TMEM164 is a transmembrane protein that functions as a positive regulator of ferroptosis through multiple mechanisms. The protein promotes ATG5-dependent autophagosome formation specifically during ferroptosis, leading to selective autophagic degradation of ferritin, GPX4, and lipid droplets, which increases iron accumulation and lipid peroxidation to drive ferroptotic cell death 1. TMEM164 is also involved in phospholipid remodeling, catalyzing the acylation of ether lysophospholipids with arachidonoyl chains to generate C20:4 ether glycerophospholipids that promote ferroptosis 2. In cancer contexts, TMEM164 expression is downregulated in lung adenocarcinoma and associated with poor prognosis, while overexpression inhibits cell proliferation, migration, and invasion 1. Additionally, TMEM164 (also termed SHERMER) is expressed in endothelial cells and responds to shear stress, interacting with GRP78/BiP to activate ATF6-mediated endoplasmic reticulum stress signaling and IL-6/STAT3 pathways, contributing to liver fibrosis and hepatocarcinogenesis 3. The protein shows therapeutic potential, as targeting TMEM164 combined with anti-PD-1 antibodies demonstrates synergistic anti-tumor effects in preclinical models 1.