{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nProcollagen‐lysine, 2‐oxoglutarate 5‐dioxygenase 1 (PLOD1) encodes a lysyl hydroxylase that catalyzes the hydroxylation of lysine residues within collagen’s triple‐helical domain—a critical posttranslational modification required for collagen cross‐linking and proper extracellular matrix formation. This enzymatic activity is central to bone quality and strength, as genetic variations in PLOD1 have been linked to differences in bone mineral density, underscoring its importance in skeletal homeostasis. In addition, the enzyme’s cellular localization and retention in the endoplasmic reticulum, mediated by distinct peptide segments, support its proper function in collagen biosynthesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations and polymorphisms in PLOD1 not only affect collagen modification but also underlie several connective tissue disorders. Deficiency of its lysyl hydroxylase activity is a well‐recognized cause of the kyphoscoliotic type of Ehlers–Danlos syndrome, leading to fragile connective tissues, joint laxity, and abnormal scarring. Moreover, genetic variations in PLOD1 have been implicated in other structural phenotypes such as high myopia and have been linked to vascular abnormalities including aortic aneurysm/dissection, highlighting the multifaceted impact of altered PLOD1 function on tissue integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its structural role, PLOD1 is increasingly recognized as a driver in oncogenic processes. Its overexpression has been documented in a spectrum of malignancies—including mesenchymal glioblastoma, gastrointestinal, bladder, ovarian, and osteosarcoma tumors—where it promotes enhanced cellular proliferation, migration, invasion, and mesenchymal transition. In these cancers, elevated PLOD1 levels correlate with aggressive tumor behavior and poorer prognosis. Mechanistically, PLOD1 interfaces with various cellular signaling networks; it can activate oncogenic pathways such as NF‐κB and PI3K/Akt/mTOR, alter metabolic reprogramming (e.g., enhanced aerobic glycolysis), and even interact with viral proteins like EBNA1, further linking its dysregulation to tumor progression. Its role in clear cell renal cell carcinoma and malignant glioma, mediated through modulation of pathways like Hippo–YAP and HSF1 respectively, underscores the diverse consequences of its aberrant expression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPLOD1 expression is subject to complex regulatory mechanisms involving post‐transcriptional modulation by microRNAs. In several studies, miRNAs such as miR‑34c, miR‑140‑5p, and miR‑449a have been shown to target PLOD1, thereby influencing its downstream effects on cell signaling pathways including NF‑κB, PI3K/Akt/mTOR, HSF1, and Hippo–YAP. These regulatory interactions not only affect tumor cell aggressiveness but have also been linked to differences in disease progression in contexts as diverse as Alzheimer’s disease and transplant rejection, underscoring the broad clinical relevance of PLOD1 modulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yoshiji Yamada, Fujiko Ando, Hiroshi Shimokata "}, {"type": "b", "children": [{"type": "t", "text": "Association of candidate gene polymorphisms with bone mineral density in community-dwelling Japanese women and men."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2007)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17390085"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17390085"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Kati Rautavuoma, Kati Takaluoma, Kaisa Passoja, et al. 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