Evidence map›Paper›PMID 40112213›Full record

ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2025

Bilirubin Targeting WNK1 to Alleviate NLRP3-Mediated Neuroinflammation.

Linfei Mao, Jiayu Lu, Quanjun Yang, Zhenqi Liu, Cuiping Wu, Bingbing Ke, Kaiyan Su, Haolin Yuan, Yaqi Cui, Yao Wang and 5 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
  4. Article
  5. Review
  6. Bilirubin Targeting WNK1 to Alleviate NLRP3-Mediated Neuroinflammation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025
    Article
  7. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors.

Linfei MaoShanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head 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, China.
Jiayu LuDepartment of Stomatology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
Quanjun YangDepartment of Pharmacy, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
Zhenqi LiuShanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head 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, China.
Cuiping WuShanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head 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, China.
Bingbing KeShanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head 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, China.
Kaiyan SuDepartment of Pharmacy, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
Haolin YuanShanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head 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, China.
Yaqi CuiShanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head 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, China.
Yao WangShanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head 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, China.
Richard SalviCenter for Hearing and Deafness, State University of New York at Buffalo, Buffalo, NY, 14214, USA.
Guang YangShanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head 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, China.
Shankai YinShanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head 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, China.ORCID https://orcid.org/0000-0003-3689-8599
Feng LiuShanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head 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, China.
Chunyan LiShanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head 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, China.

Funding

Excellent Young Scientists Fund 82322020Ministry of Science and Technology of the People's Republic of China 2021ZD0201900National Key R&D Program of China 2023YFC2509800National Natural Science Foundation of China 82071042National Natural Science Foundation of China 82371172
6 · The paper itself

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 pathway in neurons. Manipulating endogenous bilirubin levels by deleting Blvra, the bilirubin synthesis enzyme, and Ugt1a1, its metabolic enzyme, significantly promotes and inhibits the activation of the lipopolysaccharide (LPS)-induced NLRP3 inflammasome, respectively, in mouse hippocampus. Similarly, exogenous bilirubin supplementation suppressed LPS-induced NLRP3 inflammasome activation in mouse hippocampus in a WNK1-dependent 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-inflammatory effects of bilirubin and pave the way for exploring its novel functions.

Indexed as

BilirubinNeuroinflammatory DiseasesNLR Family, Pyrin Domain-Containing 3 ProteinWNK Lysine-Deficient Protein Kinase 1AnimalsInflammasomesMaleMiceMice, Inbred C57BLSignal TransductionBilirubinInflammasomesNLR Family, Pyrin Domain-Containing 3 ProteinNlrp3 protein, mouseWnk1 protein, mouseWNK Lysine-Deficient Protein Kinase 1bilirubinneuroinflammationNLRP3phosphorylationWNK kinase

Identifiers

PMID40112213
PMCPMC12362796

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.