Bilirubin mitigates ischemic white matter injury by targeting transferrin-receptor-mediated B cell immunometabolism.

Physiological bilirubin exerts protective effects against ischemic stroke, but its role in post-stroke white matter injury (WMI) remains unclear. Here, through integrated epidemiological, genetic, and mechanistic studies, we demonstrate that mild elevation of serum bilirubin mitigates ischemic WMI by modulating B cell immunometabolism. Prospective cohort and Mendelian randomization analyses revealed an inverse association between bilirubin levels and WMI severity. In experimental models, bilirubin suppressed B cell activation and neuroinflammation by targeting transferrin receptor (TFRC), thereby reducing iron overload, restoring glucose metabolism, and improving mitochondrial homeostasis. Single-cell profiling further linked bilirubin-mediated B cell modulation to attenuated microglial activation via Fcγ receptor signaling. The existence of a bilirubin-B cell immunometabolism axis bridges preclinical findings with clinical relevance. Our findings establish bilirubin as a key immunometabolic checkpoint in B cells and propose TFRC blocking as a therapeutic strategy for ischemic WMI.