Obesity-induced cardiac dysfunction is driven by metabolic derangements, chronic inflammation, and mitochondrial impairment. Emodin, a bioactive anthraquinone, exhibits cardioprotective and metabolic-regulatory properties but suffers from limited bioavailability. Polymeric To evaluate whether EMO-NPs ameliorate cardiac dysfunction in HFD-induced obesity and elucidate their mechanistic influence on PI3K/Akt/AMPK/mTOR signaling pathways.

Rodents were fed an HFD for 16 weeks to induce obesity-associated cardiac remodeling. Emodin-loaded polymeric nanoparticles were synthesized using a biodegradable polymer and characterized for size, zeta potential, encapsulation efficiency, and release kinetics. Animals received EMO-NPs or free emodin for 4 weeks. Cardiac function was assessed using echocardiography, hemodynamics, and serum biochemical markers. Histopathology, ultrastructure analysis, and immunohistochemistry were performed to evaluate myocardial hypertrophy, fibrosis, and lipid accumulation. Expression of PI3K/Akt/AMPK/mTOR pathway components was quantified using qPCR and Western blotting.

EMO-NPs exhibited optimal nano-size distribution, high encapsulation efficiency, and sustained drug release. HFD-fed rodents showed significant myocardial dysfunction, increased oxidative stress, inflammatory infiltration, and aberrant activation of PI3K/Akt/mTOR with suppression of AMPK. EMO-NP treatment markedly improved ejection fraction, fractional shortening, and diastolic indices. EMO-NPs reduced myocardial lipid deposition, attenuated fibrosis, restored mitochondrial morphology, and improved antioxidant status. Mechanistically, EMO-NPs suppressed PI3K and phosphorylated Akt, inhibited mTOR signaling, and reactivated AMPK phosphorylation more effectively than free emodin.

Emodin-loaded polymeric nanoparticles significantly reverse obesity-induced cardiac dysfunction by simultaneously modulating PI3K/Akt and AMPK/mTOR pathways, thereby restoring metabolic homeostasis and preventing pathological remodeling. Nano-formulation greatly enhances emodin’s bioavailability and therapeutic potency, highlighting EMO-NPs as a promising cardiometabolic intervention.