MAP2K3 (mitogen-activated protein kinase kinase 3) is a dual specificity kinase that phosphorylates threonine and tyrosine residues on p38 MAPK, functioning as a critical node in stress-responsive signaling cascades 1. Activated by cytokines and environmental stress, MAP2K3 mediates cellular responses to vascular endothelial growth factor and participates in the p38MAPK cascade, regulating transcription, protein kinase activity, and signal transduction 2. MAP2K3 exhibits context-dependent roles in disease: in osteoarthritis, MAP2K3 activation downstream of STING1 promotes cartilage extracellular matrix degradation in obesity-associated disease 1, while in esophageal squamous cell carcinoma, MAP2K3 acts as a tumor suppressor by promoting STAT3 degradation and opposing a miR-19b-3p-mediated feedback loop that drives tumorigenesis 3. In lung cancer, MAP2K3 represents a core node in the p53 signaling pathway targeted by anlotinib therapy 4. MAP2K3 is also associated with body mass index and may mediate hypothalamic inflammation affecting appetite regulation 5. Epigenetic regulation by HDAC8/9 suppresses MAP2K3 expression to maintain cutaneous innate immune tolerance; dysregulation increases skin inflammation 6. Additionally, MAP2K3 activation in pancreatic acinar cells drives inflammatory-mediated transformation to ductal phenotypes 7, highlighting its role in both metabolic and inflammatory disease pathogenesis.