Tmx4, a member of the thioredoxin-related transmembrane protein family, is a type I transmembrane protein with a thioredoxin-like domain facing the endoplasmic reticulum (ER) lumen. It has reductase activity and is involved in multiple biological processes. In the ER, it may cooperate with proteins like calnexin and ERp57 to assist in protein folding [3]. Tmx4 also participates in pathways related to ER stress response and platelet activation [1,2].

In platelet-related functional studies, Tmx4-deficient mice (Tie2-Cre/TMX4fl/fl and Pf4-Cre/TMX4fl/fl) exhibited prolonged tail bleeding times and reduced platelet thrombus formation. Tmx4 deficiency inhibited platelet aggregation, integrin αIIbβ3 activation, P-selectin expression, phosphatidylserine exposure, and thrombin generation, indicating its importance in platelet activation and thrombosis [2]. In terms of ER stress, upon acute ER stress, TMX4-driven disassembly of the LINC complexes connecting the inner and outer nuclear membranes occurs, leading to outer nuclear membrane swelling. Subsequently, asymmetric autophagy of the nuclear envelope restores the normal state [1,4].

In conclusion, Tmx4 is crucial for processes such as protein folding in the ER, platelet activation, and the regulation of nuclear envelope dynamics during ER stress. The use of Tmx4-deficient mouse models has significantly contributed to understanding its role in thrombosis and ER-related stress responses, providing insights into potential therapeutic targets for related diseases.