2. Academic Validation
  3. TRIM21 ubiquitylates GPX4 and promotes ferroptosis to aggravate ischemia/reperfusion-induced acute kidney injury

TRIM21 ubiquitylates GPX4 and promotes ferroptosis to aggravate ischemia/reperfusion-induced acute kidney injury

  • Life Sci. 2023 Mar 21;121608. doi: 10.1016/j.lfs.2023.121608.
Xiaolin Sun 1,  Ning Huang 1,  Peng Li 1,  Xinyi Dong 1,  Jiahong Yang 1,  Xuemei Zhang 1,  Wei-Xing Zong 2,  Shenglan Gao 3,  Hong Xin 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA.
  • 3 Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
  • 4 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: xinhong@fudan.edu.cn.
PMID: 36958437 DOI: 10.1016/j.lfs.2023.121608
Abstract

Aims: This study aims to verify the molecular mechanism that Tripartite motif containing 21 (TRIM21) promotes ubiquitination degradation of Glutathione Peroxidase 4 (GPX4) by regulating Ferroptosis, and to discuss the feasibility of TRIM21 as a new therapeutic target for acute kidney injury (AKI).

Materials and methods: Ischemia-reperfusion (I/R)-AKI model was constructed using Trim21+/+ and Trim21-/- mice, and the expression of markers associated with kidney injury and Ferroptosis were evaluated. HK-2 cells were treated by RSL3 and Erastin, and a hypoxia/reoxygenation (H/R) model was constructed to simulate I/R injury in vivo.

Key findings: In vivo, TRIM21 is highly expressed in I/R kidney tissues. Loss of TRIM21 alleviated I/R-AKI and improved renal function. The upregulation of GPX4, a key Ferroptosis regulator, and the mild mitochondrial damage suggested that loss of TRIM21 had a negative regulation of Ferroptosis. In vitro, TRIM21 was highly expressed in H/R models, and overexpression of TRIM21 in HK-2 cells increased ROS production, promoted intracellular iron accumulation, and boosted cellular sensitivity to RSL3 and Erastin. Mechanistically, we confirmed that GPX4 is a substrate of TRIM21 and can be degraded by TRIM21-mediated ubiquitination, suggesting that inhibiting TRIM21 attenuates Ferroptosis. A JAK2 Inhibitor Fedratinib downregulated TRIM21 expression and reduced damage both in vivo and in vitro, which is correlated with the upregulation of GPX4.

Significance: Our study showed that loss of TRIM21 could alleviate Ferroptosis induced by I/R, revealed the mechanism of ubiquitination degradation of GPX4 by TRIM21 and suggested TRIM21 is a potential target for the treatment of AKI.

Keywords

AKI; Ferroptosis; GPX4; TRIM21; Ubiquitination degradation.

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