AKT1S1 (also known as PRAS40) is a negative regulator of mTORC1, a central nutrient and growth factor sensor controlling cell growth and metabolism 1. In the absence of insulin and nutrients, AKT1S1 associates with mTORC1 and directly inhibits its activity by blocking the substrate-recruitment site 1. Upon nutrient and insulin stimulation, AKT1S1 dissociates from mTORC1, allowing complex activation 1. This inhibitory function is phosphorylation-dependent and regulated by 14-3-3 binding 1. AKT1S1 dysregulation is implicated in multiple diseases. In hepatocellular carcinoma, PRAS40 hyperexpression and phosphorylation are significantly elevated and correlate with poor prognosis; Akt1s1-knockout mice show suppressed hepatocarcinogenesis 2. In atherosclerosis, AKT1S1 stability modulation via METTL3-mediated m6A methylation regulates macrophage autophagy and lipid accumulation 3. AKT1S1 also links AKT and mTORC1signaling in pancreatic islets, with phosphorylation alterations affecting diabetes susceptibility 4. In asthma, excessive PRAS40-mediated autophagy inhibition can be reversed therapeutically by blocking PRAS40-Raptor interactions to activate mTORC1 5. PKM2-mediated phosphorylation of AKT1S1 at S202/203 constitutively activates mTORC1 in cancer, promoting oncogenic growth 6.