{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSERPINB3, also known as squamous cell carcinoma antigen‐1, is a multifunctional member of the ov-serpin family that has emerged as a key modulator of cell fate in various malignancies and inflammatory disorders. It is frequently overexpressed in tumors such as hepatocellular carcinoma, melanoma, ovarian and cholangiocarcinoma, where its deregulation is associated with aggressive behavior and poor clinical outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the cellular level, SERPINB3 powerfully attenuates programmed cell death. By interfering with mitochondrial cytochrome c release and modulating caspase cascades, its upregulation confers resistance to apoptosis induced by chemotherapeutic agents and radiation. In addition, its expression is inducible in response to specific stimuli such as Toxoplasma gondii infection via STAT6 activation and is maintained by persistently activated STAT3, thereby protecting both tumor cells and infected host cells from apoptotic demise."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its antiapoptotic capacity, SERPINB3 functions as a cross-class inhibitor of cysteine proteases. It targets enzymes such as papain and various cathepsins through mechanisms that combine classical suicide-inhibitor–like actions with unique non-covalent interactions that lead to irreversible impairment of catalytic function. This inhibitory efficacy is further amplified by cofactors such as heparin, and certain polymorphic variants (for instance, the SCCA-PD isoform) exhibit heightened inhibitory activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSERPINB3 also modulates key oncogenic signaling pathways. It induces TGF-β1 production"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "and suppresses tumor-suppressive microRNAs"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", while hypoxic conditions further upregulate its expression in a HIF-2α– and ROS-dependent manner."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Moreover, SERPINB3 promotes oncogenic events by inhibiting calpain-mediated cleavage of Myc and activating the Hippo/YAP pathway"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", and it correlates with enhanced COX-2 and β-catenin signaling, collectively fostering epithelial-to-mesenchymal transition, cellular invasion, and proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its protumorigenic activities, SERPINB3 exerts significant immunomodulatory effects. In airway epithelia, its expression is induced by Th2 cytokines (IL-4 and IL-13) via STAT1/STAT6 phosphorylation, a process implicated in the pathogenesis of asthma and atopic dermatitis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " In the skin, it has been recognized as an autoantigen in psoriasis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "and, in experimental models, the mouse homolog contributes to early inflammatory responses and barrier dysfunction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " SERPINB3 is also physiologically expressed on CD27-positive B lymphocytes, with its reduced expression observed in conditions such as chronic hepatitis C and systemic lupus erythematosus, underscoring a potential role in immune cell homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " In ovarian cancer, elevated SERPINB3 levels have been associated with platinum resistance and poorer progression-free survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, SERPINB3 influences response to cancer therapies and tumor stemness. Somatic mutations in SERPINB3 have been linked to favorable outcomes following immune checkpoint blockade in melanoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ", and its overexpression in cervical cancer has been implicated in mediating radiation resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": " Furthermore, recent data point to a role for SERPINB3 in the cholangiocarcinoma stem-like compartment, suggesting its involvement in early tumorigenesis and the maintenance of cancer stem cell properties."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kiyonari Masumoto, Yasuhisa Sakata, Kazuhiko Arima, et al. 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