MAP2K4 (mitogen-activated protein kinase kinase 4) is a dual specificity kinase that serves as an essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. MAP2K4 functions alongside MAP2K7 as one of only two known kinases capable of directly activating JNK isoforms (MAPK8/JNK1, MAPK9/JNK2, MAPK10/JNK3) through phosphorylation, with MAP2K4 preferentially phosphorylating the tyrosine residue within the Thr-Pro-Tyr activation motif 1. Notably, MAP2K4 has a broader substrate specificity than MAP2K7, additionally activating p38 MAPKs (MAPK11, MAPK12, MAPK13, MAPK14), positioning it as a central hub in MAPK cascade signaling. MAP2K4 is required for maintaining peripheral lymphoid homeostasis and participates in mitochondrial death signaling pathways leading to apoptosis through cytochrome c release. The MAP2K/JNK pathway activation occurs in response to various cellular stressors and pro-inflammatory cytokines 2. In disease contexts, aberrant activation of MAPK pathways—including those downstream of MAP2K4—occurs in over 30% of human cancers, making this pathway a rational therapeutic target 1. Additionally, germline MAP2K1 and MAP2K2 variants are associated with cardiofaciocutaneous syndrome, a RASopathy with elevated early childhood cancer risk 3.