MLK4

MLK4 is a mixed-lineage kinase that interacts with TLR4 and negatively regulates LPS-induced JNK/ERK signaling and TNF production^[1]. Mechanistically, MLK4 also activates NF-κB by phosphorylating IKKα, supporting mesenchymal identity, motility, tumorigenesis, and radioresistance in glioma stem cells^[2]. In breast cancer, MLK4 upregulation is enriched in TNBC, where knockdown reduces proliferation, migration, invasion, spheroid formation, tumor growth, mesenchymal markers, and NF-κB activity^[3]. MLK4 further regulates DNA damage response signaling in TNBC by supporting ATM-NEMO-IKK-NF-κB activation, and MLK4 inhibition or depletion sensitizes cells to DNA-damaging chemotherapy^[4]. Compared with related MLK family members, MLK4 shows context-dependent behavior because colorectal cancer studies report recurrent loss-of-function mutations that suppress JNK signaling and promote colon tumorigenesis^[5]. In hepatocellular carcinoma models, MLK4 knockdown inhibits proliferation and metastasis, induces apoptosis, increases ROS, and activates p38/JNK/ERK1/2 signaling^[6]. For experimental applications, MLK4 inhibition has been explored in KRAS/BRAF-mutant colorectal cancer and computationally screened sanguinarine derivatives require in vitro and in vivo validation^[7][8].