PROTAC-mediated FTO protein degradation effectively alleviates diet-induced obesity and hepatic steatosis.

Demethylation of N-Methyladenosine (m6A) by fat mass and obesity-associated protein (FTO) occurs in the development of obesity and fatty liver disease. In this study, we synthesized FTO-degradation targeted chimera (FTO-DT), which exhibited excellent lipid-lowering activity at low concentration. At a concentration of 0.33 nM, the FTO-DT continuously and efficiently degraded FTO protein and reduced fat deposition. The FTO-DT improved energy metabolism and oxidative stress by increasing intracellular m6A levels, and further reduced fat deposition in hepatocytes, adipocytes, and mice fed a high-fat diet. The findings support the potential of FTO degradation by FTO-DT as a therapy for obesity and metabolic-associated fatty liver disease (MAFLD). This study provides a theoretical basis for the application of PROTACs in the treatment of metabolic disease and describes a novel approach for the development of drugs targeting metabolic disorders.