2. Academic Validation
  3. Targeting TRAF6 inhibits cystogenesis in autosomal dominant polycystic kidney disease

Targeting TRAF6 inhibits cystogenesis in autosomal dominant polycystic kidney disease

  • Biochem Pharmacol. 2025 Aug 9;242(Pt 2):117222. doi: 10.1016/j.bcp.2025.117222.
Ying Ren 1,  Yaoyao Pan 1,  Xiaodan Zhu 2,  Lingyi Li 1,  Wenchao Zhao 1,  Kequan Fu 1,  Yupeng Chen 3,  Yongzhan Sun 4,  Dong Guo 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004 Jiangsu, China.
  • 2 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004 Jiangsu, China; Huai'an 82 Hospital, No. 100 Jiankang East Road, Huai'an 223001 Jiangsu, China.
  • 3 The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), State Key Laboratory of Experimental Hematology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. Electronic address: ychen@tmu.edu.cn.
  • 4 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004 Jiangsu, China. Electronic address: sunyongzhan@tmu.edu.cn.
  • 5 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004 Jiangsu, China. Electronic address: guo@xzhmu.edu.cn.
PMID: 40789372 DOI: 10.1016/j.bcp.2025.117222
Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder, characterized by the progressive formation of multiple cysts in the kidneys. Post-translational modifications (PTMs) are increasingly recognized as key players in cyst formation. However, the role of ubiquitination, one of the most significant PTMs, in regulating cystogenesis in ADPKD remains largely unexplored. Here, we identified that TRAF6, an E3 ubiquitin Ligase, was significantly upregulated in ADPKD cells, mouse models, and patient tissues. TRAF6 interacted with the transcription factor STAT3, enhancing its activation and transcriptional activity by selectively increasing K63-linked ubiquitination, thereby contributing to renal cyst growth in both ADPKD cells and mice. Furthermore, the inhibition of TRAF6 significantly suppressed STAT3 transcriptional activity and slowed cyst growth in both in vitro and in vivo models. Therefore, targeting TRAF6 may represent a novel therapeutic strategy for ADPKD treatment.

Keywords

ADPKD; Cystogenesis; Eupatolide; STAT3; TRAF6.

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