Tight junction proteins: Gatekeepers turned facilitators in the pathogenesis of gastric adenocarcinoma

Gastric cancer (GC) is the fifth most prevalent malignancy worldwide and remains a leading cause of cancer-related mortality. Major risk factors for GC include <i>Helicobacter pylori</i> infection, increasing age, high dietary salt intake, and diets deficient in vegetables and fruits. Due to the often subtle and nonspecific early symptoms, coupled with the lack of routine screening programs, a significant proportion of GC cases are diagnosed at advanced stages. The etiology of GC is multifactorial, and diagnosis is confirmed histologically through endoscopic biopsy, followed by staging <i>via</i> computed tomography, positron emission tomography, staging laparoscopy, and endoscopic ultrasound. Treatment strategies typically involve a multidisciplinary approach including chemotherapy, surgical resection, radiotherapy, and emerging immunotherapeutic options. Despite advances in diagnostic and therapeutic modalities, the prognosis of advanced GC remains poor, with high rates of recurrence and metastasis. In recent years, increasing attention has been given to the role of tight junction (TJ) proteins in the pathogenesis and progression of GC. TJ proteins, critical components of epithelial barrier function, have been implicated in various stages of gastric carcinogenesis, from intestinal metaplasia to invasion and metastasis. Infection and inflammation, particularly due to <i>Helicobacter pylori</i>, disrupt TJ integrity, compromising the gastric mucosal barrier and facilitating neoplastic transformation. This review synthesizes current evidence from PubMed, EMBASE, Google Scholar, ScienceDirect, SpringerLink, and other reputable databases to provide a comprehensive overview of the involvement of TJ proteins in GC. By elucidating the molecular interplay between TJ dysregulation and gastric tumorigenesis, this work aims to highlight the potential of TJ proteins as novel diagnostic biomarkers and therapeutic targets in GC management.