Guanabenz Acetate

Guanabenz acetate binds with high affinity to the nuclear transcriptional coregulator HELZ2, a protein upregulated in human and mouse nonalcoholic fatty liver disease. Chronic oral administration of guanabenz acetate selectively activates hepatic leptin receptor isoform b (Leprb) expression via HELZ2 binding, leading to leptin sensitization specifically in the liver. This mechanism reduces lipogenesis by downregulating key lipid synthesis genes including Srebp1c and Fasn, while simultaneously activating fatty acid β-oxidation through upregulation of Pparα and Cpt1a. In high-fat diet-induced obese mice, guanabenz acetate treatment significantly decreases hepatic triglyceride accumulation, improves insulin resistance, and reduces hyperglycemia without affecting food intake. The drug also diminishes hepatocyte hypertrophy and lipid droplet formation.

Fig. 1 Administration of the medium-dose of Guanabenz Acetate improves hepatocyte hypertrophy in obese mice. (Yoshino S.; et al. 2020)

Guanabenz acetate-loaded PEGylated polycaprolactone polymersomes were developed using the nanoprecipitation method for triple-negative breast cancer treatment. The optimized formulation achieved a particle size of 90.5 nm, encapsulation efficiency of 92.11 percent, and sustained drug release over 6 days. The polymersomes significantly enhanced cellular uptake and reduced IC50 in MCF-7 cells compared to free guanabenz acetate. Mechanism studies revealed increased eIF2α phosphorylation and decreased Rac1 expression, which reduced cancer cell migration and metastasis by 60.5 and 78.1 percent respectively. In vivo studies demonstrated long-circulating properties with high passive tumor accumulation via EPR effect, resulting in significant tumor size reduction.

Fig. 2 TEM images of Guanabenz Acetate-loaded PS (F16). (Haggag Y A.; et al. 2021)