Aloe-emodin from rhubarb suppresses islet amyloid polypeptide (IAPP) aggregation and expression: Therapeutic...

Islet amyloid polypeptide (IAPP) aggregation contributes significantly to β-cell dysfunction in type 2 diabetes mellitus (T2DM). This study investigated whether bioactive compounds derived from rhubarb, particularly aloe-emodin, can serve as effective inhibitors of IAPP aggregation, thereby offering therapeutic the prevention and treatment of T2DM. Recombinant IAPP (optimally expressed in E. coli BL21 at 22 °C with 0.4 mM IPTG induction for 6 h; yield: 0.061 mg/mL, purity: 95 %) was prepared for subsequent inhibitor screening studies. Aggregation inhibition by aloe-emodin was assessed using thioflavin T fluorescence kinetics. Molecular docking, molecular dynamics (MD) simulations, and Biolayer interferometry (BLI) further characterized binding mechanisms and complex stability. Aloe-emodin demonstrated superior inhibition (46.63 %), surpassing emodin (38.22 %) and sennoside D (25.41 %). Hydrophobic interactions dominated IAPP-aloe-emodin binding, inducing static fluorescence quenching. MD simulation analyses confirmed the formation of a stable, high-affinity IAPP-aloe-emodin complex. Molecular docking revealed a binding energy of -9.37 kcal/mol, while MD simulations demonstrated rapid formation of a stable system within a short simulation timeframe. BLI quantified the binding affinity with an equilibrium dissociation constant (KD) of 3.96 × 10^-6 M, indicating a typical drug-target interaction. Cellular studies demonstrated that aloe-emodin reduced intracellular IAPP levels by 42.50 % and downregulated IAPP gene expression. These findings establish aloe-emodin as a promising dual-action therapeutic candidate targeting both IAPP proteotoxicity and transcriptional regulation.