Targeting the Immunometabolic Checkpoint IL4I1 Suppresses the Progression of Pathological Scars

Keloids are refractory fibroproliferative disorders driven by dysregulated fibrosis and chronic inflammation. Current research has largely focused on the TGF-β signaling pathway and fibroblasts-the classical drivers of keloid formation-yet clinical outcomes remain unsatisfactory. To address this, we shifted our research focus to the immunometabolic axis, with particular emphasis on the regulatory role of IL4I1 (an amino acid oxidase) as an immunometabolic checkpoint. Our results demonstrated that IL4I1 was significantly upregulated in keloid tissues, accompanied by activation of its mediated tryptophan-kynurenine metabolic pathway and increased downstream lipid peroxidation products. In vivo knockout of Il4i1 suppressed collagen deposition in a skin fibrosis model, confirming that IL4I1 plays a critical facilitatory role in fibrotic progression. We performed drug screening and identified L-carnosine as an inhibitor of IL4I1. L-carnosine inhibits the enzymatic activity and protein stability of IL4I1, and exhibits prominent therapeutic efficacy in a keloid nude-mouse xenograft model. Through its enzymatic activity, IL4I1 mediates dendritic-cell-driven immunometabolic reprogramming and the formation of an immunosuppressive microenvironment, consequently accelerating fibrotic progression. This study highlights IL4I1 as a therapeutic target, and its small-molecule inhibitor L-carnosine holds promise to be translated into a safe and clinically attractive therapeutic modality.