Abstact

Effective therapeutic agents against hepatic fibrosis remain scarce. Natural product Celastrol has demonstrated promising anti-hepatic fibrosis activity. However, further clinical development is impaired by its toxicity. We performed a bromination modification at the C-ring, an unexplored moiety of Celastrol, leading to a series of brominated derivatives. Among them, derivative 5 effectively suppressed various stimulus-induced activation of NLRP3 inflammasome to block the activation of HSCs, thus reducing the collagen deposition. Meanwhile, 5 was identified as a covalent PRDX1 inhibitor with high isoform selectivity, which accelerated ROS accumulation to induce apoptosis of the activated HSCs. Derivative 5 at a dose of 20 mg/kg exhibited superior safety profile with no significant weight loss or hepatotoxicity. At 1 mg/kg, it significantly ameliorates CCl(4)-induced hepatic damage and fibrosis in mice. Taken together, our work provided a novel brominated derivative of Celastrol as promising lead compound against hepatic fibrosis.