Luo Li, Liang Yonghong, Fu Yuanyuan, Liang Zhiyuan, Zheng Jinfen, Lan Jie, Shen Feihai, Huang Zhiying
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Pharmaceuticals (Basel). 2022 Dec 3;15(12):1509. doi: 10.3390/ph15121509.
Toosendanin (TSN) is a triterpenoid from the fruit or bark of Sieb et Zucc, which has clear antitumor and insecticidal activities, but it possesses limiting hepatotoxicity in clinical application. Autophagy is a degradation and recycling mechanism to maintain cellular homeostasis, and it also plays an essential role in TSN-induced hepatotoxicity. Nevertheless, the specific mechanism of TSN on autophagy-related hepatotoxicity is still unknown. The hepatotoxicity of TSN in vivo and in vitro was explored in this study. It was found that TSN induced the upregulation of the autophagy-marker microtubule-associated proteins 1A/1B light chain 3B (LC3B) and P62, the accumulation of autolysosomes, and the inhibition of autophagic flux. The middle and late stages of autophagy were mainly studied. The data showed that TSN did not affect the fusion of autophagosomes and lysosomes but significantly inhibited the acidity, the degradation capacity of lysosomes, and the expression of hydrolase cathepsin B (CTSB). The activation of autophagy could alleviate TSN-induced hepatocyte damage. TSN inhibited the expression of transcription factor EB (TFEB), which is a key transcription factor for many genes of autophagy and lysosomes, such as CTSB, and overexpression of TFEB alleviated the autophagic flux blockade caused by TSN. In summary, TSN caused hepatotoxicity by inhibiting TFEB-lysosome-mediated autophagic flux and activating autophagy by rapamycin (Rapa), which could effectively alleviate TSN-induced hepatotoxicity, indicating that targeting autophagy is a new strategy to intervene in the hepatotoxicity of TSN.
川楝素（TSN）是一种从川楝子果实或树皮中提取的三萜类化合物，具有明确的抗肿瘤和杀虫活性，但在临床应用中存在一定的肝毒性。自噬是一种维持细胞内稳态的降解和循环机制，在TSN诱导的肝毒性中也起着重要作用。然而，TSN对自噬相关肝毒性的具体机制仍不清楚。本研究探讨了TSN在体内和体外的肝毒性。研究发现，TSN诱导自噬标志物微管相关蛋白1A/1B轻链3B（LC3B）和P62上调、自噬溶酶体积累以及自噬流抑制。主要研究了自噬的中晚期。数据表明，TSN不影响自噬体与溶酶体的融合，但显著抑制溶酶体的酸性、降解能力以及水解酶组织蛋白酶B（CTSB）的表达。自噬的激活可减轻TSN诱导的肝细胞损伤。TSN抑制转录因子EB（TFEB）的表达，TFEB是许多自噬和溶酶体基因（如CTSB）的关键转录因子，过表达TFEB可减轻TSN引起的自噬流阻断。综上所述，TSN通过抑制TFEB-溶酶体介导的自噬流导致肝毒性，而雷帕霉素（Rapa）激活自噬可有效减轻TSN诱导的肝毒性，表明靶向自噬是干预TSN肝毒性的新策略。
