RIT1 is a small GTPase of the RAS family that regulates cellular signaling through the RAS/MAPK pathway 1. In normal physiology, RIT1 couples NGF stimulation to activation of EPHB2 and MAPK14 signaling, mediating neuronal differentiation, cell proliferation, and survival through ELK1 transactivation [UniProt]. RIT1 is subject to proteolytic degradation via the LZTR1-Cullin-3 E3 ubiquitin ligase complex, which maintains appropriate protein levels 23. Pathogenic RIT1 mutations impair this proteolysis, causing protein stabilization and dysregulated RAS/MAPK signaling 4. Clinically, RIT1 mutations cause Noonan syndrome, a RASopathy affecting development 15. In cancer, RIT1 activating mutations occur in ~13% of lung adenocarcinomas, particularly in tumors lacking other oncogenic drivers 6, and are also found in myeloid malignancies 1. Beyond MAPK activation, RIT1 regulates hepatocellular carcinoma progression by maintaining SMC3 acetylation during mitosis, promoting cell division and proliferation 7. RIT1-driven lung tumors are therapeutically actionable through SHP2 inhibitors, RAS nucleotide exchange inhibitors, and RAS tri-complex inhibitors that directly bind GTP-bound RIT1 4, offering targeted treatment strategies for RIT1-mutant malignancies.