Noncanonical NF-κB pathway driven inflammation across multiple cellular compartments identifies NIK as a therapeutic...

The noncanonical NF-κB pathway, driven by NF-κB-inducing kinase (NIK), plays a central role in inflammatory bowel disease (IBD) pathogenesis by regulating immune responses across epithelial, myeloid, and lymphoid compartments. Despite advances in IBD therapies, novel therapeutic options targeting NIK remain underexplored.

We utilized cell-type-specific knockout models for intestinal epithelial cells, dendritic cells, as well as systemic NIK-deleted mice, to investigate the role of NIK in IBD pathogenesis. A small molecule NIK inhibitor (NIK-smi) was evaluated using pharmacokinetic/pharmacodynamic (PK/PD) modeling and its efficacy tested in preclinical colitis models, including Helicobacter hepaticus + anti-IL-10R, adoptive T cell transfer, and DSS-induced colitis. Biomarker analyses were performed using flow cytometry and multiplex cytokine detection.

NIK deletion in epithelial cells disrupted M-cell differentiation, reducing CCL20-mediated recruitment of CCR6-expressing Th17 cells and ILC3s. In dendritic cells, NIK activity amplified CD40-mediated innate immune responses, while in T cells, NIK skewed differentiation toward pro-inflammatory Th1 cells at the expense of regulatory T cells. Systemic NIK deletion and pharmacologic inhibition with NIK-smi attenuated inflammation in preclinical colitis models, reducing immune cell infiltration, pro-inflammatory cytokines (e.g., IL-1β, IFNγ, IL-17A, CCL5), and improving colon histopathology. PK/PD modeling revealed that a 200 mg/kg BID dosing regimen of NIK-smi provided optimal pathway inhibition and therapeutic efficacy.

NIK is a key regulator of gut inflammation through its multi-cellular contributions in IBD pathogenesis. Pharmacologic inhibition of NIK offers a promising therapeutic strategy for IBD, with PK/PD modeling providing a translational framework to optimize dosing and efficacy.