Plumbagin rescues the granulosa cell's pyroptosis by reducing WTAP-mediated N6-methylation in polycystic ovary syndrome

J Ovarian Res. 2022 Dec 3;15(1):126. doi: 10.1186/s13048-022-01058-1.

Abstract

The survival of ovary granulosa cells (GC) is critical in the initiation and progression of polycystic ovary syndrome (PCOS) in females. Here, we found that the PCOS process is accompanied by massive GC pyroptosis resulting from Caspase-1 inflammasome activation. Administration of plumbagin, an effective compound isolated from plant medicine, can prevent the pyroptosis of GC and the onset of PCOS. Mechanistic study indicates the over-activation of the inflammasome in GC is due to the upregulation of WTAP, a key regulator of the RNA N6-methylase complex. WTAP mediates the mRNA N6-methylation of NLRP3 inflammasome component ASC and enhances ASC RNA stability, which results in the overactivation of the inflammasome in GCs from the PCOS model. Plumbagin treatment suppresses the WTAP-mediated N6-methylation of ASC mRNA and reduces the pyroptosis of GCs. This study supports the profound potential of plumbagin in PCOS treatment.

MeSH terms

  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / immunology
  • Female
  • Granulosa Cells* / drug effects
  • Granulosa Cells* / immunology
  • Humans
  • Inflammasomes / genetics
  • Inflammasomes / immunology
  • Methylation / drug effects
  • Naphthoquinones* / immunology
  • Naphthoquinones* / pharmacology
  • Naphthoquinones* / therapeutic use
  • Polycystic Ovary Syndrome* / drug therapy
  • Polycystic Ovary Syndrome* / genetics
  • Polycystic Ovary Syndrome* / immunology
  • Pyroptosis* / drug effects
  • Pyroptosis* / genetics
  • Pyroptosis* / immunology
  • RNA Splicing Factors / genetics
  • RNA Splicing Factors / immunology
  • RNA, Messenger

Substances

  • Cell Cycle Proteins
  • Inflammasomes
  • plumbagin
  • RNA Splicing Factors
  • RNA, Messenger
  • WTAP protein, human
  • Naphthoquinones