MAPK6 (ERK3) is an atypical mitogen-activated protein kinase that plays distinct roles in cancer progression and cellular signaling. Unlike conventional MAPKs, MAPK6 functions as an atypical kinase with unique regulatory mechanisms 1. The protein directly phosphorylates and activates AKT at serine 473 independently of mTORC2, promoting oncogenic signaling and tumor growth 2. This MAPK6-AKT axis contributes to resistance against mTOR kinase inhibitors, suggesting a major therapeutic resistance pathway 2. MAPK6 expression is elevated in multiple cancer types including breast cancer, lung adenocarcinoma, and clear cell renal cell carcinoma, where it correlates with poor patient survival 234. In lung adenocarcinoma, HNF4G transcriptionally upregulates MAPK6, enhancing cisplatin resistance through MAPK6/Akt pathway activation 4. MAPK6 also regulates endothelial inflammation in atherosclerosis via the EGR1/CXCL12 axis, where disturbed shear stress promotes TRIM21-mediated MAPK6 degradation 5. Additionally, MAPK6 contributes to diabetic nephropathy progression through podocyte injury mechanisms 6. These findings establish MAPK6 as a promising therapeutic target, with siRNA-loaded nanoparticles showing anticancer efficacy in breast cancer models 3.