{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPLOD2 encodes a key lysyl hydroxylase that catalyzes the hydroxylation of lysine residues in collagen telopeptides, a post‐translational modification essential for the formation of stable pyridinoline cross‐links. Such cross‐linking plays a central role in fibrotic processes and in disorders of connective tissue such as Bruck syndrome and osteogenesis imperfecta, where mutations in PLOD2 impair proper collagen maturation and lead to skeletal fragility and joint contractures. In addition, alternative splicing events that affect the expression of its “long” isoform have been implicated in the regulation of collagen stability in scleroderma‐related fibrosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn a variety of solid tumors, up‐regulation of PLOD2—often driven by hypoxic conditions and transforming growth factor–β (TGF‐β) signaling—leads to increased collagen cross‐linking and matrix stiffening, thereby facilitating cancer cell invasion and metastasis. Elevated PLOD2 expression has been shown to promote metastatic behavior in sarcoma, glioma, lung, and head and neck cancers, as well as in colorectal, gastric, ovarian, and renal carcinomas. In these settings, PLOD2‐driven remodeling of the extracellular matrix not only creates a “highway” for tumor cell dissemination but also contributes to metabolic reprogramming (for example through the regulation of hexokinase 2) and interactions with key cell surface receptors such as integrins and EGFR that further potentiate migration and invasiveness."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA complex network of regulatory mechanisms controls PLOD2 expression and activity. Hypoxia‐inducible factor–1α (HIF‐1α), TGF‐β/SMAD pathways, and transcription factors such as FOXA1 have been shown to activate PLOD2 transcription, while microRNAs and other epigenetic modifiers finely tune its expression. Furthermore, interactions with cofactors like FKBP65 and post‐translational modifications including dimerization are critical for achieving its full enzymatic activity. Such regulation not only determines the extent of collagen stabilization in fibrotic diseases but also impacts tumor progression by modifying the extracellular environment, thereby influencing signaling cascades and metabolic pathways that contribute to cancer cell stemness and invasion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "43"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Annemarie J van der Slot, Anne-Marie Zuurmond, Alfons F J Bardoel, et al. 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