{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HtrA3 is a multifunctional serine protease belonging to the HtrA family that is expressed in a highly tissue‐ and context‐dependent manner. In reproductive tissues it is best known for its roles in placental development and ovarian function. Two alternatively spliced isoforms—a long form containing a PDZ domain and a short form lacking this domain—are produced, and both appear to be active proteases. HtrA3 is highly expressed in the placenta, where it is involved in regulating trophoblast differentiation and invasiveness, thereby contributing to proper implantation and placentation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " In the primate and rodent ovary HtrA3 has been implicated in folliculogenesis and luteinization, with altered expression potentially affecting fertility and reproductive outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its reproductive functions, HtrA3 has emerged as a key player in cancer biology. Loss or epigenetic downregulation of HtrA3 is observed in several malignancies such as lung, breast, endometrial, ovarian, and gastric cancers, where its diminished expression is associated with increased cell survival, chemoresistance, metastasis, and poor prognosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": " In contrast, in some contexts—for example, in oral squamous cell carcinoma—upregulation of HtrA3 has been linked to the acquisition of an invasive phenotype."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Furthermore, experimental inhibition of HtrA3 proteolytic activity using dominant‐negative mutants or specific monoclonal antibodies enhanced trophoblast and cancer cell invasion, suggesting that HtrA3 normally acts to restrain invasive behavior."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structural and biochemical studies have further delineated the regulatory mechanisms of HtrA3 activity. Crystal structures reveal that although the PDZ domain is not essential for substrate binding and protease activity, its presence modulates oligomerization and may contribute to substrate specificity and stability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " As a secreted protease with a complex domain organization, HtrA3 also shows promise as a diagnostic marker; for instance, elevated serum levels have been suggested as an early indicator for preeclampsia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in reproduction and cancer, HtrA3 has been identified as a candidate gene in neurodevelopmental disorders"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", highlighting its broader significance in cell signaling and apoptosis. Collectively, these data support the notion that HtrA3 functions as a critical regulator of cell fate and tissue homeostasis, with its dysregulation contributing to pathologies ranging from placental dysfunction and infertility to tumor progression and chemoresistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " \n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Gui-Ying Nie, Anne Hampton, Ying Li, et al. 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