Therefore, we suggest that the intracellular (cytoplasmic) distribution of LOXL2 in ESCC probably has a novel biological function, independent of its classical secreted role as extracellular LOXL2, whereby LOXL2 indirectly causes perturbation of actin cytoskeleton through its PPIs in ESCC, and contributes to hyperactivation or loss‐of‐function of some key proteins in carcinogenic pathways to enhance oncogenicity. This evidence concerns the gene LOXL2 and esophageal squamous cell carcinoma.