Immune-stimulatory cytokine IL-18 induces inflammatory senescence and impairs stem cell-mediated experimental skeletal regeneration

Stem cell–based therapies offer potential for repairing large skeletal defects, yet persistent inflammation limits their efficacy. Here, we identify macrophage–derived IL-18 as an immune switch that impairs skeletal regeneration by disrupting immune–mesenchymal cell interactions. IL-18 is elevated in male mouse non-healing models and human bone nonunion samples, supporting its translational relevance. Mechanistically, IL-18 acts as an upstream amplifier of inflammation by inducing Serpina3f transcription, thereby driving macrophage senescence and M1 polarization and triggering a feed-forward inflammatory cascade that suppresses mesenchymal stem/stromal cell osteogenesis. Single-cell RNA sequencing and functional assays further show that IL-18 directly impairs mesenchymal stem/stromal cell proliferation, clonogenicity, and mitochondrial fitness. Genetic deletion of IL-18 restores regenerative potential, whereas pharmacological blockade with IL-18–neutralizing antibodies or IL-18 binding protein reverses macrophage dysfunction and promotes bone healing. These findings establish IL-18 as a key mediator of inflammation–induced regenerative failure and a potential therapeutic target for skeletal regeneration. This study identifies IL-18 as an inflammatory switch that drives macrophage dysfunction and impairs stem cell function, thereby limiting skeletal regeneration and revealing a potential therapeutic target for bone repair.