Journal
ACTA PHARMACEUTICA SINICA B
Volume 12, Issue 5, Pages 2300-2314Publisher
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2021.12.007
Keywords
Celastrol; Ferroptosis; Peroxiredoxin; HO-1; Hepatic fibrosis; ABPP; Anti-oxidant; Reactive oxygen species
Categories
Funding
- National Key Research and Development Program of China [2020YFA0908000]
- Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (China) [ZYYCXTD-C-202002]
- National Natural Science Foundation of China (China) [81903588, 81803456, 82074098, 81841001]
- Fundamental Research Funds for the Central Public Welfare Research Institutes (China) [ZXKT18003, ZZ15-YQ-063]
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Celastrol exerts anti-fibrotic effects by inducing ferroptosis and promoting the production of ROS. It directly binds to PRDXs and HO-1, inhibiting their antioxidant activities and increasing ROS levels, thereby inducing ferroptosis.
Ferroptosis is a form of regulated cell death, characterized by excessive membrane lipid per oxidation in an iron-and ROS-dependent manner. Celastrol, a natural bioactive triterpenoid extracted from Tripterygium wilfordii, shows effective anti-fibrotic and anti-inflammatory activities in multiple hepatic diseases. However, the exact molecular mechanisms of action and the direct protein targets of celastrol in the treatment of liver fibrosis remain largely elusive. Here, we discover that celastrol exerts anti-fibrotic effects via promoting the production of reactive oxygen species (ROS) and inducing ferroptosis in activated hepatic stellate cells (HSCs). By using activity-based protein profiling (ABPP) in combination with bio-orthogonal click chemistry reaction and cellular thermal shift assay (CETSA), we show that celastrol directly binds to peroxiredoxins (PRDXs), including PRDX1, PRDX2, PRDX4 and PRDX6, through the active cysteine sites, and inhibits their anti-oxidant activities. Celastrol also targets to heme oxygenase 1 (HO-1) and upregulates its expression in activated-HSCs. Knockdown of PRDX1, PRDX2, PRDX4, PRDX6 or HO-1 in HSCs, to varying extent, elevated cellular ROS levels and induced ferroptosis. Taken together, our findings reveal the direct protein targets and molecular mechanisms via which celastrol ameliorates hepatic fibrosis, thus supporting the further development of celastrol as a promising therapeutic agent for liver fibrosis. (C) 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
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