TMEM33 is a transmembrane protein that serves as a critical regulator of endoplasmic reticulum (ER) homeostasis and cellular signaling pathways. The protein's primary function involves modulating intracellular calcium homeostasis by interacting with polycystin-2 (PC2) at the ER membrane, enhancing PC2 channel opening across the physiological calcium range and consequently reducing intracellular calcium content 1. TMEM33 regulates ER tubular network organization by suppressing reticulon-induced ER tubulation through direct binding to multiple reticulon family members 2. The protein plays essential roles in angiogenesis by mediating VEGF-induced calcium oscillations in endothelial cells, which are critical for tip cell filopodia formation and cell migration 3. In lipid metabolism, TMEM33 acts as a downstream effector of pyruvate kinase M2 (PKM2), forming complexes with RNF5 to facilitate SCAP degradation and regulate SREBP activation 4. Clinically, TMEM33 expression is elevated in multiple cancers including cervical cancer and lung adenocarcinoma, where high expression correlates with poor prognosis and reduced survival 56. The protein's dysregulation is also implicated in endometriosis through ER stress mechanisms 7.