Evidence map›Paper›PMID 41876502›Full record

ArticleCell discovery2026

Bilirubin directly activates RIPK3 to induce non-classical necroptosis.

Qian Xue, Xi Ma, Ziyuan Chen, Feifei Ge, Jiawen Wu, Wenhao Bao, Li Zhou, Wei Yi, Min Wu, Siyan Liao and 10 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell discovery, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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2 · The registry

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

20 authors.

Qian XueGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
Xi MaGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
Ziyuan ChenGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
Feifei GeGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
Jiawen WuGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
Wenhao BaoGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
Li ZhouGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
Wei YiGuangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
Min WuGuangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
Siyan LiaoGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
Wenwen XuGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.ORCID http://orcid.org/0000-0003-2756-3498
Rongrong HeState Key Laboratory of Bioactive Molecules and Druggability Assessment/Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangzhou, Guangdong, China.ORCID http://orcid.org/0000-0001-5505-5672
Jingcheng FengState Key Laboratory of Bioactive Molecules and Druggability Assessment/Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangzhou, Guangdong, China.
Yameng HuGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
Xi ChenGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
Xintian WuGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
Ding YanGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
Daolin TangDepartment of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.ORCID http://orcid.org/0000-0002-1903-6180
Xin ChenGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China. chenxin@gzhmu.edu.cn.ORCID http://orcid.org/0000-0003-3668-4830
Jinbao LiuGuangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China. jliu@gzhmu.edu.cn.ORCID http://orcid.org/0000-0003-2220-2407

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Bilirubin, a byproduct of heme metabolism, is traditionally recognized for its antioxidant properties. However, its accumulation under pathological conditions can result in severe clinical manifestations, including neurotoxicity. Here, we report that bilirubin acts as an activator of receptor-interacting protein kinase 3 (RIPK3), inducing necroptosis and contributing to neurotoxic effects. Unlike the canonical pathway, in which RIPK3-mediated necroptosis is dependent on RIPK1, bilirubin directly binds to the D161 and S102 residues within the kinase domain of RIPK3. This binding facilitates RIPK3 oligomerization and autophosphorylation, leading to the activation of MLKL, the primary effector of necroptosis. Notably, bilirubin-induced necroptosis does not require the RHIM domain of RIPK3 or other RHIM-containing proteins, such as ZBP1 and TRIF. Functionally, the depletion of Ripk3 reduces bilirubin-induced neurotoxicity in murine models. These findings reveal a previously unrecognized mechanism of RIPK3-mediated non-canonical necroptosis, establishing it as a key mediator of bilirubin-induced neurotoxicity.

Identifiers

PMID41876502
PMCPMC13013812

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