Antibiotic‐Loaded Polymethyl Methacrylate Cement Drives Fibroblast‐Mediated Angiogenesis via <scp>LOXL2</scp> to Accelerate Diabetic Foot Ulcer Healing

ABSTRACT Antibiotic‐loaded polymethylmethacrylate (PMMA) cement (APC) improves healing in diabetic foot ulcers (DFUs), yet the cellular mechanisms underlying its pro‐angiogenic effects remain unclear. This study aimed to identify key cell populations and molecular pathways by integrating scRNA‐seq and proteomic profiling. DFU wound tissues, treated with APC or controls, were analyzed for differentially expressed proteins (DEPs) using label‐free quantitative proteomics. Paired scRNA‐seq identified APC‐responsive cell populations, and pseudotime and BEAM analyses, integrated with proteomic data, pinpointed key regulatory genes. The analysis revealed that APC treatment specifically upregulated 63 DEPs. scRNA‐seq of 20 245 cells identified six major cell types, with fibroblasts showing significant expansion and transcriptional changes. Further analysis identified LOXL2 as a central regulator of fibroblast remodeling. LOXL2 high fibroblasts were enriched in healed wounds and promoted angiogenesis through ANGPTL2‐ITGA5‐mediated endothelial interactions. In vivo, LOXL2 facilitated wound closure and collagen deposition. Our findings suggest that LOXL2 emerges as a core molecular target for APC therapy in diabetic foot ulcers by reshaping fibroblast heterogeneity and enhancing fibroblast‐endothelial cell communication.