A Keap1-recruiting BRD4 degrader offers a single-molecular polypharmacology approach for the treatment of metabolic dysfunction-associated steatohepatitis

Abstract

The pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) involves multiple pathophysiological processes, including abnormal lipid metabolism, insulin resistance, oxidative stress, endoplasmic reticulum stress, inflammatory response, and fibrosis. These factors interact to form a complex network and the development of synergistic and pleiotropic drug modalities targeting multiple pathogenesis of MASH may have a better therapeutic effect. Herein, the bifunctional proteolytic targeting chimeras (PROTAC) technology was utilized for developing pleiotropic drugs for MASH treatment. We constructed a Keap1-recruiting degrader KB-3 which stabilizes the natural Keap1 target Nrf2 and degrades BRD4 synergistically, exhibiting combined therapeutic advantages against MASH-related pathologies. Experimental results confirmed that KB-3 could effectively alleviate MASH in mice by improving lipid metabolic disorder, enhancing the defense against oxidative stress, reducing inflammation, and delaying the progression of liver fibrosis. Such Keap1-recruiting degrader offering a single-molecular approach with polypharmacology effects may be an attractive strategy for the treatment of multifactorial disease.