2. Academic Validation
  3. Lutein attenuates rhabdomyolysis-induced acute kidney injury by inhibiting ACSL4-mediated ferroptosis

Lutein attenuates rhabdomyolysis-induced acute kidney injury by inhibiting ACSL4-mediated ferroptosis

  • Biomed Pharmacother. 2025 Jul:188:118222. doi: 10.1016/j.biopha.2025.118222.
Chao Liu 1,  Zhangning Fu 2,  Wuhong Zhou 3,  Xian Chang 4,  Yating Cui 1,  Xiaodong Geng 5,  Quan Hong 2,  Yangfan Lv 6,  Feihu Zhou 7
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, The First Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100853, People's Republic of China.
  • 2 Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, 100853, People's Republic of China.
  • 3 Outpatient Department, 984th Hospital of Joint Logistic Support Force of Chinese People's Liberation Army, Beijing, People's Republic of China.
  • 4 Department of Orthopaedics, Xinqiao Hospital, The Army Medical University, Chongqing 400037, People's Republic of China.
  • 5 Department of Nephrology, First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, 100853, People's Republic of China; Healthcare Office of Service Bureau, Agency for Offices Administration, Central Military Commission, People's Republic of China, Beijing 100034, People's Republic of China.
  • 6 Department of Pathology, Xinqiao Hospital, Army Medical University, Chongqing 400037, People's Republic of China. Electronic address: lovelvyangfan@163.com.
  • 7 Department of Critical Care Medicine, The First Medical Center of Chinese People's Liberation Army General Hospital, Beijing, 100853, People's Republic of China. Electronic address: feihuzhou301@126.com.
PMID: 40460552 DOI: 10.1016/j.biopha.2025.118222
Abstract

Background: The nephrotoxicity of myoglobin released during rhabdomyolysis (RM) is the main cause of RM-induced acute kidney injury (AKI), leading to iron overload in renal tubular cells. Ferroptosis is characterized by iron overload and iron-dependent accumulation of lipid peroxidation. ACSL4 is a sensitive regulator and important contributor to Ferroptosis which promotes lipid peroxidation and consequently results in acute tubular necrosis. The role of Ferroptosis and ACSL4 in RM-induced AKI remains unclear. Therefore, we conducted this study, aiming to evaluate the potential role of Ferroptosis in the progression of RM-induced AKI and determine whether lutein could act as a potential pharmaceutical against Ferroptosis in renal tubules by suppressing ACSL4 expression.

Methods: The Real-Time PCR, western blot, TUNEL staining, immunohistochemistry and transmission electron microscopy were used to evaluate the renal function, lipid peroxidation changes, histological changes and mitochondrial morphology changes in this model.

Results: The KEGG pathway analysis suggested that Ferroptosis pathway played a significant role in RM-induced AKI. ACSL4 was upregulated in the RM-induced AKI mice model and tubule-specific knockout of ACSL4 markedly reduced Ferroptosis as well as attenuated the functional, pathological and mitochondrial damage in this model. Furthermore, lutein improves renal function by combining with ACSL4 to reduce the occurrence of Ferroptosis.

Conclusions: Tubule-specific knockout of ACSL4 confers protection against RM-induced AKI by inhibiting Ferroptosis. Lutein has been shown to prevent Ferroptosis in renal tubules by suppressing the expression of ACSL4, suggesting its potential as a pharmaceutical agent to alleviate RM-induced AKI.

Keywords

ACSL4; Acute Kidney Injury; Ferroptosis; Lutein; Rhabdomyolysis.

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