Urea functions as a risk signal driving astrocyte-mediated neuroinflammation following stroke
Urea, traditionally recognized as the final product of protein metabolism and a regulator of urine concentration, has recently emerged as a potential contributor to central nervous system (CNS) pathologies. However, its role in ischemic stroke remains largely unexplored. In this study, we identify urea as a previously unrecognized risk signal, whose levels rapidly increase in the brain following ischemic stroke. Elevated urea triggers the induction of neurotoxic A1-type astrocytes and promotes neuronal pyroptosis. Mechanistically, this process is mediated by the astrocytic urea transporter UT-B, which facilitates urea influx and initiates a cascade of neuroinflammatory responses. Through quantitative proteomics and gene silencing, we further demonstrate that urea exacerbates DNA damage via activation of the transcriptional coactivator Wwtr1, thereby amplifying the generation of A1 astrocytes. Collectively, our findings reveal a novel pathophysiological role for urea in ischemic brain injury and underscore the critical involvement of astrocytes in modulating neuroinflammation and neuronal death.
Authors
- Li Xuan (ORCID: https://orcid.org/0000-0002-6176-7411)
- Yang Han (ORCID: https://orcid.org/0000-0002-3105-6248)
- Tongshuai Zhang (ORCID: https://orcid.org/0000-0003-2046-9490)
- Guangzhi Wang (ORCID: https://orcid.org/0009-0004-1284-4179)
- Jing Lan (ORCID: https://orcid.org/0000-0001-9307-8517)
- Jiachen He
- Xianfeng Li (ORCID: https://orcid.org/0000-0001-8549-537X)
- Guangyou Wang
- Baoxue Yang (ORCID: https://orcid.org/0000-0002-7966-2095)
- Hui Tao (ORCID: https://orcid.org/0000-0002-3404-3418)
- Yao Zhang (ORCID: https://orcid.org/0000-0003-3853-3550)
- Dandan Wang (ORCID: https://orcid.org/0000-0002-3628-9569)
- Fan Zhu (ORCID: https://orcid.org/0000-0001-7031-2956)
- Liwei Zhao (ORCID: https://orcid.org/0000-0001-5077-327X)
- Shanshan Yang (ORCID: https://orcid.org/0009-0005-0951-5179)
- Yixiang Jiang (ORCID: https://orcid.org/0000-0001-5690-2116)
- Haicheng Yang
- Changyong Tang
Institutions
- Harbin Medical University (CN)
- Sun Yat-sen University (CN)
- Second Affiliated Hospital of Harbin Medical University (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- First Affiliated Hospital of Harbin Medical University (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- Journal of Neuroinflammation
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1186/s12974-025-03620-2
- Citations
- 1
- Primary Topic
- Gout, Hyperuricemia, Uric Acid
- Type
- article
- Field-Weighted Citation Impact
- 1.43