Antibiotic-Loaded Polymethyl Methacrylate Cement Drives Fibroblast-Mediated Angiogenesis via LOXL2 to Accelerate Diabetic Foot Ulcer Healing.

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. LOXL2high 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.