MARVELD3 (MARVEL domain containing 3) is a transmembrane tight junction protein with dual roles in barrier function and cell signaling regulation. As a component of tight junctions, MARVELD3 contributes to paracellular ion conductivity 1 and maintains epithelial barrier integrity through interactions with other tight junction-associated MARVEL proteins 2. Beyond structural functions, MARVELD3 acts as a critical signaling hub that couples junctions to the MEKK1-JNK pathway, thereby suppressing cell migration and proliferation while promoting cell survival 3. In cancer contexts, MARVELD3 expression is frequently downregulated and inversely correlates with malignant progression. Loss of MARVELD3 promotes epithelial-mesenchymal transition (EMT) and metastasis in hepatocellular carcinoma 4 and non-small cell lung cancer via Wnt/β-catenin pathway activation 5. Conversely, in oral squamous cell carcinoma, R-loop accumulation upregulates MARVELD3, which paradoxically promotes tumor progression by suppressing TTC9 and activating MAPK signaling 6. In inflammatory bowel disease, MARVELD3 upregulation provides protective effects during colitis, though not through direct barrier enhancement 7. These findings reveal MARVELD3 as a context-dependent regulator where its expression and signaling function determine tissue-specific outcomes in disease.