Abstract：
Toosendanin (TSN) is the main active component in the traditional herb Melia toosendan Siebold & Zucc, which exhibits promising potential for development due to its diverse pharmacological properties. However, the hepatotoxicity associated with TSN needs further investigation. Previous research has implicated autophagy dysregulation in TSN-induced hepatotoxicity, yet the underlying mechanisms remain elusive. In this study, the mechanisms of signal transducer and activator of transcription 3 (STAT3) in TSN-induced autophagy inhibition and liver injury were explored using Stat3 knockout C57BL/6 mice and HepG2 cells. TSN decreased cell viability, increased lactate dehydrogenase (LDH) production in vitro, and elevated serum aspartate transaminase (AST) and alanine aminotransferase (ALT) levels as well as liver lesions in vivo, suggesting TSN had significant hepatotoxicity. TSN inhibited Janus kinase 2 (JAK2)/STAT3 pathway and the expression of cathepsin C (CTSC). Inhibition of STAT3 exacerbated TSN-induced autophagy inhibition and hepatic injury, whereas activation of STAT3 attenuated these effects of TSN. Mechanistically, STAT3 transcriptionally regulated the level of CTSC gene, which in turn affected autophagy and the process of liver injury. TSN-administered Stat3 knockout mice showed more severe hepatotoxicity, CTSC downregulation, and autophagy blockade than wildtype mice. In summary, TSN caused hepatotoxicity by inhibiting STAT3/CTSC axis-dependent autophagy and lysosomal function.
摘要：
Toosendanin（TSN）是传统草药MeliaToosendanSiebold＆Zucc中的主要活性成分，由于其不同的药理特性，显示出有希望的发展潜力。然而,与TSN相关的肝毒性需要进一步研究.先前的研究涉及自噬失调在TSN诱导的肝毒性中，然而，潜在的机制仍然难以捉摸。在这项研究中,利用Stat3敲除C57BL/6小鼠和HepG2细胞,探讨了信号转导和转录激活因子3(STAT3)在TSN诱导的自噬抑制和肝损伤中的作用机制。TSN降低了细胞活力，增加乳酸脱氢酶（LDH）的体外生产，和血清天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平升高以及体内肝脏病变，提示TSN有明显的肝毒性。TSN抑制Janus激酶2(JAK2)/STAT3通路和组织蛋白酶C(CTSC)的表达。抑制STAT3会加剧TSN诱导的自噬抑制和肝损伤，而STAT3的激活减弱了TSN的这些作用。机械上,STAT3转录调控CTSC基因水平,进而影响自噬和肝损伤的过程。TSN给药的Stat3敲除小鼠表现出更严重的肝毒性，CTSC下调,和自噬阻断比野生型小鼠。总之,TSN通过抑制STAT3/CTSC轴依赖性自噬和溶酶体功能引起肝毒性。
