KSR2 (kinase suppressor of Ras 2) is a scaffold protein with very low intrinsic kinase activity that primarily functions as a MEK1-dependent allosteric activator of BRAF within the RAS-MAPK pathway 1. As a molecular scaffold, KSR2 promotes Raf/MEK/ERK signaling by stabilizing KSR-MEK interactions and enhancing RAF-KSR heterodimerization 2. KSR2 also negatively regulates MAP3K3-mediated inflammatory signaling pathways. Clinically, KSR2 variants are strongly associated with severe early-onset obesity and type 2 diabetes. KSR2 knockout mice exhibit profound obesity due to leptin-resistant hyperphagia mediated through mTOR pathway hyperactivation in the hypothalamus 3. Rare coding variants in KSR2 (p.I402F, p.T193I) are identified in individuals with severe obesity 4, while common variants are implicated in BMI variation in larger populations 5. Beyond metabolic disease, endothelial KSR2 protects against atherosclerosis by stabilizing AMPKα1 and suppressing inflammation 6. In bone metabolism, KSR2 negatively regulates femoral bone mass by promoting adipocyte differentiation over osteoblast formation 7. Additionally, KSR2 is overexpressed in hepatocellular carcinoma and small cell lung carcinoma, where it promotes tumor cell proliferation, migration, and self-renewal through MAPK pathway activation 8, 9.