{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSERPINE2—also known as protease nexin‑1 or serpinE2—is a secreted serine protease inhibitor that has emerged as a multifaceted regulator in cancer. In several tumor types including breast, colorectal, esophageal, testicular, gastric, melanoma, osteosarcoma and thyroid cancers, aberrant SERPINE2 expression (or that of its circular RNA isoforms) has been linked to enhanced tumor cell invasion, metastasis, and the acquisition of stem‐like properties. Through modulation of extracellular proteolysis, activation of key mitogenic pathways (such as ERK signaling) and promotion of epithelial‐to‐mesenchymal transition as well as vascular mimicry, SERPINE2 helps create a tumor‐promoting microenvironment and is being investigated both as a prognostic marker and potential therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the pulmonary and vascular systems, genetic association studies have implicated SERPINE2 as a modifier in chronic obstructive pulmonary disease and related emphysematous changes. Its expression in platelets, endothelial cells and pericytes helps modulate key processes such as thrombin‐ and plasminogen activator–dependent proteolysis, thereby influencing coagulation, fibrinolysis and angiogenesis. Furthermore, SERPINE2 is linked to variations in bronchodilator responsiveness and airway wall remodeling, emphasizing its role in maintaining pulmonary homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond cancer and pulmonary disease, SERPINE2 is also involved in other physiological and pathological processes. In articular cartilage, for example, its expression in chondrocytes is regulated by proinflammatory stimuli and may modulate matrix metalloproteinase induction in osteoarthritis. In reproductive tissues, elevated SERPINE2 in cumulus cells is associated with impaired oocyte maturation, while in the brain, SERPINE2 produced by astrocytes and modulated by glycosaminoglycan‐dependent uptake mechanisms may regulate protease activity relevant to neural function. Additional studies have connected SERPINE2 to intervertebral disc homeostasis, diabetic neuropathy and extracellular matrix remodeling in fibrotic and inflammatory states—all of which underscore the diverse regulatory roles of this serpin at the tissue and cellular levels."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Albrecht Neesse, Martin Wagner, Volker Ellenrieder, et al. 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