2. Academic Validation
  3. PRPF19 mediates the proteasomal degradation of VDR to exacerbate ferroptosis in diabetic nephropathy

PRPF19 mediates the proteasomal degradation of VDR to exacerbate ferroptosis in diabetic nephropathy

  • Cell Commun Signal. 2025 May 25;23(1):242. doi: 10.1186/s12964-025-02253-5.
Qiongyao He 1 2,  Wu He 3,  Yanlin Ren 4,  Wenbin Wu 1,  Hui Dong 5,  Gang Yuan 2,  Huihui Ren 2,  Xinwei Wang 6,  Fuer Lu 7,  Dingkun Wang 8
Affiliations

Affiliations

  • 1 Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 2 Department of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 3 Division of Cardiology, Department of Internal Medicine, Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
  • 4 Department of Traditional Chinese Medicine, Zhongshan Hospital of Hubei Province, Wuhan, 430030, China.
  • 5 Department of Integrated Traditional Chinese and Western Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 6 College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, China.
  • 7 Department of Integrated Traditional Chinese and Western Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China. felutjh88@163.com.
  • 8 Department of Integrated Traditional Chinese and Western Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China. wdkung@163.com.
PMID: 40414879 DOI: 10.1186/s12964-025-02253-5
Abstract

Ferroptosis, an iron-dependent form of programmed cell death, is closely associated with tubular damage in diabetic nephropathy (DN). Glutathione Peroxidase 4 (GPX4) is an important anti-oxidant enzyme, and plays a crucial role in protecting against Ferroptosis. However, the regulatory mechanism of GPX4 expression levels in renal tubular epithelial cells (RTECs) remains elusive. This study reveals that Ferroptosis occurs in the late-stage of DN, and the GPX4 level is significantly downregulated in DN patients, animal models and cell models. By applying database predictions, luciferase reporter assays and chromatin immunoprecipitation, we find that vitamin D receptor (VDR) transcription factor promotes GPX4 expression and plays a key role in inhibiting Ferroptosis of RTECs. VDR knockout exacerbates Ferroptosis in RTECs and worsens renal function, while intraperitoneal injection of VDR agonist paricalcitol significantly improves renal injury. Proteomics analysis suggests that E3 Ligase PRPF19 mediates ubiquitination degradation of VDR and is an important therapeutic target for DN. Therefore, through molecular docking, targeted fishing technology using high-performance affinity beads, and surface plasmon resonance (SPR), we screen and identify berberine (BBR) as a novel inhibitor of PRPF19, which offers renal protection by inhibiting VDR degradation and tubular Ferroptosis. These findings elucidate the role of Ferroptosis in DN renal tubular injury, and suggest that PRPF19 is a promising therapeutic target.

Keywords

Diabetic nephropathy; Ferroptosis; PRPF19; Renal tubule; VDR.

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