(+)-Clausenamide protects against drug-induced liver injury by inhibiting hepatocyte ferroptosis.

Autor: Wang M; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, 510632, Guangzhou, China.; Department of Pharmacy, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), 570311, Haikou, Hainan, China., Liu CY; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, 510632, Guangzhou, China.; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 510632, Guangzhou, China.; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, 510632, Guangzhou, China., Wang T; Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, 250012, Jinan, China., Yu HM; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, 510632, Guangzhou, China.; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 510632, Guangzhou, China.; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, 510632, Guangzhou, China., Ouyang SH; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, 510632, Guangzhou, China.; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 510632, Guangzhou, China.; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, 510632, Guangzhou, China., Wu YP; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, 510632, Guangzhou, China.; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 510632, Guangzhou, China.; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, 510632, Guangzhou, China., Gong HB; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, 510632, Guangzhou, China.; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 510632, Guangzhou, China.; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, 510632, Guangzhou, China., Ma XH; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, 510632, Guangzhou, China.; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 510632, Guangzhou, China.; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, 510632, Guangzhou, China., Jiao GL; The Spine Surgery Department, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, China., Fu LL; School of Life Science and Engineering, Southwest Jiaotong University, 610031, Chengdu, China., Wu QS; Department of Pharmacy, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), 570311, Haikou, Hainan, China., Kurihara H; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, 510632, Guangzhou, China.; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 510632, Guangzhou, China.; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, 510632, Guangzhou, China., Li YF; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, 510632, Guangzhou, China. liyifang706@jnu.edu.cn.; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 510632, Guangzhou, China. liyifang706@jnu.edu.cn.; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, 510632, Guangzhou, China. liyifang706@jnu.edu.cn., Shen T; Key Lab of Chemical Biology (MOE), School of Pharmaceutical Sciences, Shandong University, 250012, Jinan, China. shentao@sdu.edu.cn., He RR; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, 510632, Guangzhou, China. rongronghe@jnu.edu.cn.; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 510632, Guangzhou, China. rongronghe@jnu.edu.cn.; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, 510632, Guangzhou, China. rongronghe@jnu.edu.cn.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2020 Sep 19; Vol. 11 (9), pp. 781. Date of Electronic Publication: 2020 Sep 19.
DOI: 10.1038/s41419-020-02961-5
Abstrakt: Drug-induced liver injury is the major cause of acute liver failure. However, the underlying mechanisms seem to be multifaceted and remain poorly understood, resulting in few effective therapies. Here, we report a novel mechanism that contributes to acetaminophen-induced hepatotoxicity through the induction of ferroptosis, a distinctive form of programmed cell death. We subsequently identified therapies protective against acetaminophen-induced liver damage and found that (+)-clausenamide ((+)-CLA), an active alkaloid isolated from the leaves of Clausena lansium (Lour.) Skeels, inhibited acetaminophen-induced hepatocyte ferroptosis both in vivo and in vitro. Consistently, (+)-CLA significantly alleviated acetaminophen-induced or erastin-induced hepatic pathological damages, hepatic dysfunctions and excessive production of lipid peroxidation both in cultured hepatic cell lines and mouse liver. Furthermore, treatment with (+)-CLA reduced the mRNA level of prostaglandin endoperoxide synthase 2 while it increased the protein level of glutathione peroxidase 4 in hepatocytes and mouse liver, confirming that the inhibition of ferroptosis contributes to the protective effect of (+)-CLA on drug-induced liver damage. We further revealed that (+)-CLA specifically reacted with the Cys-151 residue of Keap1, which blocked Nrf2 ubiquitylation and resulted in an increased Nrf2 stability, thereby leading to the activation of the Keap1-Nrf2 pathway to prevent drug-induced hepatocyte ferroptosis. Our studies illustrate the innovative mechanisms of acetaminophen-induced liver damage and present a novel intervention strategy to treat drug overdose by using (+)-CLA.
Databáze: MEDLINE
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