FICD is a bifunctional adenylyltransferase that catalyzes both AMPylation and de-AMPylation of proteins, with primary physiological significance in endoplasmic reticulum (ER) stress regulation 1. The enzyme's dual catalytic activity is determined by the glutamate-231 residue, enabling context-dependent switching between AMPylase and de-AMPylase functions. FICD's key substrate is BiP/GRP78, the ER-resident chaperone; in unstressed cells, FICD mediates BiP AMPylation at threonine-518 to inactivate it, while ER stress triggers de-AMPylation to restore BiP activity and support the unfolded protein response 2. Beyond ER homeostasis, FICD-mediated AMPylation regulates human neurogenesis by accelerating neural progenitor differentiation 3. Dysregulated FICD function associates with human disease; pathogenic FICD variants cause neonatal diabetes mellitus through impaired de-AMPylation activity, leading to excessive BiP AMPylation and pancreatic β-cell dysfunction 42. Small-molecule FICD inhibitors (C22 and C73) selectively suppress pathologic BiP AMPylation while preserving de-AMPylation capacity, improving proinsulin processing and representing a novel therapeutic strategy 1. FICD mutations also underlie autosomal recessive spastic paraplegia 92, emphasizing its broader neurological importance.