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  3. Multi-omics Analysis Reveals the Propagation Mechanism of Ferroptosis in Acute Kidney Injury

Multi-omics Analysis Reveals the Propagation Mechanism of Ferroptosis in Acute Kidney Injury

  • Inflammation. 2025 May 13. doi: 10.1007/s10753-025-02311-7.
Yu Hong 1,  Qi An 1,  Zheng Wang 1,  Bin Hu 1,  Yi Yang 2,  Rui Zeng 3 4,  Ying Yao 5 6
Affiliations

Affiliations

  • 1 Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
  • 2 Department of Public Health, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
  • 3 Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. zengrui@tjh.tjmu.edu.cn.
  • 4 Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, China. zengrui@tjh.tjmu.edu.cn.
  • 5 Department of Nephrology, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China. yaoyingkk@126.com.
  • 6 Department of Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China. yaoyingkk@126.com.
PMID: 40358793 DOI: 10.1007/s10753-025-02311-7
Abstract

Acute kidney injury (AKI) is a prevalent and critical clinical condition characterized by high morbidity and mortality. Recently, numerous studies have implicated Ferroptosis, an iron-dependent programmed cell death process, in the pathophysiology of AKI. Despite this, the mechanism underlying the widespread occurrence of Ferroptosis in AKI remains elusive. To address this, our study analyzed snRNA-seq data from AKI and healthy renal tissues. The analysis revealed notable differences in Ferroptosis activity within proximal tubule (PT) cells of AKI patients, specifically highlighting a strong correlation between Ferroptosis and the expression of genes GPX4, FTH1, and FTL. Spatial transcriptomics confirmed that the genes GPX4, FTH1, and FTL play a crucial role in driving Ferroptosis propagation in AKI. Furthermore, utilizing a mouse model of bilateral renal ischemia-reperfusion injury, we validated the emergence of Ferroptosis mediated by these key genes following AKI. The findings from our in vivo experiments were consistent with the spatial transcriptomics data. Chromatin accessibility and transcription factor analysis identified KLF6 as a repressor of ferroptosis-related genes. An in-depth analysis of PT revealed a subpopulation closely associated with Ferroptosis. The cellular microenvironment within this subpopulation may regulate Ferroptosis through the SPP1 signaling pathway, ultimately influencing the outcome of PT following AKI. In conclusion, this study elucidates the crucial role of GPX4, FTH1, and FTL in Ferroptosis propagation during AKI and underscores the potential therapeutic benefits of targeting Ferroptosis in the management of AKI.

Keywords

Acute kidney injury (AKI); FTH1; FTL; Ferroptosis; GPX4; Proximal tubules.

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