Abstract: TH-PO0212
Orphan Nuclear Receptor NR4A2 Facilitates Ferroptosis in Renal Tubular Cells by Promoting Degradation of Mitochondrial GPX4
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Author
- Li, Jingyao, Shanghai 6th Peoples Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
Background
Ferroptosis in renal tubular epithelial cells is a key driver of renal fibrosis and the progression of chronic kidney disease (CKD), The nuclear receptor NR4A2 is aberrantly upregulated in injured renal tubules, yet its functional role in ferroptosis remain undefined. Mitochondrial glutathione peroxidase 4 (mtGPX4) is indispensable for maintaining mitochondrial redox balance and tightly linked to ferroptosis in CKD. Previous study reported that phosphorylation of GPX4 regulate its stability, whether the mtGPX4 is regulated by the mitochondrial phosphatase remains defined. Notably, the mitochondrial phosphatase PGAM5 has been implicated in cell death pathways through dephosphorylating its substrate suggesting a potential role in modulating mtGPX4.
Methods
1. Human CKD specimens, ischemia reperfusion-induced CKD mouse models and Ang-II-induced HK2 cell were used to detect NR4A2 and PGAM5 expression and their correlation with ferroptosis and fibrosis.
2. Luciferase reporter and ChIP-PCR assays verified NR4A2 transcriptional regulation in PGAM5. Tubule-specific NR4A2 and PGAM5 knockout mice were constructed to validate lipid peroxides, the expression of mtGPX4 and fibrosis markers.
3. CO-IP detect the interaction between PGAM5 and mtGPX4, while TEM, MitoPeDPP, and Liperfluo were employed to observe mitochondrial function.
Results
1.We identified NR4A2 and PGAM5 was increased in proximal renal tubular epithelial cells of CKD patients, CKD mice and Ang II-treated HK2 cells. Renal tubular cell specific knockout of NR4A2 or PGAM5 ameliorates mitochondrial dysfunction-induced ferroptosis and renal fibrosis.
2. NR4A2 nuclear translocation promotes PGAM5 transcription.
3. PGAM5 dephosphorylates mtGPX4 at serine 104 residue, leading to mtGPX4 degradation and lipid peroxide accumulation.
4. we identify O-DMA as a first-in-class inhibitor of the PGAM5–mtGPX4 interaction, effectively halting ferroptosis and protecting against renal fibrosis.
Conclusion
This study demonstrates that NR4A2-mediated PGAM5 activation drives renal tubular cell ferroptosis and CKD progression. PGAM5 dephosphorylates mtGPX4 at S104, resulting in the degradation of mtGPX4 and accumulation of mitochondrial ROS and LPO. The natural compound O-DMA is a novel and effective inhibitor of PGAM5-mtGPX4 interaction, providing a druggable target and translational strategy for CKD anti-fibrotic therapy.