TMX3 (thioredoxin-related transmembrane protein 3) is a membrane-bound protein disulfide isomerase localized to the endoplasmic reticulum (ER) that functions in oxidative protein folding and redox signaling 1. As a member of the PDI family, TMX3 catalyzes formation, isomerization, and disassembly of disulfide bonds in proteins containing cysteine residues, demonstrating dithiol oxidase activity with a redox potential similar to PDI 1. Beyond classical protein folding, TMX3 acts as a regulator of ER-mitochondria contact sites by modulating redox signals, with upregulation in melanoma cells correlating with enhanced mitochondrial-derived ROS generation and poor disease outcomes 2. TMX3 is released from platelets and localizes to the cell surface, participating in thrombus formation and hemostasis regulation 3, 4. Disease relevance includes cardiac developmental disorders: TMX3 variants cosegregate with MIB1 mutations in families with left ventricular noncompaction and bicuspid aortic valve, where quadruple heterozygous combinations promote valve defects 5. Additionally, TMX3 haploinsufficiency causes microphthalmia and ocular coloboma, with mutations impairing rescue of small eye phenotypes in zebrafish models 6. Elevated TMX3 expression also associates with endoplasmic reticulum stress in endometriosis pathogenesis 7.