TMEM109 is a transmembrane protein localized to the endoplasmic reticulum (ER) and sarcoplasmic reticulum (SR) membrane that functions as a voltage-gated cation channel permeable to both potassium and calcium 1. It plays a critical role in regulating calcium leakage at the ER/SR, with evidence suggesting it functions as a non-selective cation channel mediating pathophysiological remodeling 1. TMEM109 participates in cellular responses to DNA damage and is involved in apoptotic signaling pathways [UniProt annotation]. In cancer biology, TMEM109 has emerged as a significant prognostic biomarker across multiple malignancies. In glioblastoma, TMEM109 overexpression inhibits ferroptosis, a regulated cell death pathway, with its transcriptional repression by ZBTB20 promoting ferroptosis in tumor cells 1. TMEM109 was identified as one of 11 pyroptosis-related genes in a prognostic model for bladder cancer, correlating with patient outcomes and immune microenvironment characteristics 2. Similarly, it was incorporated into a 13-gene exosome-based prognostic signature for acute myeloid leukemia risk stratification 3. Notably, reduced TMEM109 expression in bone marrow was identified as a strong biomarker for thrombotic thrombocytopenic purpura (TTP) relapse with superior discriminative capacity (AUC=0.929) 4. TMEM109 also serves as a component in the SRP-independent SND protein targeting pathway to the ER 5.