Noncanonical NF-κB pathway driven inflammation across multiple cellular compartments identifies NIK as a therapeutic target for inflammatory bowel disease

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The noncanonical NF-κB pathway, driven by NIK, is crucial in the pathogenesis of inflammatory bowel disease (IBD).
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NIK deletion in epithelial cells impairs M-cell differentiation and reduces recruitment of Th17 cells and ILC3s in IBD models.
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NIK activity in dendritic cells enhances CD40-mediated innate immune responses, while in T cells, it promotes pro-inflammatory Th1 differentiation.
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Pharmacologic inhibition of NIK with NIK-smi reduced inflammation and improved colon histopathology in preclinical colitis models.
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PK/PD modeling indicated that a 200 mg/kg BID dosing regimen of NIK-smi optimally inhibited the pathway and enhanced therapeutic efficacy.

Frontiers In Immunology

by Hao Xu, Dun Li, Jie Liang, Nathan Adamson, Alexis Scherl, Luli Zou, Crystal Hu, Elaine E. Storm, Christian B. Cox, Adam Johnson, Mary E. Keir, Hua Zhang, Saiyu Hang
June 9, 2026

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