IL-1β/EPAS1-Associated Ferroptotic Stress Impairs Skeletal Stem/Progenitor Cell Function in Inflammation-Associated...

Area of Science:

• Biomedical Engineering
• Cell Biology
• Regenerative Medicine

Background:

• Atrophic fracture nonunion is a complex failure of bone repair, especially under inflammation.
• The specific cellular mechanisms impairing skeletal stem/progenitor cells (SSPCs) in nonunion are not fully understood.

Purpose of the Study:

• To investigate the cell-intrinsic programs affecting SSPCs in inflammation-associated fracture nonunion.
• To identify molecular targets for improving bone repair in nonunion.

Main Methods:

• Integrated single-cell RNA sequencing data from mouse models of fracture healing and nonunion.
• Employed trajectory inference, transcription factor network analysis, and intercellular communication modeling.
• Validated findings using in vitro and in vivo experiments, including ferroptosis inhibition and EPAS1 pharmacological inhibition.

Main Results:

• SSPCs in nonunion exhibit an undifferentiated, pro-inflammatory, and pro-ferroptotic phenotype, with increased ferroptosis gene expression (e.g., Acsl4).
• Interleukin-1β (IL-1β) was identified as a key inflammatory signal, inducing ferroptosis and impairing osteogenic differentiation in SSPCs via NF-κB and EPAS1.
• Inhibition of EPAS1 with PT2385 rescued SSPC differentiation and improved fracture repair in vivo.
• Mendelian randomization analysis suggested links between IL-1β, EPAS1, and human nonunion risk.

Conclusions:

• An IL-1β/EPAS1-driven ferroptotic program contributes to SSPC dysfunction in inflammation-associated fracture nonunion.
• This ferroptotic pathway represents a potential therapeutic target for enhancing bone repair in nonunion conditions.