Enzyme-Activated Self-Assembling Peptides Mimicking Adiponectin Multimers for Nonalcoholic Fatty Liver Disease...

Adiponectin is a multifunctional adipokine that regulates metabolic homeostasis, particularly lipid metabolism, through activation of adiponectin receptors (AdipoRs). Its high molecular weight (HMW) form exhibits the greatest biological activity, yet therapeutic peptides derived from adiponectin typically exist as monomers or aggregates, limiting their efficacy. To mimic the multimeric architecture of adiponectin and enhance peptide efficacy, we developed two alkaline phosphatase (ALP)-activated self-assembling peptides, 1P and 2P, based on a conserved adiponectin sequence (¹⁴⁸GKFH-CNIPGL-YYFAY¹⁶²). These peptides undergo in situ self-assembly into stable nanofibers in ALP-overexpressing liver tissue, enhancing structural stability and receptor engagement. The assembled peptides effectively bind AdipoRs and reduce lipid accumulation in vitro. In a high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) mouse model, treatment with these peptides led to significant reductions in body weight, blood glucose levels, and hepatic steatosis. Transcriptomic analysis further revealed modulation of key pathways involved in inflammation, lipid synthesis, and metabolism. This study offers a promising strategy for mimicking multimeric adipokine structures and advancing peptide-based therapeutics for NAFLD.