LOXL4: a key regulatory factor at the intersection of fibrosis and tumor progression

Lysyl oxidase-like protein 4 (LOXL4), a key member of the lysyl oxidase (LOX) family, is an important regulator of extracellular matrix (ECM) remodeling. Emerging evidence indicates that LOXL4 contributes to organ fibrosis by promoting collagen and elastin cross-linking, increasing matrix stiffness, and modulating aberrant mechanotransduction. In tumors, LOXL4 also facilitates the establishment of a fibrotic and immunosuppressive microenvironment. Through collagen cross-linking and ECM stiffening, LOXL4 can enhance TGF-β signaling, reinforce the ECM barrier, and promote immune exclusion, thereby altering the functions of immune cells such as T cells and macrophages and contributing to both fibrotic and tumor progression. Beyond its classical enzymatic activity, LOXL4 exerts non-enzymatic effects on cell adhesion, migration, and cell-microenvironment interactions, further expanding its pathological roles. In this review, we summarize the molecular characteristics, expression regulation, and enzymatic and non-enzymatic functions of LOXL4, with particular emphasis on the shared mechanisms linking fibrosis and tumor progression, including TGF-β signaling, ECM barrier formation, and immune microenvironment remodeling. We further discuss therapeutic strategies targeting LOXL4 and other LOX family members, as well as current challenges in clinical translation and opportunities for precision intervention. Collectively, LOXL4 represents a key molecular link between ECM remodeling, fibrotic responses, and tumor progression. However, the clinical development of LOXL4-targeted therapies remains limited by functional heterogeneity, the lack of robust biomarkers, and compensatory mechanisms within the LOX family. Future studies integrating precise patient stratification, dynamic assessment of therapeutic responses, and rational combination strategies may facilitate the clinical translation of LOXL4-targeted interventions.