期刊
REDOX BIOLOGY
卷 65, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.redox.2023.102826
关键词
WBP2; GPX4; Ferroptosis; Cisplatin; Acute kidney injury
This study identified WW domain binding protein-2 (WBP2) as a potential modulator of acute kidney injury (AKI) and cisplatin-induced AKI (CP-AKI) through bioinformatics analysis. WBP2 was found to be downregulated in CP-AKI and was shown to decelerate ferroptosis to alleviate CP-AKI. Mechanistically, WBP2 interacted with glutathione peroxidase 4 (GPX4) to inhibit ferroptosis. Additionally, WBP2 competed with heat shock cognate protein 70 (HSC70) for binding with GPX4, leading to the deceleration of chaperon-mediated autophagy of GPX4. Overall, this study provides novel insights into the modulation of ferroptosis in cisplatin-related nephropathy and highlights the beneficial role of WBP2 in CP-AKI.
Cisplatin is one of the major causes of acute kidney injury (AKI) in clinical practice, and ferroptosis is an essential form of cell death in cisplatin-induced AKI (CP-AKI). WW domain binding protein-2 (WBP2), a molecular chaperon, is involved in the progression of various malignancies, but its role in renal injuries has not been investigated. Our present study employed bioinformatics analysis to identify WBP2 as a potential modulator of AKI and ferroptosis. Preliminary laboratory investigations showed that WBP2, highly expressed in renal proximal tubular cells, was downregulated in CP-AKI. Further studies demonstrated that WBP2 decelerated ferroptosis to alleviate CP-AKI. Mechanistically, WBP2 interacted with glutathione peroxidase 4 (GPX4, a key detoxicating enzyme for ferroptosis) via its PPXY1 motif to inhibit ferroptosis. Furthermore, the in-depth investigations revealed that WBP2 competed with heat shock cognate protein 70 (HSC70) for the binding with the KEFRQ-like motifs of GPX4, leading to the deceleration of chaperon-mediated autophagy of GPX4. All in all, this study indicated the beneficial effect of WBP2 in CP-AKI and its relevance with ferroptosis, thus providing a novel insight into the modulation of ferroptosis in cisplatin-related nephropathy.
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