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Published on: March 15, 2024
FOSB deacetylation by HDAC6 drives HAMP-mediated ferroptosis in pulmonary ischemia-reperfusion injury
Tian Xia1, Wantong Zheng1, Chen Wang1
1Department of Thoracic Surgery, Zhengzhou University People's Hospital, Zhengzhou, Henan, 450000, China.
Background:
Pulmonary ischemia-reperfusion (I/R) injury is a life-threatening complication of thoracic surgery with limited therapeutic options. While ferroptosis contributes significantly to lung damage, its transcriptional regulation remains poorly understood.
Methods:
Murine pulmonary I/R models and hypoxia/reoxygenation (H/R)-treated lung epithelial cells were integrated to explore the molecular mechanisms underlying ferroptosis. Transcriptomics, proximity-dependent biotin labeling using a promiscuous biotin ligase (TurboID), chromatin immunoprecipitation (ChIP), co-immunoprecipitation (co-IP), luciferase reporter assays, and functional rescue assays were employed to delineate the FosB proto-oncogene, activator protein-1 (AP-1) transcription factor subunit (FOSB)-histone deacetylase 6 (HDAC6)-hepcidin antimicrobial peptide (HAMP) axis. Molecular markers were assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunoblotting, and biochemical kits.
Results:
I/R injury upregulated FOSB expression in lung tissues, correlating with alterations in ferroptosis markers, including reduced expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), concomitant with elevated expression of acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), accumulation of ferrous iron (Fe2+), and increased levels of reactive oxygen species (ROS). FOSB directly bound the HAMP promoter at -600/-300 bp, inducing HAMP expression. HDAC6 physically interacted with and deacetylated FOSB. This deacetylation enhanced the promoter occupancy and transcriptional activity of FOSB, thereby amplifying HAMP production. HAMP overexpression reversed FOSB knockdown-mediated protection against ferroptosis in vitro.
Conclusion:
The FOSB-HDAC6 complex, via deacetylation of FOSB, transcriptionally activates HAMP to drive HAMP-mediated iron overload and ferroptosis in pulmonary I/R injury, revealing a targetable axis for lung protection.
