TMEM9 is a conserved transmembrane protein localized to lysosomes, late endosomes, and early endosomes 1 that functions as a regulatory β-subunit for endosomal chloride/proton exchangers. TMEM9 directly interacts with ClC-3, ClC-4, and ClC-5 transporters, inhibiting their ion transport activity to prevent pathogenic chloride accumulation and endosomal swelling 23. This inhibition requires phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) stabilization 2. TMEM9 also regulates endosomal ion homeostasis and trafficking; mice lacking both TMEM9 and TMEM9B die embryonically or perinatally 3. Beyond ion transport, TMEM9 modulates Wnt/β-catenin signaling through lysosomal acidification and APC degradation, relevant to hepatic regeneration 4. Clinically, TMEM9 is significantly upregulated across multiple cancer types, including lung adenocarcinoma and hepatocellular carcinoma 56. In lung adenocarcinoma, TMEM9 overexpression activates the MEK/ERK/STAT3 pathway to induce VEGF expression, promoting tumor angiogenesis and metastasis 6. Elevated TMEM9 correlates with poor prognosis and serves as an independent prognostic indicator in several cancers 5, highlighting its potential as a therapeutic target.