MAP3K14 (mitogen-activated protein kinase kinase kinase 14), also known as NF-κB-inducing kinase (NIK), is a serine/threonine kinase that functions as a rate-limiting activator of the non-canonical NF-κB signaling pathway 1. MAP3K14 phosphorylates CHUK/IKKA to promote proteolytic processing of NFKB2/P100 into its active P52 form, driving NF-κB activation 2. This pathway is essential for B-cell survival, lymphoid organogenesis, and immune homeostasis. MAP3K14 activity is fine-tuned by a negative feedback mechanism involving SIX1 and SIX2 transcription factors, which directly inhibit RELA and RELB trans-activation function 1. Beyond its canonical NF-κB role, MAP3K14 demonstrates targeted antiviral activity against multiple RNA viruses, including hepatitis C virus and West Nile virus 3. MAP3K14 dysfunction contributes to multiple diseases: mutations promote kidney injury through excessive inflammation and tubular cell death 2, drive mantle cell lymphoma progression 4, and support Hodgkin lymphoma survival via NF-κB deregulation 5. Additionally, MAP3K14 promotes ferroptosis in intervertebral disc degeneration through NF-κB pathway activation 6. MAP3K14 alterations are emerging biomarkers in colorectal cancer diagnostics 7. Targeting MAP3K14 represents a therapeutic opportunity in kidney disease and lymphoproliferative disorders.