Natural killer cell dysfunction drives keloid pathogenesis.

Keloids are pathological scars caused by dysregulated wound healing, characterized by fibroblast hyperproliferation and excessive extracellular matrix deposition. Natural killer (NK) cells restrain aberrant cell growth through IFN-γ but also produce amphiregulin (AREG), which promotes tissue repair and cell survival. The role of NK cells in keloid pathogenesis remains unclear. Here, we identify functional alterations in NK cells in lesional skin and peripheral blood from people with keloids. In lesions, NK cell-derived IFN-γ limits fibroblast survival and matrix production, whereas NK cell-derived AREG counteracts these effects. Fibroblast-derived TGF-β further suppresses NK cell IFN-γ production, forming a local immunoregulatory loop. Systemically, people with keloids exhibit increased plasma IFN-β, which induces a distinct circulating NK cell subset with elevated IFN-stimulated genes and reduced IFN-γ production. Elevated IFN-β suppresses PI3K-AKT signaling and promotes NK cell exhaustion through mitochondrial and metabolic dysfunction, linking local and systemic NK cell dysregulation in keloids.