Bilirubin Targeting WNK1 to Alleviate NLRP3-Mediated Neuroinflammation.

ABSTRACT: Bilirubin, an endogenous metabolite with many significant physiological roles, particularly anti-inflammatory properties, shows great promise as a treatment for inflammatory diseases. However, the binding targets and downstream signaling mechanisms of bilirubin remain unclear. Here, by using quantitative phosphorylation proteomics and several powerful chemical biology techniques such as the Cellular Thermal Shift Assay (CETSA), molecular docking, and MicroScale Thermophoresis (MST), it is identified and confirmed that with-no-lysine (K) kinase 1 (WNK1) is the primary target of bilirubin at physiological concentrations. Bilirubin binds to the kinase domain of WNK1, activating its kinase activity and increasing the intracellular chloride ion concentration via the downstream SPAK/OSR1-KCC2 pa

SUBMITTER: Mao L 

PROVIDER: S-EPMC12362796 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature