RHEB (Ras homolog, mTORC1 binding) is a small GTPase that functions as a critical allosteric activator of mTORC1, a central nutrient sensor controlling cellular growth and metabolism 1. RHEB activation occurs in response to growth factors, nutrients, and amino acids, triggering a conformational change in mTOR that realigns active-site residues and accelerates phosphorylation of downstream substrates including RPS6KB1/2 and EIF4EBP1 1. Unlike Rag GTPases, which mediate amino acid signaling, RHEB primarily responds to growth factor stimuli and maintains mTORC1 localization to lysosomal compartments 2. During nutrient starvation, the TSC-TBC complex inactivates RHEB, preventing mTORC1 activation 3. Dysregulation of RHEB contributes to several pathologies: somatic gain-of-function RHEB mutations cause focal cortical dysplasia type II and hemimegalencephaly through mTOR hyperactivation, leading to drug-resistant epilepsy 45. RHEB deletion in myeloid cells suppresses mTORC1 and enhances M2 macrophage polarization, alleviating experimental osteoarthritis 3. These findings establish RHEB as a key metabolic signaling node and potential therapeutic target in mTOR-related developmental and inflammatory disorders.