A small‐molecule inhibitor of NF‐κB‐inducing kinase (NIK) protects liver from toxin‐induced inflammation, oxidative stress, and injury

Abstract

Potent and selective chemical probes are valuable tools for discovery of novel treatments for human diseases. NF-κB-inducing kinase (NIK) is a key trigger in the development of liver injury and fibrosis. Whether inhibition of NIK activity by chemical probes ameliorates liver inflammation and injury is largely unknown. In this study, a small-molecule inhibitor of NIK, B022, was found to be a potent and selective chemical probe for liver inflammation and injury. B022 inhibited the NIK signaling pathway, including NIK-induced p100-to-p52 processing and inflammatory gene expression, both in vitro and in vivo Furthermore, in vivo administration of B022 protected against not only NIK but also CCl-induced liver inflammation and injury. Our data suggest that inhibition of NIK is a novel strategy for treatment of liver inflammation, oxidative stress, and injury.-Ren, X., Li, X., Jia, L., Chen, D., Hou, H., Rui, L., Zhao, Y., Chen, Z. A small-molecule inhibitor of NF-κB-inducing kinase (NIK) protects liver from toxin-induced inflammation, oxidative stress, and injury.

Identification of new NIK inhibitors by discriminatory analysis‐based molecular docking and biological evaluation

“…These 70 compounds were purchased and tested by the NIK adenosine triphosphate (ATP) consumption assay for NIK inhibitory activities. Compound B022 was used as positive control, showing an IC 50 value of 9.9 ± 2.5 nM, which is consistent with the report. All these 70 compounds were initially evaluated for their ability to inhibit NIK at the concentration of 10 μg/ml.…”

METTL3 is essential for postnatal development of brown adipose tissue and energy expenditure in mice

“…For insulin tolerance test experiment, mice fasted for 6 h were injected intraperitoneally with human insulin (Lily) (1 U/kg). Blood glucose levels were measured from the tail vein at indicated times using a glucometer 65 . Blood samples were collected from orbital sinus.…”

“…Quantitative Real-Time PCR (qPCR). Total RNA was isolated using TriPure Isolation Reagent (94015120, Roche), and the first-strand cDNAs were synthesized using Random Primers and M-MLV reverse transcriptase (M1701, Promega) 65,68 . RNA abundance was measured using SYBR Green Mixs (4913914001, Roche) and Roche LightCycler 480 real-time PCR system (Roche, Mannheim, Germany).…”

The non-canonical NF-κB pathway in immunity and inflammation

“…NIK is also implicated as an inflammatory mediator in liver inflammation and injury induced by hepatitis viruses and alcohol consumption, and NIK over expression in hepatocytes induces fatal liver injury and fibrosis 165,166 . Inhibition of NIK with a small-molecule inhibitor protects mice from toxin-induced liver inflammation and injury 167 . Furthermore, non-canonical NF-κB pathway activation in pancreatic β-cells via the conditional deletion of TRAF2 or TRAF3, which act as negative regulators of NIK, reduces insulin secretion and causes exacerbated glucose intolerance in a mouse model of diet-induced obesity 163 .…”