The role of the LOX family in cancer

Lysyl oxidase (LOXs) are copper-dependent enzymes traditionally known for catalyzing the cross-linking of collagen and elastin, thereby ensuring extracellular matrix (ECM) stability. However, growing evidence reveals that their biological functions extend far beyond ECM remodeling. This review highlights the diverse roles of the LOX family, comprising LOX, LOXL1, LOXL2, LOXL3, and LOXL4, in tissue repair, vascular remodeling, inflammation, and cancer. Each isoform exhibits unique structural domains, regulatory pathways, and functional interactions with signaling cascades such as TGF-β, PDGF, VEGF, and HIF-1α. LOXs are essential for wound healing, coordinating ECM synthesis and cross-linking during different phases of tissue regeneration. Their expression is tightly modulated by inflammatory cytokines, and their dysregulation has been implicated in pathological fibrosis and impaired tissue repair. In cancer, LOXs contribute to epithelial-to-mesenchymal transition (EMT), cell invasion, and metastasis through both enzymatic and non-enzymatic mechanisms, including intracellular signaling, Snail1 stabilization, and cytoskeletal modulation. They also influence angiogenesis by regulating VEGF expression and promoting endothelial cell activation via PDGFRβ-AKT signaling. Intracellular and nuclear functions further expand their impact on gene regulation and chromatin structure. Given their involvement in matrix dynamics, mechanotransduction, and cell fate determination, LOXs emerge as key players in both physiological and pathological contexts. Understanding their multifactorial roles opens potential avenues for therapeutic targeting in cancer, fibrosis, and chronic inflammatory diseases.