Betulinic acid mitigates septic cardiomyopathy in mice through modulating the TLR4/MyD88/NF-κB signaling axis and NLRP3 inflammasome pathway.

BACKGROUND: Although betulinic acid (BA) possesses diverse pharmacological properties, its cardioprotective potential in sepsis-associated myocardial damage remains undefined. This investigation explores BA's therapeutic potential and underlying mechanisms against lipopolysaccharide (LPS)-induced septic cardiomyopathy in murine models. METHODS: Experimental sepsis was induced via intraperitoneal LPS administration (10 mg/kg), with subjects randomized into six cohorts: normal controls, LPS model group, positive control (imipenem 120 mg/kg), and BA treatment arms (15/30/60 mg/kg oral gavage). Pharmacological interventions preceded the LPS challenge by seven days. Comprehensive cardiac evaluation encompassed echocardiographic parameters, ELISA quantification, histopathological assessment (H&E), with complementary TUNEL and DCFH-DA staining for pyroptotic quantification and oxidative stress evaluation. Immunoblotting analyzed the TLR4/MyD88/NF-κB cascade, MAPK phosphorylation states, and NLRP3 inflammasome activation. RESULTS: validation using H9c2 cardiomyoblasts (12.5-50 μM BA) confirmed NLRP3 inflammasome downregulation, evidenced by reduced GSDMD cleavage, caspase-1 activation, and interleukin maturation. CONCLUSION: These findings substantiate BA's myocardial preservation through coordinated modulation of the TLR4/NF-κB/MAPK axis and NLRP3 inflammasome activation, proposing BA as a novel multi-target therapeutic candidate for sepsis-induced cardiac dysfunction.