2. Academic Validation
  3. Crucial roles of asprosin in cisplatin-induced ferroptosis and acute kidney injury

Crucial roles of asprosin in cisplatin-induced ferroptosis and acute kidney injury

  • Free Radic Biol Med. 2025 Feb 1:227:296-311. doi: 10.1016/j.freeradbiomed.2024.12.024.
Fen Zheng 1,  Jian-Zhen Lei 2,  Jing-Xiao Wang 2,  Xiao-Yu Xu 2,  Bing Zhou 3,  Rui Ge 2,  Min Dai 2,  Hong-Ke Dong 2,  Nan Wu 2,  Yue-Hua Li 4,  Guo-Qing Zhu 5,  Ye-Bo Zhou 6
Affiliations

Affiliations

  • 1 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, and Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China; The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
  • 2 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, and Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
  • 3 Department of Pathology, Yijishan Hospital, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, 241001, China.
  • 4 Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
  • 5 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, and Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. Electronic address: gqzhucn@njmu.edu.cn.
  • 6 Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, and Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. Electronic address: zhouyebo666@njmu.edu.cn.
PMID: 39653130 DOI: 10.1016/j.freeradbiomed.2024.12.024
Abstract

Ferroptosis is a type of non-apoptotic regulated cell death characterized by iron accumulation and lipid peroxidation. Cisplatin is an effective chemotherapy drug with several serious side effects including acute kidney injury (AKI). Asprosin is a peptide contributing to metabolism regulation and metabolic disorders. This study aimed to determine the role and mechanism of asprosin in AKI. Cisplatin was used to induce cell damage in mouse renal tubular epithelial (TCMK-1) cells and AKI in C57BL/6 mice. Cisplatin caused asprosin upregulation in cisplatin-treated TCMK-1 cells and mice. In TCMK-1 cells, asprosin overexpression led to iron overload and lipid peroxidation, while asprosin knockdown attenuated cisplatin-induced iron overload, lipid peroxidation and Ferroptosis. Exogenous asprosin promoted cell damage and Ferroptosis, which were attenuated by Ferroptosis inhibitors. Asprosin-induced iron overload, lipid peroxidation, cell damage and SMAD1/5/8 phosphorylation were prevented by bone morphogenetic protein (BMP) type I receptor inhibitor. Integrin Antagonist prevented asprosin-induced SMAD1/5/8 phosphorylation, and asprosin can specifically bind to Integrin β3. Inhibition of Integrin β3 reduced the asprosin-induced increases in Fe2+ and MDA levels. Asprosin knockdown relieved cisplatin-induced hepcidin upregulation, while hepcidin knockdown attenuated asprosin-induced iron overload, lipid peroxidation and Ferroptosis. In cisplatin-induced AKI mice, specific knockdown of asprosin in the kidney not only attenuated renal dysfunction and damage, but also alleviated iron overload, lipid peroxidation and Ferroptosis. These results indicated that excessively increased asprosin promotes TCMK-1 cells Ferroptosis and damage via Integrin β3/BMP/hepcidin-mediated iron overload and lipid peroxidation. Silencing of asprosin attenuates renal injury and dysfunction in cisplatin-induced AKI by inhibiting Ferroptosis.

Keywords

Acute kidney injury; Asprosin; Cisplatin; Ferroptosis; Iron overload; Lipid peroxidation.

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