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WTAP Deficiency Promotes Podocyte PANoptosis and FSGS via SPP1 Signaling

Yanfang Lu1,2,3,4, Peipei Li1,2,3,4, Yang Liu1,2,3,4

  • 1Department of Nephrology (Y.L., P.L., L.Y., X.S., D.L., S.L., J.H., R.H., Z.L., S.Z.), The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.

Circulation Research
|July 7, 2026
PubMed
Abstract

Insights

Wilms

Area of Science:

  • Nephrology
  • Molecular Biology
  • Epigenetics

Background:

  • Focal segmental glomerulosclerosis (FSGS) is a leading cause of glomerular disease.
  • Podocyte injury and loss are hallmarks of FSGS progression.
  • The role of RNA methylation regulators in FSGS pathogenesis is largely unknown.

Purpose of the Study:

  • To investigate Wilms' tumor 1-associated protein (WTAP) as a novel pathogenic factor in FSGS.
  • To elucidate the functional role of WTAP in podocyte injury and FSGS development.
  • To identify potential therapeutic targets within the WTAP signaling pathway.

Main Methods:

  • WTAP expression analysis in human FSGS kidney biopsies and a mouse model.
  • Generation of podocyte-specific Wtap-deficient mouse models (constitutive and inducible knockouts).
  • In vivo and in vitro loss- and gain-of-function studies of WTAP in podocytes.
  • Investigation of WTAP's mechanism involving SPP1 (secreted phosphoprotein 1) methylation.

Main Results:

  • WTAP expression was significantly reduced in FSGS patients and models.
  • Wtap deficiency in podocytes led to progressive glomerulosclerosis and podocyte injury.
  • WTAP overexpression protected against podocyte injury.
  • WTAP regulates SPP1 methylation, influencing its stability and expression.
  • SPP1 signaling was identified as a key mediator of renal pathology in FSGS, and its neutralization ameliorated injury.

Conclusions:

  • The WTAP/SPP1 signaling pathway is implicated in FSGS pathogenesis.
  • Targeting the WTAP/SPP1 pathway offers a potential therapeutic strategy for FSGS.
  • Developed novel FSGS mouse models for further research into disease mechanisms and treatments.
Keywords:
RNA methylationcell deathglomerulosclerosis, focal segmentalpodocytessignal transduction

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