{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T21:23:25Z","timestamp":1790198605099,"version":"4.1.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The noncanonical NF-\u03baB pathway, driven by NF-\u03baB-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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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-1\u03b2, IFN\u03b3, 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1825442","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T11:05:40Z","timestamp":1781003140000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Noncanonical NF-\u03baB pathway driven inflammation across multiple cellular compartments identifies NIK as a therapeutic target for inflammatory bowel disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Hao","family":"Xu","sequence":"first","affiliation":[{"name":"Translational Immunology, Genentech, Inc.","place":["South San Francisco, CA, United 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