WWOX protects against ferroptosis to alleviate acute lung injury by mediating p53 deacetylation

Cheng Wang; Cheng Qing; Weiguo Chen; Huiming Yao; Zhiguo Hu; Chaoqi Zhou; Yuting Yang; Sunit Singla; Zhenguo Zeng

doi:10.1016/j.intimp.2025.116067

WWOX protects against ferroptosis to alleviate acute lung injury by mediating p53 deacetylation

Int Immunopharmacol. 2026 Feb 1:170:116067. doi: 10.1016/j.intimp.2025.116067. Epub 2025 Dec 23.

Authors

Cheng Wang¹, Cheng Qing¹, Weiguo Chen², Huiming Yao¹, Zhiguo Hu¹, Chaoqi Zhou¹, Yuting Yang¹, Sunit Singla³, Zhenguo Zeng⁴

Affiliations

¹ Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China; Key Laboratory of Critical Care Medicine, Jiangxi Provincial Health Commission, Nanchang 330000, China.
² Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, IL, United States.
³ Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, IL, United States. Electronic address: ssingl6@uic.edu.
⁴ Department of Critical Care Medicine, Medical Center of Anesthesiology and Pain, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China; Key Laboratory of Critical Care Medicine, Jiangxi Provincial Health Commission, Nanchang 330000, China. Electronic address: zengzhenguo@ncu.edu.cn.

PMID: 41443103
DOI: 10.1016/j.intimp.2025.116067

Abstract

Ferroptosis plays a crucial role in the pathophysiology of acute lung injury (ALI), but its regulatory mechanisms remain elusive. In this study, we found that WW domain-containing oxidoreductase (WWOX) acts as a pivotal regulator of lung epithelial cell ferroptosis during ALI. Initially, the involvement of ferroptosis in the onset and progression of lipopolysaccharide (LPS)-induced ALI was confirmed through ferrostatin-1 (Fer-1) intervention. RNA-seq revealed a negative correlation between WWOX expression and ferroptosis. Erastin consistently exacerbated LPS-induced ALI and ferroptosis, and these effects were significantly mitigated by WWOX overexpression. Mechanistically, SLC7A11 is negatively regulated by p53, a ferroptosis-related gene. In this study, we observed that WWOX mediated p53 deacetylation and enhanced SLC7A11 expression. Our findings suggest that WWOX is a crucial regulator of ferroptosis anda potential therapeutic target for ALI treatment.

Keywords: Acute lung injury (ALI); Deacetylation; Ferroptosis; WWOX; p53.

MeSH terms

Acetylation
Acute Lung Injury* / chemically induced
Acute Lung Injury* / genetics
Acute Lung Injury* / metabolism
Acute Lung Injury* / pathology
Amino Acid Transport System y+ / genetics
Amino Acid Transport System y+ / metabolism
Animals
Ferroptosis*
Humans
Lipopolysaccharides
Lung / pathology
Male
Mice
Mice, Inbred C57BL
Piperazines
Tumor Suppressor Protein p53* / metabolism
Tumor Suppressor Proteins* / genetics
Tumor Suppressor Proteins* / metabolism
WW Domain-Containing Oxidoreductase* / genetics
WW Domain-Containing Oxidoreductase* / metabolism

Substances

WW Domain-Containing Oxidoreductase
Tumor Suppressor Protein p53
Lipopolysaccharides
Amino Acid Transport System y+
Tumor Suppressor Proteins
WWOX protein, human
SLC7A11 protein, human
erastin
Piperazines