Buyang huanwu decoction (BYHWD) attenuates sepsis-induced myocardial injury by suppressing aberrant iron accumulation in preclinical mouse models

BACKGROUND: Sepsis-induced myocardial injury (SIMI), in particular, myocardial fibrosis, is frequently detected in septic patients and regarded as a key factor associated with sepsis-related mortality. PURPOSE: We sought to investigate whether the traditional Chinese medicine (TCM) prescription Buyang Huanwu Decoction (BYHWD) can alleviate early onset SIMI and improve the survival of septic mice. STUDY DESIGN: The lipopolysaccharide (LPS) and cecal ligation and puncture (CLP)-induced SIMI preclinical models were utilized to assess the therapeutic effect of BYHWD at low (1 mg/kg), median (5 mg/kg), and high (15 mg/kg) doses. METHODS: Multiple staining assays were employed for histopathological inspection, iron detection, and fibrotic status determination. In silico Network pharmacological and bioinformatics analyses were exploited to dissect molecular mechanism followed by in vitro and in vivo experimental validations using the immunostaining, immunoblotting, flow cytometry, RT-qPCR, and Ultra high performance liquid chromatography (UHPLC) assays. RESULTS: BYHWD attenuates SIMI and improves the survival of septic mice in a dose-dependent fashion. Mechanistically, sepsis-induced iron accumulation contributes to early onset SIMI. The aberrant iron overload in cardiac tissues is caused by elevated Heme Oxygenase-1 (Hmox1), which catalyzes Heme degradation and generates Biliverdin, Carbonic oxide (CO), and labile iron, thereby leading to iron accumulation. BYHWD-treated septic mice showed reduced cardiac Hmox1 expression. Mass spectrum assays unveil that the effective compound of BYHWD is Hydroxysafflor Yellow A (HSYA) on alleviating SIMI via blockade Hmox1-mediated iron overload in septic mice. CONCLUSION: Our study demonstrates an anti-fibrotic effect of BYHWD via HSYA by suppressing Hmox1-mediated iron metabolic dysregualtion in preclinical models.