MARCHF6 is an endoplasmic reticulum (ER) membrane-embedded E3 ubiquitin ligase that functions as a metabolic integrator regulating cholesterol synthesis, lipid homeostasis, and ferroptosis 1. It operates through two major degradation pathways: the Ac/N-degron pathway, recognizing N-terminally acetylated substrates like RGS2 and PLIN2, and the ER-associated protein degradation (ERAD-C) pathway for misfolded proteins 2. MARCHF6 coordinates cholesterol homeostasis by ubiquitinating multiple cholesterol synthesis enzymes including HMGCR, SQLE, and CYP51A1 13. Notably, MARCHF6 functions as an NADPH sensor that prevents ferroptosis during lipid peroxidation by degrading pro-ferroptotic and anti-ferroptotic substrates 42. In hypoxia, MARCHF6 stabilizes SREBP2, promoting cholesterol uptake over synthesis and protecting tumor cells from statin toxicity 3. Clinically, MARCHF6 is associated with familial adult myoclonus epilepsy (FAME), where intronic TTTTA/TTTCA repeat expansions cause cortical myoclonus; smaller numbers of TTTCA repeats correlate with later disease onset 56. Its role as a NADPH sensor linking oxidative stress to metabolic adaptation positions MARCHF6 as a potential therapeutic target for ferroptosis-related diseases including neurodegeneration and cancer 4.