovascular disease in a nationwide population of Danish women with polycystic ovary syndrome. Cardiovasc Diabetol 17(1):37. https://doi.org/10.1186/s12933-018-0680-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Libby P (2021) The changing landscape of atherosclerosis. Nature 592(7855):524–533. https://doi.org/10.1038/s41586-021-03392-8

    Article  CAS  PubMed  Google Scholar 

  103. Wolf D, Ley K (2019) Immunity and inflammation in atherosclerosis. Circ Res 124(2):315–327. https://doi.org/10.1161/CIRCRESAHA.118.313591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Guarnotta V, Lucchese S, Mineo MI, Mangione D, Venezia R, Almasio PL, Giordano C (2021) Predictive factors of polycystic ovary syndrome in girls with precocious pubarche. Endocr Connect 10(7):796–804. https://doi.org/10.1530/EC-21-0118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Diamanti-Kandarakis E, Papavassiliou AG, Kandarakis SA, Chrousos GP (2007) Pathophysiology and types of dyslipidemia in PCOS. Trends Endocrinol Metab 18(7):280–285. https://doi.org/10.1016/j.tem.2007.07.004

    Article  CAS  PubMed  Google Scholar 

  106. Ketenci Gencer F, Yuksel S, Goksever CH (2021) Do serum hepassocin levels change in women with polycystic ovary syndrome? Eur J Obstet Gynecol Reprod Biol 267:137–141. https://doi.org/10.1016/j.ejogrb.2021.10.034

    Article  CAS  PubMed  Google Scholar 

  107. Pirillo A, Norata GD, Catapano AL (2013) LOX-1, OxLDL, and atherosclerosis. Mediators Inflamm 2013:152786. https://doi.org/10.1155/2013/152786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chistiakov DA, Melnichenko AA, Grechko AV, Myasoedova VA, Orekhov AN (2018) Potential of anti-inflammatory agents for treatment of atherosclerosis. Exp Mol Pathol 104(2):114–124. https://doi.org/10.1016/j.yexmp.2018.01.008

    Article  CAS  PubMed  Google Scholar 

  109. Zhu Y, **an X, Wang Z, Bi Y, Chen Q, Han X, Tang D, Chen R (2018) Research progress on the relationship between atherosclerosis and inflammation. Biomolecules 8(3):80. https://doi.org/10.3390/biom8030080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gwon WG, Joung EJ, Kwon MS, Lim SJ, Utsuki T, Kim HR (2017) Sargachromenol protects against vascular inflammation by preventing TNF-alpha-induced monocyte adhesion to primary endothelial cells via inhibition of NF-kappaB activation. Int Immunopharmacol 42:81–89. https://doi.org/10.1016/j.intimp.2016.11.014

    Article  CAS  PubMed  Google Scholar 

  111. Mussbacher M, Salzmann M, Brostjan C, Hoesel B, Schoergenhofer C, Datler H, Hohensinner P, Basilio J, Petzelbauer P, Assinger A et al (2019) Cell type-specific roles of NF-kappaB linking inflammation and thrombosis. Front Immunol 10:85. https://doi.org/10.3389/fimmu.2019.00085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Denk A, Goebeler M, Schmid S, Berberich I, Ritz O, Lindemann D, Ludwig S, Wirth T (2001) Activation of NF-kappa B via the Ikappa B kinase complex is both essential and sufficient for proinflammatory gene expression in primary endothelial cells. J Biol Chem 276(30):28451–28458. https://doi.org/10.1074/jbc.M102698200

    Article  CAS  PubMed  Google Scholar 

  113. Ashida N, Senbanerjee S, Kodama S, Foo SY, Coggins M, Spencer JA, Zamiri P, Shen D, Li L, Sciuto T et al (2011) IKKbeta regulates essential functions of the vascular endothelium through kinase-dependent and -independent pathways. Nat Commun 2:318. https://doi.org/10.1038/ncomms1317

    Article  CAS  PubMed  Google Scholar 

  114. Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI (2000) The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci U S A 97(16):9052–9057. https://doi.org/10.1073/pnas.97.16.9052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Gareus R, Kotsaki E, Xanthoulea S, van der Made I, Gijbels MJ, Kardakaris R, Polykratis A, Kollias G, de Winther MP, Pasparakis M (2008) Endothelial cell-specific NF-kappaB inhibition protects mice from atherosclerosis. Cell Metab 8(5):372–383. https://doi.org/10.1016/j.cmet.2008.08.016

    Article  CAS  PubMed  Google Scholar 

  116. Takashiba S, Van Dyke TE, Amar S, Murayama Y, Soskolne AW, Shapira L (1999) Differentiation of monocytes to macrophages primes cells for lipopolysaccharide stimulation via accumulation of cytoplasmic nuclear factor kappaB. Infect Immun 67(11):5573–5578. https://doi.org/10.1128/IAI.67.11.5573-5578.1999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Ferreira V, van Dijk KW, Groen AK, Vos RM, van der Kaa J, Gijbels MJ, Havekes LM, Pannekoek H (2007) Macrophage-specific inhibition of NF-kappaB activation reduces foam-cell formation. Atherosclerosis 192(2):283–290. https://doi.org/10.1016/j.atherosclerosis.2006.07.018

    Article  CAS  PubMed  Google Scholar 

  118. Xu S, Chen H, Ni H, Dai Q (2021) Targeting HDAC6 attenuates nicotine-induced macrophage pyroptosis via NF-kappaB/NLRP3 pathway. Atherosclerosis 317:1–9. https://doi.org/10.1016/j.atherosclerosis.2020.11.021

    Article  CAS  PubMed  Google Scholar 

  119. Ben J, Jiang B, Wang D, Liu Q, Zhang Y, Qi Y, Tong X, Chen L, Liu X, Zhang Y et al (2019) Major vault protein suppresses obesity and atherosclerosis through inhibiting IKK-NF-kappaB signaling mediated inflammation. Nat Commun 10(1):1801. https://doi.org/10.1038/s41467-019-09588-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Escobar-Morreale HF, Alvarez-Blasco F, Botella-Carretero JI, Luque-Ramirez M (2014) The striking similarities in the metabolic associations of female androgen excess and male androgen deficiency. Hum Reprod 29(10):2083–2091. https://doi.org/10.1093/humrep/deu198

    Article  CAS  PubMed  Google Scholar 

  121. Zhao L, Zhu Z, Lou H, Zhu G, Huang W, Zhang S, Liu F (2016) Polycystic ovary syndrome (PCOS) and the risk of coronary heart disease (CHD): a meta-analysis. Oncotarget 7(23):33715–33721. https://doi.org/10.18632/oncotarget.9553

    Article  PubMed  PubMed Central  Google Scholar 

  122. Macut D, Antic IB, Bjekic-Macut J (2015) Cardiovascular risk factors and events in women with androgen excess. J Endocrinol Invest 38(3):295–301. https://doi.org/10.1007/s40618-014-0215-1

    Article  CAS  PubMed  Google Scholar 

  123. Pandurevic S, Macut D, Fanelli F, Pagotto U, Gambineri A (2021) Biomediators in polycystic ovary syndrome and cardiovascular risk. Biomolecules 11(9):1350. https://doi.org/10.3390/biom11091350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Yu J, Akishita M, Eto M, Ogawa S, Son BK, Kato S, Ouchi Y, Okabe T (2010) Androgen receptor-dependent activation of endothelial nitric oxide synthase in vascular endothelial cells: role of phosphatidylinositol 3-kinase/akt pathway. Endocrinology 151(4):1822–1828. https://doi.org/10.1210/en.2009-1048

    Article  CAS  PubMed  Google Scholar 

  125. Li D, Wang X, Huang Q, Li S, Zhou Y, Li Z (2018) Cardioprotection of CAPE-oNO2 against myocardial ischemia/reperfusion induced ROS generation via regulating the SIRT1/eNOS/NF-kappaB pathway in vivo and in vitro. Redox Biol 15:62–73. https://doi.org/10.1016/j.redox.2017.11.023

    Article  CAS  PubMed  Google Scholar 

  126. Incalza MA, D’Oria R, Natalicchio A, Perrini S, Laviola L, Giorgino F (2018) Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vascul Pharmacol 100:1–19. https://doi.org/10.1016/j.vph.2017.05.005

    Article  CAS  PubMed  Google Scholar 

  127. Wu CC, Cheng J, Zhang FF, Gotlinger KH, Kelkar M, Zhang Y, Jat JL, Falck JR, Schwartzman ML (2011) Androgen-dependent hypertension is mediated by 20-hydroxy-5,8,11,14-eicosatetraenoic acid-induced vascular dysfunction: role of inhibitor of kappaB Kinase. Hypertension 57(4):788–794. https://doi.org/10.1161/HYPERTENSIONAHA.110.161570

    Article  CAS  PubMed  Google Scholar 

  128. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332(6163):411–415. https://doi.org/10.1038/332411a0

    Article  CAS  PubMed  Google Scholar 

  129. Kostov K (2021) The causal relationship between endothelin-1 and hypertension: focusing on endothelial dysfunction, arterial stiffness, vascular remodeling, and blood pressure regulation. Life (Basel) 11(9):1350. https://doi.org/10.3390/life11090986

    Article  CAS  Google Scholar 

  130. Kuczmarski AV, Welti LM, Moreau KL, Wenner MM (2021) ET-1 as a sex-specific mechanism impacting age-related changes in vascular function. Front Aging 2:727416. https://doi.org/10.3389/fragi.2021.727416

    Article  PubMed  PubMed Central  Google Scholar 

  131. Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, Pollock DM, Webb DJ, Maguire JJ (2016) Endothelin. Pharmacol Rev 68(2):357–418. https://doi.org/10.1124/pr.115.011833

    Article  PubMed  PubMed Central  Google Scholar 

  132. Shihoya W, Nishizawa T, Okuta A, Tani K, Dohmae N, Fujiyoshi Y, Nureki O, Doi T (2016) Activation mechanism of endothelin ETB receptor by endothelin-1. Nature 537(7620):363–368. https://doi.org/10.1038/nature19319

    Article  CAS  PubMed  Google Scholar 

  133. Stone T, Stachenfeld NS (2020) Pathophysiological effects of androgens on the female vascular system. Biol Sex Differ 11(1):45. https://doi.org/10.1186/s13293-020-00323-6

    Article  PubMed  PubMed Central  Google Scholar 

  134. Usselman CW, Yarovinsky TO, Steele FE, Leone CA, Taylor HS, Bender JR, Stachenfeld NS (2019) Androgens drive microvascular endothelial dysfunction in women with polycystic ovary syndrome: role of the endothelin B receptor. J Physiol 597(11):2853–2865. https://doi.org/10.1113/JP277756

    Article  CAS  PubMed  Google Scholar 

  135. Verzella D, Cornice J, Arboretto P, Vecchiotti D, Di Vito NM, Capece D, Zazzeroni F, Franzoso G (2022) The NF-kappaB pharmacopeia: novel strategies to subdue an intractable target. Biomedicines 10(9):2233. https://doi.org/10.3390/biomedicines10092233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Medeiros M, Candido MF, Valera ET, Brassesco MS (2021) The multifaceted NF-kB: are there still prospects of its inhibition for clinical intervention in pediatric central nervous system tumors? Cell Mol Life Sci 78(17–18):6161–6200. https://doi.org/10.1007/s00018-021-03906-7

    Article  CAS  PubMed  Google Scholar 

  137. Nelson KM, Dahlin JL, Bisson J, Graham J, Pauli GF, Walters MA (2017) The Essential Medicinal Chemistry of Curcumin. J Med Chem 60(5):1620–1637. https://doi.org/10.1021/acs.jmedchem.6b00975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Zhang Y, Weng Y, Wang D, Wang R, Wang L, Zhou J, Shen S, Wang H, Wang Y (2021) Curcumin in combination with aerobic exercise improves follicular dysfunction via inhibition of the hyperandrogen-induced IRE1alpha/XBP1 Endoplasmic reticulum stress pathway in PCOS-like rats. Oxid Med Cell Longev 2021:7382900. https://doi.org/10.1155/2021/7382900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Raja MA, Maldonado M, Chen J, Zhong Y, Gu J (2021) Development and evaluation of curcumin encapsulated self-assembled nanoparticles as potential remedial treatment for PCOS in a female rat model. Int J Nanomedicine 16:6231–6247. https://doi.org/10.2147/IJN.S302161

    Article  PubMed  PubMed Central  Google Scholar 

  140. Mohammadi S, Kayedpoor P, Karimzadeh-Bardei L, Nabiuni M (2017) The effect of curcumin on TNF-alpha, IL-6 and CRP expression in a model of polycystic ovary syndrome as an inflammation state. J Reprod Infertil 18(4):352–360

    PubMed  PubMed Central  Google Scholar 

  141. Mohammadi S, Karimzadeh Bardei L, Hojati V, Ghorbani AG, Nabiuni M (2017) Anti-inflammatory effects of curcumin on insulin resistance index, levels of interleukin-6, C-reactive protein, and liver histology in polycystic ovary syndrome-induced rats. Cell J 19(3):425–433. https://doi.org/10.22074/cellj.2017.4415

    Article  PubMed  PubMed Central  Google Scholar 

  142. Abuelezz NZ, Shabana ME, Abdel-Mageed HM, Rashed L, Morcos GNB (2020) Nanocurcumin alleviates insulin resistance and pancreatic deficits in polycystic ovary syndrome rats: insights on PI3K/AkT/mTOR and TNF-alpha modulations. Life Sci 256:118003. https://doi.org/10.1016/j.lfs.2020.118003

    Article  CAS  PubMed  Google Scholar 

  143. Fatemi Abhari SM, Khanbabaei R, Hayati Roodbari N, Parivar K, Yaghmaei P (2020) Curcumin-loaded super-paramagnetic iron oxide nanoparticle affects on apoptotic factors expression and histological changes in a prepubertal mouse model of polycystic ovary syndrome-induced by dehydroepiandrosterone - A molecular and stereological study. Life Sci 249:117515. https://doi.org/10.1016/j.lfs.2020.117515

    Article  CAS  PubMed  Google Scholar 

  144. Malvasi A, Tinelli A, Dellino M, Trojano G, Vinciguerra M, Mina M (2022) Curcumin and Teupolioside attenuate signs and symptoms severity associated to hirsutism in PCOS women: a preliminary pilot study. Eur Rev Med Pharmacol Sci 26(17):6187–6191. https://doi.org/10.26355/eurrev_202209_29635

    Article  CAS  PubMed  Google Scholar 

  145. Sohaei S, Amani R, Tarrahi MJ, Ghasemi-Tehrani H (2019) The effects of curcumin supplementation on glycemic status, lipid profile and hs-CRP levels in overweight/obese women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled clinical trial. Complement Ther Med 47:102201. https://doi.org/10.1016/j.ctim.2019.102201

    Article  PubMed  Google Scholar 

  146. Ghanbarzadeh-Ghashti N, Ghanbari-Homaie S, Shaseb E, Abbasalizadeh S, Mirghafourvand M (2023) The effect of Curcumin on metabolic parameters and androgen level in women with polycystic ovary syndrome: a randomized controlled trial. BMC Endocr Disord 23(1):40. https://doi.org/10.1186/s12902-023-01295-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Sohrevardi SM, Heydari B, Azarpazhooh MR, Teymourzadeh M, Simental-Mendia LE, Atkin SL, Sahebkar A, Karimi-Zarchi M (2021) Therapeutic effect of curcumin in women with polycystic ovary syndrome receiving metformin: a randomized controlled trial. Adv Exp Med Biol 1308:109–117. https://doi.org/10.1007/978-3-030-64872-5_9

    Article  CAS  PubMed  Google Scholar 

  148. Heshmati J, Moini A, Sepidarkish M, Morvaridzadeh M, Salehi M, Palmowski A, Mojtahedi MF, Shidfar F (2021) Effects of curcumin supplementation on blood glucose, insulin resistance and androgens in patients with polycystic ovary syndrome: a randomized double-blind placebo-controlled clinical trial. Phytomedicine 80:153395. https://doi.org/10.1016/j.phymed.2020.153395

    Article  CAS  PubMed  Google Scholar 

  149. Jamilian M, Foroozanfard F, Kavossian E, Aghadavod E, Shafabakhsh R, Hoseini A, Asemi Z (2020) Effects of curcumin on body weight, glycemic control and serum lipids in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Clin Nutr ESPEN 36:128–133. https://doi.org/10.1016/j.clnesp.2020.01.005

    Article  PubMed  Google Scholar 

  150. Heshmati J, Golab F, Morvaridzadeh M, Potter E, Akbari-Fakhrabadi M, Farsi F, Tanbakooei S, Shidfar F (2020) The effects of curcumin supplementation on oxidative stress, Sirtuin-1 and peroxisome proliferator activated receptor gamma coactivator 1alpha gene expression in polycystic ovarian syndrome (PCOS) patients: A randomized placebo-controlled clinical trial. Diabetes Metab Syndr 14(2):77–82. https://doi.org/10.1016/j.dsx.2020.01.002

    Article  PubMed  Google Scholar 

  151. Banerjee S, Li Y, Wang Z, Sarkar FH (2008) Multi-targeted therapy of cancer by genistein. Cancer Lett 269(2):226–242. https://doi.org/10.1016/j.canlet.2008.03.052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Rajan RK, M SS, and Balaji B. (2017) Soy isoflavones exert beneficial effects on letrozole-induced rat polycystic ovary syndrome (PCOS) model through anti-androgenic mechanism. Pharm Biol 55(1):242–251. https://doi.org/10.1080/13880209.2016.1258425

    Article  CAS  PubMed  Google Scholar 

  153. Amanat S, Ashkar F, Eftekhari MH, Tanideh N, Doaei S, Gholamalizadeh M, Koohpeyma F, Mokhtari M (2021) The effect of genistein on insulin resistance, inflammatory factors, lipid profile, and histopathologic indices in rats with polycystic ovary syndrome. Clin Exp Reprod Med 48(3):236–244. https://doi.org/10.5653/cerm.2020.04231

    Article  PubMed  PubMed Central  Google Scholar 

  154. Khezri S, Alihemmati A, Abedelahi A (2022) Genistein blunted detrimental effects of polycystic ovary syndrome on the ovarian tissue of rats by improving follicular development and gonadotropin secretion. JBRA Assist Reprod 26(3):379–386. https://doi.org/10.5935/1518-0557.20210089

    Article  PubMed  PubMed Central  Google Scholar 

  155. Chi XX, Zhang T, Chu XL, Zhen JL, Zhang DJ (2018) The regulatory effect of Genistein on granulosa cell in ovary of rat with PCOS through Bcl-2 and Bax signaling pathways. J Vet Med Sci 80(8):1348–1355. https://doi.org/10.1292/jvms.17-0001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Alivandi Farkhad S, Khazali H (2019) Therapeutic effects of isoflavone-aglycone fraction from soybean (Glycine max L. Merrill) in rats with estradiol valerate-induced polycystic ovary syndrome as an inflammatory state. Gynecol Endocrinol 35(12):1078–1083. https://doi.org/10.1080/09513590.2019.1624715

    Article  CAS  PubMed  Google Scholar 

  157. Rajaei S, Alihemmati Ph DA, Abedelahi Ph DA (2019) Antioxidant effect of genistein on ovarian tissue morphology, oxidant and antioxidant activity in rats with induced polycystic ovary syndrome. Int J Reprod Biomed 17(1):11–22. https://doi.org/10.18502/ijrm.v17i1.3816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Luo M, Zheng LW, Wang YS, Huang JC, Yang ZQ, Yue ZP, Guo B (2021) Genistein exhibits therapeutic potential for PCOS mice via the ER-Nrf2-Foxo1-ROS pathway. Food Funct 12(18):8800–8811. https://doi.org/10.1039/d1fo00684c

    Article  CAS  PubMed  Google Scholar 

  159. Khani B, Mehrabian F, Khalesi E, Eshraghi A (2011) Effect of soy phytoestrogen on metabolic and hormonal disturbance of women with polycystic ovary syndrome. J Res Med Sci 16(3):297–302

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Jamilian M, Asemi Z (2016) The effects of soy isoflavones on metabolic status of patients with polycystic ovary syndrome. J Clin Endocrinol Metab 101(9):3386–3394. https://doi.org/10.1210/jc.2016-1762

    Article  CAS  PubMed  Google Scholar 

  161. Haudum C, Lindheim L, Ascani A, Trummer C, Horvath A, Munzker J, Obermayer-Pietsch B (2020) Impact of short-term isoflavone intervention in polycystic ovary syndrome (PCOS) patients on microbiota composition and metagenomics. Nutrients 12(6):1622. https://doi.org/10.3390/nu12061622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Parsamanesh N, Asghari A, Sardari S, Tasbandi A, Jamialahmadi T, Xu S, Sahebkar A (2021) Resveratrol and endothelial function: A literature review. Pharmacol Res 170:105725. https://doi.org/10.1016/j.phrs.2021.105725

    Article  CAS  PubMed  Google Scholar 

  163. Nallasamy P, Kang ZY, Sun X, Anandh Babu PV, Liu D, Jia Z (2021) Natural compound resveratrol attenuates TNF-alpha-induced vascular dysfunction in mice and human endothelial cells: the involvement of the NF-kappaB signaling pathway. Int J Mol Sci 22(22):12486. https://doi.org/10.3390/ijms222212486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Shojaei-Zarghani S, Rafraf M (2022) Resveratrol and markers of polycystic ovary syndrome: a systematic review of animal and clinical studies. Reprod Sci 29(9):2477–2487. https://doi.org/10.1007/s43032-021-00653-9

    Article  CAS  PubMed  Google Scholar 

  165. Wang D, Wang T, Wang R, Zhang X, Wang L, **ang Z, Zhuang L, Shen S, Wang H, Gao Q et al (2020) Suppression of p66Shc prevents hyperandrogenism-induced ovarian oxidative stress and fibrosis. J Transl Med 18(1):84. https://doi.org/10.1186/s12967-020-02249-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Ghowsi M, Khazali H, Sisakhtnezhad S (2018) Evaluation of TNF-alpha and IL-6 mRNAs expressions in visceral and subcutaneous adipose tissues of polycystic ovarian rats and effects of resveratrol. Iran J Basic Med Sci 21(2):165–174. https://doi.org/10.22038/IJBMS.2017.24801.6167

    Article  PubMed  PubMed Central  Google Scholar 

  167. Ashkar F, Eftekhari MH, Tanideh N, Koohpeyma F, Mokhtari M, Irajie C, Iraji A (2020) Effect of hydroalcoholic extract of Berberis integerrima and resveratrol on ovarian morphology and biochemical parameters in Letrozole-induced polycystic ovary syndrome rat model: an experimental study. Int J Reprod Biomed 18(8):637–650. https://doi.org/10.18502/ijrm.v13i8.7505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Furat Rencber S, Kurnaz Ozbek S, Eraldemir C, Sezer Z, Kum T, Ceylan S, Guzel E (2018) Effect of resveratrol and metformin on ovarian reserve and ultrastructure in PCOS: an experimental study. J Ovarian Res 11(1):55. https://doi.org/10.1186/s13048-018-0427-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Zhang N, Zhuang L, Gai S, Shan Y, Wang S, Li F, Chen L, Zhao D, Liu X (2021) Beneficial phytoestrogenic effects of resveratrol on polycystic ovary syndromein rat model. Gynecol Endocrinol 37(4):337–341. https://doi.org/10.1080/09513590.2020.1812569

    Article  CAS  PubMed  Google Scholar 

  170. Banaszewska B, Wrotynska-Barczynska J, Spaczynski RZ, Pawelczyk L, Duleba AJ (2016) Effects of resveratrol on polycystic ovary syndrome: a double-blind, randomized. Placebo-controlled Trial J Clin Endocrinol Metab 101(11):4322–4328. https://doi.org/10.1210/jc.2016-1858

    Article  CAS  PubMed  Google Scholar 

  171. Bahramrezaie M, Amidi F, Aleyasin A, Saremi A, Aghahoseini M, Brenjian S, Khodarahmian M, Pooladi A (2019) Effects of resveratrol on VEGF & HIF1 genes expression in granulosa cells in the angiogenesis pathway and laboratory parameters of polycystic ovary syndrome: a triple-blind randomized clinical trial. J Assist Reprod Genet 36(8):1701–1712. https://doi.org/10.1007/s10815-019-01461-6

    Article  PubMed  PubMed Central  Google Scholar 

  172. Mansour A, Samadi M, Sanginabadi M, Gerami H, Karimi S, Hosseini S, Shirzad N, Hekmatdoost A, Mahdavi-Gorabi A, Mohajeri-Tehrani MR et al (2021) Effect of resveratrol on menstrual cyclicity, hyperandrogenism and metabolic profile in women with PCOS. Clin Nutr 40(6):4106–4112. https://doi.org/10.1016/j.clnu.2021.02.004

    Article  CAS  PubMed  Google Scholar 

  173. Hassan S, Shah M, Malik MO, Ehtesham E, Habib SH, Rauf B (2023) Treatment with combined resveratrol and myoinositol ameliorates endocrine, metabolic alterations and perceived stress response in women with PCOS: a double-blind randomized clinical trial. Endocrine 79(1):208–220. https://doi.org/10.1007/s12020-022-03198-2

    Article  CAS  PubMed  Google Scholar 

  174. Malvasi A, Tinelli A, Lupica G, Vimercati A, Spyropoulou K, Dellino M, Mynbaev O (2022) Effects of a combination of resveratrol and alpha-lipoic acid on body weight and adipose composition in women with PCOS: a preliminary pilot study. Eur Rev Med Pharmacol Sci 26(18):6578–6582. https://doi.org/10.26355/eurrev_202209_29757

    Article  CAS  PubMed  Google Scholar 

  175. Sethi G, Ahn KS, Aggarwal BB (2008) Targeting nuclear factor-kappa B activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis. Mol Cancer Res 6(6):1059–1070. https://doi.org/10.1158/1541-7786.MCR-07-2088

    Article  CAS  PubMed  Google Scholar 

  176. Taghvaee Javanshir S, Yaghmaei P, Hajebrahimi Z (2018) Thymoquinone ameliorates some endocrine parameters and histological alteration in a rat model of polycystic ovary syndrome. Int J Reprod Biomed 16(4):275–284

    PubMed  PubMed Central  Google Scholar 

  177. Saha P, Kumar S, Datta K, Tyagi RK (2021) Upsurge in autophagy, associated with mifepristone-treated polycystic ovarian condition, is reversed upon thymoquinone treatment. J Steroid Biochem Mol Biol 208:105823. https://doi.org/10.1016/j.jsbmb.2021.105823

    Article  CAS  PubMed  Google Scholar 

  178. Eini F, Joharchi K, Kutenaei MA, Mousavi P (2020) Improvement in the epigenetic modification and development competence in PCOS mice oocytes by hydro-alcoholic extract of Nigella sativa during in-vitro maturation: an experimental study. Int J Reprod Biomed 18(9):733–746. https://doi.org/10.18502/ijrm.v13i9.7668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Eini F, Bidadkosh A, Nazarian H, Piryaei A, Ghaffari Novin M, Joharchi K (2019) Thymoquinone reduces intracytoplasmic oxidative stress and improves epigenetic modification in polycystic ovary syndrome mice oocytes, during in-vitro maturation. Mol Reprod Dev 86(8):1053–1066. https://doi.org/10.1002/mrd.23222

    Article  CAS  PubMed  Google Scholar 

  180. Shao YY, Chang ZP, Cheng Y, Wang XC, Zhang JP, Feng XJ, Guo YT, Liu JJ, Hou RG (2019) Shaoyao-Gancao Decoction alleviated hyperandrogenism in a letrozole-induced rat model of polycystic ovary syndrome by inhibition of NF-kappaB activation. Biosci Rep. https://doi.org/10.1042/BSR20181877

  181. Lian Y, Zhao F, Wang W (2020) Use of Bao Gui capsule in treatment of a polycystic ovary syndrome rat model. Mol Med Rep 21(3):1461–1470. https://doi.org/10.3892/mmr.2020.10953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Naka** S, Shively JE, Yuan PM, Hall PF (1981) Microsomal cytochrome P-450 from neonatal pig testis: two enzymatic activities (17 alpha-hydroxylase and c17,20-lyase) associated with one protein. Biochemistry 20(14):4037–4042. https://doi.org/10.1021/bi00517a014

    Article  CAS  PubMed  Google Scholar 

  183. Sun J, ** C, Wu H, Zhao J, Cui Y, Liu H, Wu L, Shi Y, Zhu B (2013) Effects of electro-acupuncture on ovarian P450arom, P450c17alpha and mRNA expression induced by letrozole in PCOS rats. PLoS ONE 8(11):e79382. https://doi.org/10.1371/journal.pone.0079382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. ** W, Wang C, Cui M, Wang M, Fu B, Sun L, Chen X (2022) Inhibitory effect of bushen huoxue formula against dehydroepiandrosterone-induced inflammation in granulosa cells through TLR4/NF-kappaB signaling pathway. Pak J Pharm Sci 35(3):701–710

    CAS  PubMed  Google Scholar 

  185. Moshfegh F, Balanejad SZ, Shahrokhabady K, Attaranzadeh A (2022) Crocus sativus (saffron) petals extract and its active ingredient, anthocyanin improves ovarian dysfunction, regulation of inflammatory genes and antioxidant factors in testosterone-induced PCOS mice. J Ethnopharmacol 282:114594. https://doi.org/10.1016/j.jep.2021.114594

    Article  CAS  PubMed  Google Scholar 

  186. Zhao FQ, Zhao Y, Liu JY, Gou YJ, Yang YQ (2022) Effects of berberine on LPS /NF-kappaB and MAPK signaling pathways in PCOS model rats. Zhongguo Ying Yong Sheng Li Xue Za Zhi 38(2):181–186. https://doi.org/10.12047/j.cjap.6229.2022.029

    Article  PubMed  Google Scholar 

  187. Shen HR, Xu X, Li XL (2021) Berberine exerts a protective effect on rats with polycystic ovary syndrome by inhibiting the inflammatory response and cell apoptosis. Reprod Biol Endocrinol 19(1):3. https://doi.org/10.1186/s12958-020-00684-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Miao X, Cui W (2022) Berberine alleviates LPS-induced apoptosis, oxidation, and skewed lineages during mouse preimplantation developmentdagger. Biol Reprod 106(4):699–709. https://doi.org/10.1093/biolre/ioac002

    Article  PubMed  PubMed Central  Google Scholar 

  189. Wang Z, Zhai D, Zhang D, Bai L, Yao R, Yu J, Cheng W, Yu C (2017) Quercetin decreases insulin resistance in a polycystic ovary syndrome rat model by improving inflammatory microenvironment. Reprod Sci 24(5):682–690. https://doi.org/10.1177/1933719116667218

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by cross-innovation talent project in Renmin Hospital of Wuhan University (Grant No. JCRCZN-2022–016); Natural Science Foundation of Hubei Province (Grant No. 2022CFB252); Undergraduate education quality construction comprehensive reform project (Grant No. 2022ZG282) and the National Natural Science Foundation of China (Grant nGrant No. 82071655).

Author information

Author notes

  1. Wei Tan and Jie Zhang have contributed to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, 99 Zhang Zhidong Road, Wuhan, 430060, Hubei, People’s Republic of China

    Wei Tan, Jie Zhang, Fangfang Dai, Dongyong Yang, Ran Gu, Lujia Tang, Hua Liu & Yan-xiang Cheng

Authors
  1. Wei Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fangfang Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dongyong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ran Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lujia Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hua Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yan-xiang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WT and FD are the main writers of the review, completing the collection and analysis of relevant literature and the writing of the first draft of the paper. FD, DY, RG, LT participated in the analysis and arrangement of the literature. DY participated in collating of first draft. JZ participated in the initial topic discussion, and undertook the revision of the key content of article. Besides, HL was also provided some help for polishing with YC. YC was in charge of the project, and guides the writing of the thesis. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Hua Liu or Yan-xiang Cheng.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tan, W., Zhang, J., Dai, F. et al. Insights on the NF-κB system in polycystic ovary syndrome, attractive therapeutic targets. Mol Cell Biochem 479, 467–486 (2024). https://doi.org/10.1007/s11010-023-04736-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-023-04736-w

Keywords

Search

Navigation