ADSL (adenylosuccinate lyase) is a critical enzyme in de novo purine synthesis that catalyzes two non-sequential reactions: converting SAICAR to phosphoribosylaminoimidazole carboxamide (contributing to IMP synthesis) and converting succinyladenosine monophosphate to AMP, both reactions producing fumarate as a byproduct 1. Beyond its canonical metabolic role, ADSL exhibits important moonlighting functions in cancer biology. Under hypoxic conditions, ADSL becomes phosphorylated at T350 by IKKβ and translocates to the endoplasmic reticulum where its fumarate product binds STING, inhibiting cGAMP binding and suppressing immune activation, thereby promoting tumor immune evasion 2. Additionally, ADSL is phosphorylated at S140 by PERK during ER stress or lipid deprivation, enhancing its interaction with Beclin1. ADSL-produced fumarate inhibits lysine demethylase 8, leading to increased Beclin1 K117 dimethylation, which disrupts BCL-2-Beclin1 binding and promotes autophagy and liver tumor growth 34. ADSL deficiency, caused by various mutations including R303C, results in a rare autosomal recessive disorder characterized by neurological symptoms ranging from mild psychomotor delay to severe encephalopathy, with accumulation of substrate metabolites in body fluids 561. These findings highlight ADSL's dual role in both purine metabolism and cancer progression through its metabolite fumarate.