β-Hydroxybutyrate as an emerging drug ameliorates sepsis-like symptoms and cardiac dysfunction in septic rats through inhibition of Fkbp5

Sepsis-induced cardiomyopathy (SIC) is a severe complication with high mortality, lacking effective targeted therapies. β-Hydroxybutyrate (BHB), a ketone body, has shown potential anti-inflammatory and cardioprotective effects, but its specific role and mechanism in SIC remain elusive. A sepsis model was established in Sprague–Dawley rats via cecal ligation and puncture (CLP). Rats were treated with BHB (10 mg/kg). Cardiac function was assessed by echocardiography. Histological changes, inflammatory cytokines, apoptosis, and autophagy markers were evaluated. Bioinformatics analysis was performed to identify potential targets, which were validated using FKBP5 knockdown (sh-FKBP5) in vivo. Sepsis significantly impaired cardiac function, evidenced by marked reductions in left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), accompanied by severe histological injury, elevated inflammatory cytokines, and increased cardiomyocyte apoptosis. BHB treatment markedly attenuated these pathological changes, restored LVEF and LVFS, and modulated autophagy markers (increased LC3-II/I ratio and decreased p62 levels). Mechanistically, BHB significantly inhibited the expression of FKBP5. Crucially, FKBP5 knockdown abolished the protective effects of BHB, leading to worsened cardiac dysfunction and inflammation despite BHB administration, thereby confirming FKBP5 as an essential mediator. Bioinformatics analysis further identified FKBP5 as a hub gene correlated with sepsis severity. Our findings suggest that BHB ameliorates sepsis-induced cardiac dysfunction, likely through the inhibition of FKBP5, which subsequently regulates apoptosis and autophagy. While further studies are needed to fully elucidate the downstream signaling cascades and metabolic profiles, this study identifies FKBP5 as a promising therapeutic target and highlights BHB as a potential intervention strategy for sepsis-induced cardiomyopathy.