{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNephronectin (NPNT) is an extracellular matrix protein that has been implicated in genetic regulation of pulmonary function and plays an indispensable role in kidney development. Genome‐wide association studies have identified NPNT among loci associated with forced expiratory volume, hinting at potential contributions to lung physiology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, NPNT is critical for proper renal morphogenesis, as evidenced by murine knockout studies that frequently resulted in kidney agenesis or hypoplasia, and human genetic studies describing NPNT truncating and missense variants leading to congenital renal anomalies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its developmental roles, NPNT modulates tissue homeostasis and differentiation. In osteoblastic cells, NPNT overexpression enhances differentiation and bone nodule formation, with its glycosylation status further influencing these processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In the kidney, NPNT localizes to the glomerular basement membrane and is subject to post‐transcriptional repression by microRNAs, which can compromise glomerular integrity and lead to proteinuria."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Altered NPNT expression has also been observed in diabetic nephropathy"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "and serum NPNT levels are elevated in silicosis patients, correlating with the progression of fibrosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Furthermore, NPNT secreted by osteoblasts acts as a paracrine angiogenic factor, stimulating endothelial cell migration and tube formation during bone remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNPNT is increasingly recognized for its oncogenic roles in various cancers. In gastric cancer, NPNT is markedly overexpressed, where its expression is associated with deeper tumor invasion, advanced stage, and poor prognosis due to enhanced cell proliferation, migration, invasion, and epithelial–mesenchymal transition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In hepatocellular carcinoma, NPNT upregulation promotes metastasis via activation of the FAK/PI3K/AKT signaling pathway."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Additionally, in lung adenocarcinoma, NPNT is involved in the regulation of cancer cell stemness through a microRNA-mediated axis, underscoring its potential as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Dana B Hancock, Mark Eijgelsheim, Jemma B Wilk, et al. 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