TMX2 is a thioredoxin-related transmembrane protein localized to endoplasmic reticulum-mitochondria-associated membranes (MAMs) that functions as a critical regulator of cellular redox state and protein homeostasis 1. As a member of the protein disulfide isomerase family, TMX2 possesses disulfide oxidoreductase activity and facilitates protein folding and post-translational modification 2. TMX2 controls ER-mitochondria membrane contact site formation through redox-mediated interactions with outer mitochondrial membrane proteins like TOM70, thereby moderating mitochondrial calcium uptake and metabolic activity 3. Additionally, TMX2 regulates nuclear protein transport by maintaining the Ran-importin-β gradient at nuclear pore complexes 4. Functionally, TMX2 acts as a redox sensor in neural development, indirectly regulating neuronal proliferation, migration, and organization 1. Loss-of-function TMX2 mutations cause neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, characterized by hyperactive mitochondria and impaired neural development 3. In hepatocellular carcinoma, TMX2 is upregulated and promotes cell viability by facilitating autophagy and cytoprotective mitophagy 5. TMX2 represents a potential therapeutic target in cancer, with TMX2 knockdown enhancing chemotherapy efficacy 5. TMX2 expression is also associated with epigenetic age acceleration 6.