TTYH2 (tweety family member 2) is a transmembrane protein with multiple cellular functions extending beyond its initial characterization as an anion channel. Structurally, TTYH2 contains five transmembrane domains with an extended extracellular region 1. Recent cryo-EM structures reveal that TTYH2 adopts a previously unobserved fold and forms Ca2+-dependent homomeric cis-dimers or trans-dimers bridged by extracellularly coordinated calcium, though it lacks ion-conducting pathways 2. A primary function of TTYH2 involves facilitating endosomal lipid transfer. TTYH2 interacts with apolipoprotein E (APOE) in endosomal compartments and accelerates lipid transfer from APOE-containing lipoproteins, with particular relevance in the brain where APOE mediates lipid transfer between astrocytes and neurons 3. Additionally, TTYH2 serves as a glycan-dependent binding partner for SARS-CoV-2 spike protein on myeloid cells, promoting proinflammatory responses correlated with COVID-19 severity 4. Clinically, TTYH2 expression is significantly upregulated in multiple cancers. It is elevated in renal cell carcinoma, colon carcinoma, and osteosarcoma, where TTYH2 silencing reduces cancer cell proliferation, invasion, and migration 156. TTYH2 expression also serves as a transcriptional biomarker for severe COVID-19, with predictive accuracy of ~88% for disease severity classification 7.