Paeoniflorin attenuates cardiac remodeling by targeting AKT1 and suppressing the AKT/NF-κB inflammatory axis

Background Cardiac remodeling induced by continuous pressure overload exacerbates heart failure (HF), yet effective treatments remain limited. This study investigates the therapeutic efficacy and underlying mechanisms of paeoniflorin (Pae) in the treatment of HF. Methods A transverse aortic constriction (TAC)-induced HF model in male Sprague-Dawley (SD) rats was used to evaluate four groups: Sham, TAC, TAC + Pae (10 mg/kg/day, i.p.), and TAC + fosinopril (5 mg/kg/day, p.o.). Cardiac function, morphology, and biomarker expression were assessed via echocardiography, hemodynamics, histology, ELISA, Western blot, and qPCR. Therapeutic targets were identified using network pharmacology, molecular docking, pull-down, and cellular thermal shift assays. Additionally, in vitro rescue assays were performed using Ang II-treated H9c2 cells and the AKT1 agonist SC79. Results Pae improved cardiac function, characterized by enhanced myocardial contractility and decreased serum NT-proBNP levels. Pae treatment decreased cardiomyocyte cross-sectional area (CSA), collagen deposition, and the expression of ANP , BNP , and β-MHC . Mechanistic studies identified AKT1 as a key binding partner of Pae. Pae binding to AKT1 inhibited its phosphorylation, thereby suppressing the downstream NF-κB inflammatory pathway and reducing the expression of pro-inflammatory cytokines ( IL-1β , IL-6 , and TNF-α ). Pae reversed Ang II-induced hypertrophy, fibrosis, and NF-κB nuclear translocation in H9c2 cells. Furthermore, the protective effects of Pae against hypertrophy, fibrosis, and inflammation were abolished by SC79. Pae demonstrated an excellent safety profile. Conclusion Pae alleviates HF by targeting the AKT1/NF-κB signaling axis to mitigate pathological remodeling and inflammation, presenting a safe and promising therapeutic candidate for heart failure management.