EDL6D, a bioactive peptide phenocopying SHBG-associated metabolic effects: a new preclinical lead compound for treating the metabolic dysfunction-associated fatty liver disease.

Low plasma sex hormone-binding globulin (SHBG) levels are commonly observed in metabolic dysfunction-associated fatty liver disease (MASLD), a spectrum of disorders ranging from simple hepatocellular steatosis to steatohepatitis, fibrosis, and irreversible cirrhosis. We have previously demonstrated that SHBG overexpression reduces hepatic lipid accumulation by inhibiting lipogenesis both in vitro and in vivo. In the present proof-of-concept study, we have developed a bioactive peptide that phenocopies SHBG-associated metabolic effects (EDL6D) and have evaluated its ability to inhibit lipogenesis in vitro using HepG2 cells treated daily with 30 mM fructose. In addition, we assessed the preventive and therapeutic effects of EDL6D in vivo in wild-type mice with MASLD induced by a high-fat diet combined with 30% fructose in drinking water. Treatment with EDL6D exerted both preventive and therapeutic effects, significantly reducing hepatic fat accumulation and promoting regression of MASLD compared with vehicle-treated mice. Mechanistically, EDL6D downregulated the mRNA expression and protein levels of key lipogenic enzymes, including ATP-citrate lyase, acetyl-CoA carboxylase, and fatty acid synthase, as well as peroxisome proliferator-activated receptor gamma, a central lipogenic transcription factor. Notably, EDL6D prevented the development of mild fibrosis by reducing the expression of collagen type I alpha 1 chain (Col1a1) and transforming growth factor beta 1 (TGF-β1). MASLD remains as an unmet medical need and disease progression to fibrosis represents a major clinical challenge. This study identifies EDL6D as a novel preclinical lead compound that targets both hepatic lipid accumulation and suggests an antifibrotic effect. These findings support the translational potential of bioactive peptides phenocopying SHBG for the treatment and prevention of MASLD.