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.