A novel deacetylase inhibitor KLX suppresses liver fibrosis by deacetylating PPARγ through promoting ubiquitination-mediated HDAC1 degradation.

Abstract

Liver fibrosis is a pathological response following liver injury induced by various etiologies. Herein, we present the therapeutic potential of a novel anthraquinone compound, kanglexin (KLX), in the treatment of liver fibrosis. We observed significant suppression of the inflammatory response and extracellular matrix deposition in mice with liver fibrosis induced by CCL₄, by bile duct ligation, and by a methionine-choline-deficient diet. Mechanistically, through screening, we found that KLX interacts with HDAC1. Additionally, KLX facilitates binding between HDAC1 and KCTD11, promoting the ubiquitination-mediated degradation of HDAC1 and consequently reducing its protein level. Moreover, HDAC1 was found to bind to PPARγ, influencing its acetylation level. Following KLX treatment, the level of PPARγ deacetylation mediated by HDAC1 decreases, leading to increased protein expression of PPARγ. This effectively inhibited the NFκB and TGF-β/Smad2/3 signaling pathways, thereby reducing inflammation and extracellular matrix deposition. Ultimately, this intervention can halt the progression of liver fibrosis and ameliorate liver damage. In summary, our study demonstrated that KLX can effectively inhibit the progression of liver fibrosis by modulating the protein level and activity of HDAC1. These findings provide valuable insights for the development of effective drugs and treatment strategies for liver fibrosis.