摘要The root of Aconitum carmichaelii Debx.(Fuzi)is an herbal medicine used in China that exerts significant efficacy in rescuing patients from severe diseases.A key toxic compound in Fuzi,aconitine(AC),could trigger unpredictable cardiotoxicities with high-individualization,thus hinders safe application of Fuzi.In this study we investigated the individual differences of AC-induced cardiotoxicities,the biomarkers and underlying mechanisms.Diversity Outbred(DO)mice were used as a genetically heterogeneous model for mimicking individualization clinically.The mice were orally administered AC(0.3,0.6,0.9 mg kg-1-d-1)for 7 d.We found that AC-triggered cardiotoxicities in DO mice shared similar characteristics to those observed in clinic patients.Most importantly,significant individual differences were found in DO mice(variation coefficients:34.08％-53.17％).RNA-sequencing in AC-tolerant and AC-sensitive mice revealed that hemoglobin subunit beta(HBB),a toxic-responsive protein in blood with 89％homology to human,was specifically enriched in AC-sensitive mice.Moreover,we found that HBB overexpression could significantly exacerbate AC-induced cardiotoxicity while HBB knockdown markedly attenuated cell death of cardiomyocytes.We revealed that AC could trigger hemolysis,and specifically bind to HBB in cell-free hemoglobin(cf-Hb),which could excessively promote NO scavenge and decrease cardioprotective S-nitrosylation.Meanwhile,AC bound to HBB enhanced the binding of HBB to ABHD5 and AMPK,which correspondingly decreased HDAC-NT generation and led to cardiomyocytes death.This study not only demonstrates HBB achievement a novel target of AC in blood,but provides the first clue for HBB as a novel biomarker in determining the individual differences of Fuzi-triggered cardiotoxicity.