LOXL3 in cancer and human disease from molecular mechanisms to therapeutic translation

Lysyl oxidase-like 3 (LOXL3) is a copper-dependent member of the lysyl oxidase family that links extracellular matrix remodeling with context-dependent intracellular regulation. Its conserved catalytic region supports collagen and elastin cross-linking, whereas its N-terminal scavenger receptor cysteine-rich domains mediate protein interactions and contribute to non-canonical functions. Genetic variants, engineered animal models, and cancer studies have implicated LOXL3 in developmental disorders, tissue homeostasis, and tumor progression. However, interpretation of this evidence remains challenging. Extracellular and intracellular activities are often considered together, the effects of different isoforms and subcellular pools remain incompletely resolved, and LOXL3-specific functions are sometimes inferred from studies using dual or pan-LOX inhibitors. Moreover, most clinical associations are derived from retrospective expression analyses rather than prospective validation. These limitations obscure which LOXL3 functions are causal, non-redundant, and clinically actionable. This review critically synthesizes structural, genetic, mechanistic, and translational evidence across malignant and non-malignant diseases. It examines how isoform identity, subcellular localization, and tissue context influence LOXL3 activity, distinguishes causal evidence from associative findings, and evaluates its potential as a biomarker and therapeutic target. The available evidence most strongly supports context-dependent roles in developmental abnormalities and selected intracellular mechanisms, whereas oncological and therapeutic applications remain largely preclinical. Together, this review provides a framework for developing isoform-aware models, selective pharmacological tools, standardized biomarkers, and tissue-specific strategies for the clinical investigation of LOXL3.