Rational design and discovery of potent PROTAC degraders of ASK1: a targeted therapy in MASH

(60) effectively reduced ASK1 protein levels, suppressed p38 MAPK activation, and decreased hepatic lipid content, indicating significant therapeutic benefits. This work underscores the importance of rational PROTAC design, precise linker engineering, and innovative E3 ligase selection in optimizing target protein degradation. Our findings pave the way for developing VHL-based PROTACs, offering a novel therapeutic approach for metabolic and inflammatory liver diseases.