MAP4K2 is a serine/threonine kinase that functions as a mitogen-activated protein kinase kinase kinase kinase (MAP4K), serving as an upstream activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway and p38 MAPK pathway. MAP4K2 is required for efficient JNK activation by TRAF6-dependent stimuli, including pathogen-associated molecular patterns such as lipopolysaccharides and peptidoglycans, and mediates responses to IL-1 and CD40 engagement. Beyond canonical MAPK signaling, MAP4K2 activates the Hippo signaling pathway through phosphorylation and activation of LATS1/2, functioning in parallel with STK3/MST2 and STK4/MST1 kinases 1. Mechanistically, MAP4K2 phosphorylates LC3A to drive autophagosome-lysosome fusion via the RAB3GAP-RAB18 axis and connects the Hippo pathway to autophagy during energy stress 2. MAP4K2 also promotes Treg differentiation by phosphorylating DDX39B, leading to nuclear translocation and Foxp3 RNA splicing, thereby suppressing antitumor immunity 3. Clinically, MAP4K2 is implicated in osteoporosis pathogenesis, where it regulates osteogenic differentiation of bone marrow mesenchymal stem cells through MAPK, autophagy, and apoptosis pathways 4, 5. MAP4K2 is also elevated in head and neck cancer and represents a potential therapeutic target 2.