{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Claudin domain–containing 1 (CLDND1), also known as claudin‐25, is a novel member of the claudin family that contributes to the formation and regulation of tight junctions (TJs) in diverse tissues. Exogenous expression studies in epithelial cell lines have demonstrated that CLDND1 localizes to both TJs and the cytoplasm"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", while studies in the brain have revealed that CLDND1 is highly expressed in regions such as the cerebellum. In this context, transient downregulation of CLDND1 after cerebellar hemorrhage is associated with increased permeability to low–molecular weight solutes in brain endothelial cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", underscoring its role in maintaining vascular barrier integrity."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Transcriptional control of CLDND1 is mediated by key regulatory factors. Retinoic acid receptor–related orphan receptor α (RORα) directly binds to a response element in the CLDND1 promoter to enhance its expression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", whereas myeloid zinc finger 1 (MZF1) interacts with an intronic element to upregulate CLDND1, thereby contributing to effective tight junction formation and preserving endothelial function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In addition, post‐transcriptional regulation by microRNA‐124 has been shown to influence CLDND1 levels in brain tissue, with lower miR‐124 levels correlating with higher CLDND1 expression in stroke‐prone models."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the cancer setting, particularly in basal–like breast cancer cell lines, CLDND1 acts as a survival factor. Downregulation of CLDND1 in these cells induces caspase–dependent apoptosis via the intrinsic mitochondrial pathway, an effect that is further modulated by concurrent alterations in ERK1/2 phosphorylation; inhibition of MEK1/2 markedly potentiates the apoptosis triggered by CLDND1 knockdown."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in cell–cell adhesion and survival, CLDND1 is subject to dynamic regulation in response to environmental and physiological stimuli. For instance, activation of the aryl hydrocarbon receptor (AhR) by xenobiotic ligands alters CLDND1 expression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", and altered CLDND1 expression is a component of smoking–related gene expression signatures that have been linked to cardio–metabolic risk factors and stroke."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": " Furthermore, evolutionary studies in aquatic models have identified only a limited contribution of CLDND1 to marine–freshwater divergence"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", suggesting its functional roles may be context dependent.\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings position CLDND1 as a crucial mediator of tight junction integrity, vascular permeability, and cell survival, with broad implications for cerebrovascular disease, cancer progression, and systemic responses to environmental exposures."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hiroshi Matsuoka, Akiho Shima, Arisa Uda, et al. 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