The Claudins (CLDNs) protein family is a type of integrin membrane protein found in the tight junctions of epithelial and endothelial cells. Its structure includes four transmembrane domains and two extracellular loops, making it a transmembrane protein located on the cell membrane surface. To date, 24 human Claudins genes have been discovered, with family members showing high consistency, particularly in the transmembrane domains. CLDNs are closely related to the maintenance of osmotic pressure, barrier function, and cell polarity in epithelial cells ^[1]. In addition, the expression of CLDNs changes significantly during the development of many tumors, and numerous studies on tumor treatment specifically targeting CLDNs have been conducted. The human CLDN18 gene has two optional first exons, producing two different protein isoforms, CLDN18.1 and CLDN18.2, which differ by only eight amino acids in the first extracellular domain ^[2]. CLDN18.1 is mainly expressed in lung tissue, while CLDN18.2 shows specificity in the digestive tract. In normal tissues, the expression of CLDN18.2 is low, but it is abnormally high during the development of various malignant tumors in the digestive system. Especially in gastric cancer tissues, the expression of CLDN18.2 is consistently and stably high. In addition, abnormal activation and overexpression of CLDN18.2 have been observed in malignant tumors such as colon cancer, liver cancer, head and neck cancer, bronchial cancer, and non-small cell lung cancer ^[3]. This strain is a humanized mouse model of the Cldn18 gene. Through gene editing technology, the mouse Cldn18 gene is replaced with the human CLDN18.2 gene CDS sequence, while retaining the 3’UTR region of the mouse Cldn18 gene. Homozygous hCLDN18.2 mice are viable and fertile and can be used for the development and validation of CLDN18.2-targeted drugs and the study of the mechanism of gastrointestinal tumors.