Gut Microbiota and Aldosterone Regulate Natriuretic Peptide B Expression to Drive Mitophagy and Metabolic Reprogramming in Sepsis‐Like Model of Myocardial Injury

BACKGROUND: Myocardial injury is a major contributor to mortality in sepsis, yet the mechanisms underlying gut-heart communication in sepsis-induced myocardial injury remain insufficiently defined. Natriuretic peptide B (NPPB) is a cardiac stress-responsive gene, but its involvement in mitochondrial homeostasis and metabolic regulation is unclear. This study investigated how gut microbiota and aldosterone influence myocardial mitophagy and metabolic reprogramming through NPPB in sepsis-induced myocardial injury. METHODS: A sepsis-like myocardial injury model was induced in mice by intraperitoneal lipopolysaccharide (LPS). Fecal microbiota transplantation from septic mice into pseudo-germ-free recipients assessed microbial contributions. Metagenomic, metabolomic, and transcriptomic analyses identified disrupted metabolites and cardiac gene signatures. Heart-specific NPPB-knockout mice were used to determine its in vivo role. Mitochondrial function and metabolic alterations were evaluated by energy metabolism assays. In vitro, aldosterone-treated AC16 cardiomyocytes were used to examine NPPB-mediated mitophagy and metabolic changes. Molecular docking, dynamics simulation, and machine-learning screening identified Lestaurtinib, whose therapeutic effects were validated pharmacologically. RESULTS: Sepsis caused pronounced microbial dysbiosis and elevated aldosterone levels. Multi-omics analysis identified NPPB as a central regulator of mitophagy and metabolic remodeling. NPPB deficiency mitigated mitochondrial impairment and metabolic disturbances in vivo. Aldosterone upregulated NPPB in cardiomyocytes, promoting mitophagy and metabolic reprogramming. Lestaurtinib, identified as a candidate targeting the aldosterone-NPPB axis, improved cardiac structure and function while partially restoring microbial and metabolic homeostasis. CONCLUSIONS: This study uncovers a novel gut microbiota-aldosterone-NPPB axis driving LPS-induced myocardial injury through dysregulated mitophagy and metabolism and highlights Lestaurtinib as a potential therapeutic strategy for sepsis-induced myocardial injury.