TMEM117 (transmembrane protein 117) is a multi-pass transmembrane protein that mediates endoplasmic reticulum (ER) stress-induced cell death through mitochondrial dysfunction. Structurally, TMEM117 contains intrinsically disordered regions on its cytoplasmic side that facilitate protein-protein interactions and signaling functions 1. Functionally, TMEM117 maintains mitochondrial membrane potential (ΔΨm); its knockdown causes ΔΨm loss, increased reactive oxygen species, upregulation of ER stress sensors (C/EBP homologous protein), and caspase-3 activation, leading to apoptotic cell death 2. TMEM117 expression is downregulated in response to ER stressors like thapsigargin, positioning it as a critical node in ER stress-mediated mitochondrial apoptosis 2. TMEM117 also regulates mitochondrial biogenesis genes; its knockdown reduces expression of TFAM and UCP2, suggesting roles in metabolic homeostasis 3. Disease relevance extends beyond cancer to neurodevelopmental disorders: genome-wide association studies identified TMEM117 variants associated with ADHD pharmacological treatment response and body conformation traits in mammals 45. These findings suggest TMEM117 represents a therapeutic target for cancer and potentially neuropsychiatric disorders through modulation of ER stress and mitochondrial function.