MAP3K21 is a mitogen-activated protein kinase kinase kinase that functions as a negative regulator of TLR4 signaling and does not activate JNK1, p38, or ERK2 pathways. The gene encodes a serine/threonine protein kinase capable of protein phosphorylation and homodimerization, primarily localized to the cytoplasm 1. MAP3K21 belongs to the family of 24 characterized MAP3K enzymes involved in cellular signal transduction, though its specific role in kidney disease remains largely unexplored compared to other MAP3K family members like MAP3K5 and MAP3K7 1. Clinically, MAP3K21 variants have emerging relevance to metabolic and malignant diseases. A coding variant rs189326455 in MAP3K21 was identified as genome-wide significantly associated with pediatric adiposity in Chinese children, functioning as an expression quantitative trait locus affecting obesity-related gene expression 2. In cancer contexts, a genetic variant rs1294255 in MAP3K21 was associated with decreased risk of lymph node metastasis in triple-negative breast cancer, with the G allele correlating with decreased overall survival in TNBC/Basal-like cohorts 3. Additionally, MAP3K21 was among genes showing nominal statistical significance for heterogeneity by mutation status in hypermutated colorectal tumors regarding folate intake associations, though this did not survive multiple testing correction 4. These findings suggest MAP3K21 warrants further investigation as a potential biomarker and therapeutic target in metabolic and neoplastic diseases.