MAP2K5 (mitogen-activated protein kinase kinase 5) functions as a scaffold protein that activates the MEK5-ERK5 signaling cascade, a distinct branch of the MAPK pathway. The protein acts as a kinase that phosphorylates ERK5 at specific residues (Ser731+Thr733 or Ser496), promoting its nuclear translocation and subsequent transcriptional changes 1. Beyond canonical stress responses, MAP2K5 regulates diverse cellular processes including proliferation, survival, and migration 2. In cancer biology, MAP2K5 has emerged as a significant oncogenic driver. Gain-of-function variants (A321T, M367T) located in the kinase domain are associated with familial non-medullary thyroid carcinoma susceptibility, activating the MEK5-ERK5 pathway to promote thyroid epithelial cell malignant transformation 1. MAP2K5 variants also predict poor survival outcomes in hepatocellular carcinoma, with the rs17300363 C allele associated with elevated MAP2K5 expression and worse prognosis 3. In osteosarcoma, the MEK5-ERK5 pathway promotes tumorigenesis through Nur77-mediated mitophagy regulation 4. Genetic variants in MAP2K5 are additionally associated with restless legs syndrome in both Chinese and US populations, suggesting roles beyond cancer pathogenesis 5 6. These findings highlight MAP2K5 as a potential therapeutic target for cancer prevention and treatment, with clinical applications in molecular diagnosis and risk stratification.