CD36 promotes tubular ferroptosis by regulating the ubiquitination of FSP1 in acute kidney injury

Yixin Ma; Lili Huang; Zheng Zhang; Pengfei Yang; Qingsong Chen; Xujia Zeng; Fangyan Tan; Chunxia Wang; Xiongzhong Ruan; Xiaohui Liao

doi:10.1016/j.gendis.2022.12.003

CD36 promotes tubular ferroptosis by regulating the ubiquitination of FSP1 in acute kidney injury

Genes Dis. 2023 Jan 3;11(1):449-463. doi: 10.1016/j.gendis.2022.12.003. eCollection 2024 Jan.

Authors

Yixin Ma¹, Lili Huang¹, Zheng Zhang^{1

2}, Pengfei Yang¹, Qingsong Chen¹, Xujia Zeng¹, Fangyan Tan¹, Chunxia Wang¹, Xiongzhong Ruan^{3

4

5}, Xiaohui Liao^{1

5}

Affiliations

¹ Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
² Department of Cell Biology and Genetics, Chongqing Medical University, Chongqing 400016, China.
³ Centre for Nephrology, Royal Free and University College Medical School, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, United Kingdom.
⁴ Centre for Lipid Research, Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
⁵ Kuanren Laboratory of Translational Lipidology, Centre for Lipid Research, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.

Abstract

Reactive oxidative species (ROS) production-driven ferroptosis plays a role in acute kidney injury (AKI). However, its exact molecular mechanism is poorly understood. Scavenger receptor CD36 has important roles in oxidizing lipids, lipid accumulation, metabolic syndrome, and insulin resistance in chronic kidney disease, but its roles remain unexplored in AKI. The present study investigated the role and mechanism of CD36 in regulating proximal tubular cell ferroptosis and AKI. The expression of CD36 was found to be significantly up-regulated in AKI renal tissues and correlated with renal function, which might serve as an independent biomarker for AKI patients. Moreover, in adult mice subjected to AKI, deletion of CD36 (CD36^-/-) induced tubular cell ROS accumulation, ferroptosis activation, and renal injury. Mechanistically, combining LC-MS/MS, co-IP, and ubiquitination analyses revealed that CD36 could specifically bind to ferroptosis suppressor protein 1 (FSP1) and regulate its ubiquitination at sites K16 and K24, leading to FSP1 degradation and progression of ferroptosis in AKI. The present results emphasize a novel mechanism of CD36 in cisplatin-induced AKI. The discovery of the special CD36 roles in promoting ferroptosis and AKI development by regulating the ubiquitination of FSP1 in proximal tubular cells may be potential therapeutic targets for AKI. Moreover, CD36 may play a key role in the progression of AKI. Therefore, targeting CD36 may provide a promising treatment option for AKI.

Keywords: Acute kidney injury; CD36; FSP1; Ferroptosis; Ubiquitin-dependent degradation.