{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Cathepsin Z (CTSZ), also known as cathepsin X, is a lysosomal cysteine protease with multifaceted roles in diverse biological processes. In cancer, CTSZ contributes to tumor progression by promoting cell motility, invasion, and the epithelial–mesenchymal transition. For example, combined deficiency of CTSZ with other cysteine proteases delays tumor onset and reduces metastasis in mammary cancer models"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", while upregulation of CTSZ in hepatocellular carcinoma enhances colony formation and induces EMT‐related changes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In addition, the enzyme modulates cell adhesion and migration through its RGD motif–mediated interactions with integrin receptors, as shown in studies of endothelial and pancreatic cancer cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the immune system, CTSZ is highly expressed in cells such as monocytes, macrophages, dendritic cells, and T lymphocytes, where it regulates functions including phagocytosis and migration. Its activity modulates β2 integrin–mediated adhesion and promotes T cell migration, thereby influencing immune surveillance and inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the nervous system, CTSZ processes key substrates such as γ‐enolase, leading to the loss of its neurotrophic activity and thereby impacting neuronal survival and neuritogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Furthermore, through its lysosomal functions, aberrant CTSZ expression has been associated with neurodegenerative conditions and may partake in pathological proteolysis events, such as the generation of toxic huntingtin fragments."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond these roles, CTSZ is actively sorted and secreted via ER‐to‐Golgi transport mechanisms mediated by cargo receptors such as ERGIC‐53, pointing to its regulated trafficking in secretory pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In brown adipose tissue, nuclear receptor signaling coordinately induces CTSZ as a target gene required for optimal mitochondrial respiration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, genetic association studies have linked CTSZ polymorphisms with susceptibility to infectious diseases such as tuberculosis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", and proteomic analyses in gallbladder and pancreatic cancers have noted its upregulation as a potential biomarker of malignancy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Additionally, suppression of CTSZ expression (for instance, by agents such as deguelin) can attenuate metastatic signaling through disruption of its interaction with integrins and downstream FAK/Src/Paxillin cascades in non‐small cell lung cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies highlight CTSZ as a multifunctional protease that modulates tumor progression, cell adhesion, immune cell trafficking, neurotrophic signaling, and metabolic function. Its diverse roles and regulatory mechanisms make CTSZ an attractive target for therapeutic intervention across a spectrum of diseases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lisa Sevenich, Uta Schurigt, Kathrin Sachse, et al. 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