SIRT1-mediated p53 deacetylation inhibits ferroptosis and alleviates heat stress-induced lung epithelial cells injury

Int J Hyperthermia. 2022;39(1):977-986. doi: 10.1080/02656736.2022.2094476.


Objective: Acute lung injury (ALI) is a common complication of heat stroke (HS) and a direct cause of death. However, the mechanism underlying ALI following HS remains unclear.

Method: To investigate whether ferroptosis is involved in HS-ALI. We established a HS model of mice and mouse lung epithelial-2 cells (MLE-2). The severity of lung injury was measured by H&E staining, the wet-to-dry lung weight ratio, and Transmission electron microscopy. Potential markers of ferroptosis Fe2+, malondialdehyde (MDA), hydroxynonenal (4-HNE) and lipid peroxidation were detected. The percentages of cell death and viability induced by HS were assessed by LDH and CCK8 assays. SLC7A11, ACSL4, GPX4, SIRT1, p53, and p53 K382 acetylation levels were measured by Western blot.

Results: The administration of ferroptosis inhibitor ferrostatin-1(Fer-1) could significantly ameliorate lung injury, inhibiting levels of MDA and 4-HNE, and ameliorating HS-induced increased ACSL4, decreased SLC7A11 and GPX4, suggesting ferroptosis was involved in HS-induced ALI in vivo and in vitro. Moreover, SIRT1 expression decreased, and p53 K382 acetylation levels increased in MLE-2 cells. Activation of SIRT1 could improve lung epithelial ferroptosis caused by HS in vivo ang in vitro. Besides, the activation of SIRT1 could significantly reduce the p53 K382 acetylation levels, suggesting that activation of SIRT1 could prevent ferroptosis via inhibiting p53 acetylation.

Conclusion: These findings substantiate the vital role of the SIRT1/p53 axis in mediating ferroptosis in HS-ALI, suggesting that targeting SIRT1 may represent a novel therapeutic strategy to ameliorate ALI during HS.

Keywords: Heat stroke; SIRT1; acute lung injury; ferroptosis; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury* / chemically induced
  • Acute Lung Injury* / etiology
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Ferroptosis*
  • Heat Stroke*
  • Heat-Shock Response
  • Humans
  • Lung* / cytology
  • Lung* / drug effects
  • Lung* / metabolism
  • Sirtuin 1* / metabolism
  • Tumor Suppressor Protein p53* / metabolism


  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • SIRT1 protein, human
  • Sirtuin 1