TM9SF4 is a transmembrane protein that regulates cellular adhesion, intracellular pH homeostasis, and autophagy with significant roles in both normal physiology and disease. Primary function: TM9SF4 facilitates cell surface localization of glycine-rich transmembrane proteins and assembles V-ATPase complexes to regulate intracellular pH 1. Mechanism: TM9SF4 contains an N-terminal fragment that binds F-actin to promote actin disassembly via cofilin activation, facilitating cancer cell motility 2. It also interacts with PLOD3 to activate mTOR-dependent autophagy 3 and regulates macrophage polarization and epithelial barrier function through ER stress modulation 4. Disease relevance: TM9SF4 is overexpressed in acute myeloid leukemias and metastatic melanoma, driving cannibalistic behavior—aberrant phagocytosis of neighboring cells under nutrient deprivation or acidic conditions 5. It mediates pH alterations enabling drug resistance and invasiveness in colorectal and ovarian cancers 2. Conversely, reduced TM9SF4 expression associates with inflammatory bowel disease severity 4 and intrahepatic cholestasis of pregnancy 6. Clinical significance: TM9SF4 serves as a potential biomarker and therapeutic target in multiple cancers, while restoration of expression may benefit inflammatory and metabolic diseases.