PLOD3 encodes a multifunctional enzyme catalyzing post-translational modifications of lysine residues in procollagen. It hydroxylates lysyl residues within collagenous -Xaa-Lys-Gly- sequences and plays a redundant role with PLOD1 and PLOD2 in forming hydroxylysine residues 1. Uniquely among lysyl hydroxylase isoforms, PLOD3 possesses both glucosyltransferase and galactosyltransferase activities, transferring glucose and galactose moieties to create 1,2-glucosylgalactosyl-5-hydroxylysine residues—modifications essential for normal type IV collagen biosynthesis and basement membrane formation 2. Loss-of-function variants cause BCARD syndrome (bone fragility with contractures, arterial rupture, and deafness) and connective tissue disorders due to lysyl hydroxylase-3 deficiency, reflecting the gene's critical structural role in extracellular matrix integrity. Beyond its canonical collagen-modifying function, PLOD3 has emerged as a driver of malignancy. In colorectal cancer, PLOD3 overexpression—driven by promoter hypomethylation—enhances cell proliferation, invasion, and migration through the PLOD3/TM9SF4 autophagy axis and TNF-α/NF-κB signaling, correlating with poor prognosis [PMID:40133271; 36]. In glioblastoma, hypoxia-driven M2-polarized macrophages deliver circ_0003137-enriched extracellular vesicles to tumor cells, where the circular RNA stabilizes PLOD3 expression via PTBP1, promoting epithelial-mesenchymal transition 4. PLOD3 elevation also marks high-grade intraductal papillary neoplasms of the pancreas 5. Given these cancer associations, PLOD3 represents a therapeutic target; targeting circ_0003137 or disrupting PLOD3 expression has shown promise in preclinical glioblastoma and colorectal cancer models.