{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Claudin‐9 (CLDN9), a member of the claudin family of tight junction proteins, plays several context‐dependent roles in human physiology and disease. In studies on hepatitis C virus (HCV) infection, CLDN9 has been shown to function as an entry factor that can substitute for claudin‐1 and claudin‐6 in mediating viral cell entry in certain cell lines; its first‐extracellular loop residues are critical for this activity, suggesting a specific requirement for virus–host interactions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the cancer arena, altered CLDN9 expression has been linked with tumor aggressiveness and poor clinical outcomes. For example, increased CLDN9 levels in gastric adenocarcinoma cell models have been associated with enhanced cell migration, invasiveness, and proliferation, while strong apical expression in glandular cells correlates with higher mortality rates in patients."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, elevated CLDN9 expression has been observed in invasive pituitary oncocytomas, underscoring its potential as a biomarker for tumor invasiveness. Similar pro‐metastatic functions were seen in lung cancer models where CLDN9 promoted motility and invasiveness (see"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", and in cervical carcinoma its downregulation was associated with altered lymphatic metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its roles in viral entry and cancer progression, CLDN9 is essential for normal auditory function. Loss‐of‐function mutations in this gene impair its proper membrane localization in inner ear cells, thereby causing sensorineural hearing loss in both humans and animal models."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n CLDN9 also contributes to the integrity of epithelial barriers. In airway epithelial cells, for instance, knockdown of CLDN9 disrupts tight junction integrity and impairs barrier function, emphasizing a role in maintaining paracellular permeability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Furthermore, its developmental expression in pituitary folliculo‐stellate cells suggests a key function in forming and regulating tight junctions in the anterior pituitary, where it contributes to the paracellular barrier."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, innovative studies have demonstrated that CLDN9, when presented on virus‐like particles, retains its native conformation and can elicit antibody responses with cytotoxic potential. This finding supports the exploration of CLDN9 as a target for cancer immunotherapy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, CLDN9 is a multifunctional tight junction protein that not only facilitates HCV entry in certain contexts but also modulates tumor behavior, supports auditory function, and maintains epithelial barrier integrity. Its dysregulation in various pathological conditions highlights its value both as a prognostic biomarker and as a potential target for therapeutic intervention.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Aihua Zheng, Fei Yuan, Yanqin Li, et al. 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