{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nOsteopontin (also known as SPP1) is a multifunctional matricellular glycoprotein that plays a central role in regulating immune responses and inflammation. In autoimmune settings such as multiple sclerosis and rheumatoid arthritis, SPP1 is highly expressed and modulates T‐cell polarization—shifting the balance between proinflammatory Th1/Th17 cells and anti‐inflammatory cytokines—as well as influencing dendritic cell function and T‐cell activation. These immune‐modulatory properties suggest that SPP1 contributes to disease severity and is a potential therapeutic target in immune‐mediated disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn neoplastic contexts, SPP1 is frequently overexpressed in several tumors such as hepatocellular carcinoma and gliomas. In hepatocellular carcinoma, elevated SPP1 levels are associated with intrahepatic metastasis and poor patient survival, while functional blockade of SPP1 reduces invasion in vitro and metastasis in vivo. In malignant glioma, SPP1 secreted by tumor cells and host immune cells not only promotes cancer stem cell–like features and radiation resistance but also orchestrates the recruitment of tumor‐promoting macrophages. These findings indicate that SPP1 functions as both a diagnostic marker and a contributor to tumor progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSPP1 further mediates angiogenesis and cell survival by triggering key intracellular signaling pathways. Through binding to integrins and CD44 receptors, it activates cascades such as PI3K/Akt, extracellular signal–regulated kinase (ERK), and NF‑κB, thereby upregulating proangiogenic factors like VEGF and enhancing resistance to apoptosis. In addition, interactions with integrin subtypes—including αvβ6 and αvβ3—support tumor cell migration and invasion, underpinning its role in cancer aggressiveness."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its functions in tumor cell behavior, SPP1 is critically involved in tissue remodeling, fibrosis, and metabolic dysregulation. It is required for myofibroblast differentiation induced by transforming growth factor‑β1, is markedly upregulated in fibrotic lung tissue—including idiopathic pulmonary fibrosis—and serves as a useful molecular marker for osteogenic differentiation in bone marrow stromal cells. Moreover, elevated SPP1 expression in adipose tissue and its altered isoform pattern are linked with obesity‐associated inflammation, insulin resistance, and even contribute to disease variability in Duchenne muscular dystrophy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWithin the tumor microenvironment, SPP1 influences a wide range of processes that favor malignancy. It can anchor leukemic blasts within the bone marrow niche, thereby promoting dormancy and chemotherapy resistance, and it acts as an instructive cue for converting mesenchymal cells into cancer‐associated fibroblasts—further fueling tumor growth and metastasis. In addition, SPP1 supports cell migration in prostate cancer, facilitates osteoclastogenesis and angiogenesis in multiple myeloma, and has been incorporated into prognostic signatures for esophageal adenocarcinoma. Its dysregulation, as observed in genetic disorders like spondyloenchondrodysplasia, further implicates SPP1 in autoimmune pathogenesis and vascular remodeling observed in abdominal aortic aneurysm."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOwing to its diverse roles in modulating immune responses, promoting cell survival and invasion, and orchestrating microenvironmental remodeling, SPP1 is emerging as an important biomarker with significant prognostic and diagnostic value. Elevated SPP1 levels in patient biofluids and tumor tissues have been linked with ovarian, gastric, and head and neck cancers, highlighting its potential for early detection and as a target for novel therapeutic interventions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "D Chabas, S E Baranzini, D Mitchell, et al. 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