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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\u2010no\u2010lysine (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\u2010KCC2 pathway in neurons. Manipulating endogenous bilirubin levels by deleting\n                    <jats:italic>Blvra<\/jats:italic>\n                    , the bilirubin synthesis enzyme, and\n                    <jats:italic>Ugt1a1<\/jats:italic>\n                    , its metabolic enzyme, significantly promotes and inhibits the activation of the lipopolysaccharide (LPS)\u2010induced NLRP3 inflammasome, respectively, in mouse hippocampus. Similarly, exogenous bilirubin supplementation suppressed LPS\u2010induced NLRP3 inflammasome activation in mouse hippocampus in a WNK1\u2010dependent manner. Quantitative phosphoproteomic analysis of WNK1 downstream signaling elucidated the broad biological roles of WNK1, notably its function in suppressing inflammation. The findings clarify the direct targets and signaling mechanisms underlying the anti\u2010inflammatory effects of bilirubin and pave the way for exploring its novel functions.\n                  <\/jats:p>","DOI":"10.1002\/advs.202407349","type":"journal-article","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T02:25:10Z","timestamp":1742696710000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Bilirubin Targeting WNK1 to Alleviate NLRP3\u2010Mediated Neuroinflammation"],"prefix":"10.1002","volume":"12","author":[{"given":"Linfei","family":"Mao","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Sleep Disordered Breathing Department of Otolaryngology\u2010Head and Neck Surgery Otolaryngology Institute of Shanghai Jiao Tong University Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai 200233 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