The E3 ubiquitin ligase Itch plays an essential role in kidney fibrosis by inhibiting Dvl2/GSK3β/β-catenin signaling pathway

  • Cell Death Differ. 2026 May 22. doi: 10.1038/s41418-026-01765-y.
Yue Li  1  2 ,  Wei Zhang  1 ,  Yingqing Xie  1 ,  Dongyun Wang  1 ,  Mengyu Liu  1 ,  Weixia Han  3 ,  Xinran Li  1  2 ,  Shan Song  1  2 ,  Lin Mu  2  4 ,  Guiying Li  5 ,  Yonghong Shi  6  7
Affiliations
  • 1. Department of Pathology, Hebei Medical University, Shijiazhuang, China.
  • 2. Hebei Key Laboratory of Kidney Disease, Shijiazhuang, China.
  • 3. Department of Pathology, Shanxi Medical University Second Affiliated Hospital, Taiyuan, China.
  • 4. Department of Nephrology, Second Hospital of Hebei Medical University, Shijiazhuang, China.
  • 5. Department of Nephrology, Affiliated Hospital of Hebei University of Engineering, Handan, China.
  • 6. Department of Pathology, Hebei Medical University, Shijiazhuang, China. [email protected].
  • 7. Hebei Key Laboratory of Kidney Disease, Shijiazhuang, China. [email protected].
PMID: 42168361 DOI: 10.1038/s41418-026-01765-y
Abstract

Itch, an E3 ubiquitin Ligase, is involved in various cellular functions by regulating ubiquitination and proteasomal degradation of target proteins. However, its roles are unknown in kidney fibrosis. In the present study, the decreased expression of Itch in the renal tubules of patients with chronic kidney disease (CKD) and mice induced by unilateral ureteral obstruction (UUO) or folic acid (FA) is demonstrated. Itch-/- mice exhibited more severe fibrotic lesions and inflammation after obstruction or FA treatment compared with Itch+/+ control. Itch overexpression alleviated UUO- or FA-induced kidney fibrosis and inflammation in mice. In addition, Disheveled 2 (Dvl2) deficiency reduced kidney fibrosis and inflammation in UUO mice. In vitro, Itch overexpression inhibited transforming growth factor-beta 1(TGF-β1)-induced fibrotic response in HK-2 cells. Mechanistically, Itch promoted K48-linked ubiquitination of Dvl2 at lysine 343, facilitating its proteasomal degradation, followed by suppressing GSK-3β/β-catenin signaling pathway, finally leading to the alleviation of kidney fibrosis. Collectively, our studies uncover that Itch exerts a critical role in kidney fibrosis, and it may be an attractive therapeutic target to slow the progression of fibrotic kidney disease.

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