FOSB-HDAC6 complex drives hepcidin-mediated ferroptosis in pulmonary ischemia-reperfusion injury

Pulmonary ischemia-reperfusion (I/R) injury is a severe, life-threatening complication often seen after thoracic surgery, with current therapeutic options being limited. Ferroptosis, a form of iron-dependent regulated cell death, significantly contributes to the lung damage observed in I/R injury. However, the precise transcriptional mechanisms regulating ferroptosis in this context remain poorly understood. Understanding these pathways is crucial for developing targeted interventions to protect lung tissue.

Researchers employed integrated murine pulmonary I/R models and hypoxia/reoxygenation (H/R)-treated lung epithelial cells to investigate the molecular mechanisms of ferroptosis. They utilized Transcriptomics, proximity-dependent biotin labeling (TurboID), chromatin immunoprecipitation (ChIP), co-immunoprecipitation (co-IP), and luciferase reporter assays to delineate the FOSB-HDAC6-HAMP axis. Functional rescue assays were also performed. Molecular markers were quantified using RT-qPCR, immunoblotting, and various biochemical kits to assess gene expression, protein levels, and cellular iron/ROS status.

I/R injury significantly upregulated FOSB expression in lung tissues, which correlated with distinct alterations in ferroptosis markers. Specifically, there was a reduced expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), alongside an elevated expression of acyl-coenzyme A synthetase long-chain family member 4 (ACSL4). These changes were accompanied by an accumulation of ferrous iron (Fe2+) and increased levels of reactive oxygen species (ROS). Mechanistically, FOSB was found to directly bind the HAMP promoter at the -600/-300 bp region, thereby inducing hepcidin expression. Furthermore, HDAC6 physically interacted with FOSB and enhanced its occupancy on the HAMP promoter, which amplified hepcidin production. > HAMP overexpression reversed the protective effects observed when FOSB was knocked down in vitro, confirming its critical role in mediating ferroptosis. This establishes a clear link between the FOSB-HDAC6 complex and hepcidin-driven iron overload and ferroptosis.