TMX4 (thioredoxin related transmembrane protein 4) is a type I transmembrane protein belonging to the protein disulfide isomerase (PDI) family that localizes to the endoplasmic reticulum (ER) 1. TMX4 contains a single ER-luminal thioredoxin-like domain with a CXXC catalytic motif that exhibits potent reductase activity, as demonstrated by its ability to reduce disulfide bonds with a redox potential of -171.5 mV 2. The protein is primarily found in an oxidized state under normal cellular conditions and interacts with ER chaperones calnexin and ERp57, suggesting involvement in protein folding processes 2. TMX4 localizes to the ER through a unique di-arginine motif (RQR) in its cytoplasmic tail rather than the typical di-lysine retrieval signal 1. Functionally, TMX4 plays a crucial role in platelet activation and thrombosis by reducing integrin αIIbβ3 disulfide bonds, enhancing platelet aggregation and thrombus formation 3. The protein is expressed across various tissues with high expression in melanoma cells 1. Additionally, TMX4 has been implicated in cancer progression, where its promoter regulation contributes to lung cancer invasion through the ERβ/circ-TMX4/miR-622/CXCR4 signaling pathway 4. TMX4 represents a unique member of the PDI family with distinct structural features and specialized functions in hemostasis and disease pathogenesis.