TM7SF3 is a seven-transmembrane protein with diverse cellular functions centered on stress response and cellular homeostasis. Despite its transmembrane structure, TM7SF3 localizes to nuclear speckles where it regulates alternative splicing of over 330 genes through interactions with splicing factors including HNRNPU, HNRNPK, and DHX15 1. The protein serves as a p53-regulated pro-survival homeostatic factor that attenuates cellular stress and prevents activation of the unfolded protein response (UPR) 2. TM7SF3 maintains protein homeostasis and promotes cell survival by inhibiting ER stress-induced caspase 3/7 activation, while its silencing accelerates UPR activation and apoptosis 2. In pancreatic beta cells, TM7SF3 functions as an inhibitor of cytokine-induced cell death and promotes insulin secretion 3. Recent studies suggest TM7SF3 may function as a component of a proton-coupled organic cation antiporter at the blood-brain barrier, potentially facilitating drug transport 4. Additionally, TM7SF3 controls TEAD1 splicing to prevent hepatic stellate cell activation and liver fibrosis in metabolic dysfunction-associated steatohepatitis 5. The protein exhibits broad tissue expression with highest levels in kidney 6.