Map4k4, a serine/threonine kinase belonging to the MAP kinase family, contains around 1,200 amino acids with a molecular mass of 140 kDa. It plays a critical role in embryogenesis and cellular migration, and is expressed in most examined tissues. MAP4K4 is involved in multiple signaling pathways such as c-Jun N-terminal and RAS kinases, and its signal transduction is essential for cell proliferation, transformation, invasiveness, and more [1,2,5].

Gene knockout studies have shown that Map4k4 knockout is embryonic lethal due to impaired somite development [1]. In disease-related research, down-regulation of Map4k4 in T cells enhances the IL-6+ Th17 cell population, leading to insulin resistance and type 2 diabetes in both humans and mice [6]. Inhibition of Map4k4 function using RNA interference-based knockdown reduces tumor proliferation, migration, and invasion in cancers like pancreatic cancer, glioblastoma, and medulloblastoma [1]. In ovarian cancer, down-regulation of Map4k4 inhibits cancer cell adhesion, migration, and invasion, and pharmacologic inhibition abrogates peritoneal metastases [3]. Also, in diabetic cardiomyopathy, inhibition of Map4k4 via DMX-5804 reduces endothelial ferroptosis and alleviates cardiac microvascular and cardiac dysfunction in db/db mice [4].

In summary, Map4k4 is crucial for embryogenesis and various cellular functions. Model-based research, especially gene knockout studies, has revealed its significant roles in multiple disease areas, including metabolic diseases like type 2 diabetes, cancers, and diabetic cardiomyopathy. Understanding Map4k4 can potentially provide new therapeutic strategies for these diseases.