LOXL4

LOXL4 Full Name

lysyl oxidase like 4

LOXL4 Introduction

Lysyl oxidase-like 2 (LOXL2) is a copper-dependent amine oxidase belonging to the lysyl oxidase (LOX) family of extracellular matrix (ECM)-modifying enzymes. Encoded by the LOXL2 gene on chromosome 8p21.3, LOXL2 catalyzes the oxidative deamination of the ε-amino group of lysine and hydroxylysine residues in collagen and elastin, generating highly reactive aldehyde intermediates that undergo spontaneous condensation reactions to form covalent cross-links between ECM protein monomers. This cross-linking activity is essential for the stabilization and maturation of collagen fibrils and elastic fibers, conferring tensile strength and structural integrity to connective tissues. Beyond its extracellular enzymatic function, LOXL2 has been shown to have intracellular roles in transcriptional regulation through histone modification and modulation of signaling pathways.

Figure 1. Strcuture of LOXL4.

Enzymatic Mechanism and Dual Extra- and Intracellular Functions
LOXL2 contains a conserved C-terminal catalytic domain with a copper-binding site coordinated by three histidine residues and a lysyl-tyrosyl quinone (LTQ) cofactor formed by the post-translational cross-linking of a lysine and a tyrosine residue within the active site. The LTQ cofactor mediates the oxidative deamination reaction, converting peptidyl lysine to the aldehyde allysine, with the concomitant production of hydrogen peroxide and ammonia as byproducts. LOXL2's N-terminal region contains four scavenger receptor cysteine-rich (SRCR) domains that mediate protein-protein interactions and substrate recognition. Importantly, LOXL2 is not restricted to the extracellular space: it contains a functional nuclear localization signal and has been detected in the nucleus, where it catalyzes the oxidative deamination of lysine residues on histone H3, promoting chromatin compaction and gene silencing. LOXL2 also deaminates lysine residues on non-ECM substrates including Akt and Snail, modulating their activities. This dual compartmentalization positions LOXL2 at the interface of ECM architecture and intracellular signaling.

LOXL2 in Fibrosis, Cancer Metastasis, and Therapeutic Inhibition
LOXL2 has emerged as a major pathogenic mediator of fibrosis and a driver of tumor metastasis. In fibrotic diseases including idiopathic pulmonary fibrosis (IPF), liver cirrhosis, and cardiac fibrosis, LOXL2 is strongly upregulated by TGF-β and other pro-fibrotic stimuli, and its collagen cross-linking activity stabilizes pathological ECM deposits that resist proteolytic degradation, perpetuating tissue stiffening and organ dysfunction. The humanized anti-LOXL2 monoclonal antibody simtuzumab was evaluated in clinical trials for IPF, liver fibrosis (NASH), and pancreatic cancer, though clinical efficacy endpoints were not met, prompting refinement of therapeutic strategies. In cancer, LOXL2 promotes epithelial-mesenchymal transition (EMT) through stabilization of the Snail transcription factor, leading to E-cadherin repression and acquisition of invasive and migratory properties. LOXL2-mediated ECM stiffening also activates integrin-mediated mechanosignaling pathways (including FAK and YAP/TAZ) that drive tumor progression and metastasis. A second generation of LOXL2-selective small-molecule inhibitors and antibody-drug conjugates is under active preclinical and clinical development for oncology and anti-fibrotic indications.

Alternate Names for LOXL4

LOXL4; lysyl oxidase like 4; LOXC