CLDN10 (claudin 10) is a tight junction protein that forms anion-selective paracellular channels in epithelial barriers. In renal proximal tubules, CLDN10 mediates selective chloride over bicarbonate permeability, essential for renal chloride reabsorption and salt homeostasis. 1 Biallelic CLDN10 pathogenic variants cause HELIX syndrome, a rare multiplex epithelium dysfunction characterized by hypohidrosis, electrolyte imbalance, heat intolerance, and reduced tear secretion. 2 Rare coding variants in CLDN10 are associated with altered kidney function traits. 1 Beyond structural functions, CLDN10 exhibits signaling capabilities with context-dependent roles in disease. In clear cell renal cell carcinoma (ccRCC), high CLDN10 expression at the cell surface promotes malignancy through cooperation with LAT1 amino acid transporter, activating mTOR signaling and driving tumor progression. 3 Conversely, downregulated CLDN10 in ccRCC is associated with metastasis and poor prognosis, with reduced expression linked to DNA hypermethylation and diminished immune infiltration. 4 In lung adenocarcinoma, lower CLDN10 expression in invasive lesions correlates with disease progression and unfavorable prognosis. 5 Additionally, CLDN10-AS1 lncRNA transferred via extracellular vesicles aggravates vascular endothelial injury in atherosclerosis. 6 During primate development, CLDN10 marks amnion-epiblast boundary progenitors and promotes amniotic while suppressing primordial germ cell fate. 7