Department of Gastroenterology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China.
Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China.
PeerJ. 2023 Sep 28;11:e16060. doi: 10.7717/peerj.16060. eCollection 2023.
Liver fibrosis is a key stage in the progression of various chronic liver diseases to cirrhosis and liver cancer, but at present, there is no effective treatment. This study investigated the therapeutic effect of the new antifibrotic drug fluorofenidone (AKF-PD) on liver fibrosis and its related mechanism, providing implications for liver cancer.
The effects of AKF-PD on hepatic stellate cell (HSC) autophagy and extracellular matrix (ECM) expression were assessed in a carbon tetrachloride (CCl)-induced rat liver fibrosis model. , HSC-T6 cells were transfected with Smad2 and Smad3 overexpression plasmids and treated with AKF-PD. The viability and number of autophagosomes in HSC-T6 cells were examined. The protein expression levels of Beclin-1, LC3 and P62 were examined by Western blotting. The Cancer Genome Atlas (TCGA) database was used for comprehensively analyzing the prognostic values of SMAD2 and SMAD3 in liver cancer. The correlation between SMAD2, SMAD3, and autophagy-related scores in liver cancer was explored. The drug prediction of autophagy-related scores in liver cancer was explored.
AKF-PD attenuated liver injury and ECM deposition in the CCl-induced liver fibrosis model. , the viability and number of autophagosomes in HSCs were reduced significantly by AKF-PD treatment. Meanwhile, the protein expression of FN, α-SMA, collagen III, Beclin-1 and LC3 was increased, and P62 was reduced by the overexpression of Smad2 and Smad3; however, AKF-PD reversed these effects. SMAD2 and SMAD3 were hazardous factors in liver cancer. SMAD2 and SMAD3 correlated with autophagy-related scores in liver cancer. Autophagy-related scores could predict drug response in liver cancer.
AKF-PD alleviates liver fibrosis by inhibiting HSC autophagy the transforming growth factor (TGF)-β1/Smadpathway. Our study provided some implications about how liver fibrosis was connected with liver cancer by SMAD2/SMAD3 and autophagy.
肝纤维化是各种慢性肝病向肝硬化和肝癌进展的关键阶段，但目前尚无有效的治疗方法。本研究探讨了新型抗纤维化药物氟苯尼酮（AKF-PD）治疗肝纤维化的疗效及其相关机制，为肝癌的防治提供了依据。
在四氯化碳（CCl）诱导的大鼠肝纤维化模型中，评估 AKF-PD 对肝星状细胞（HSC）自噬和细胞外基质（ECM）表达的影响。用 AKF-PD 处理转染 Smad2 和 Smad3 过表达质粒的 HSC-T6 细胞。观察 HSC-T6 细胞自噬体的数量和活力。Western blot 检测 Beclin-1、LC3 和 P62 的蛋白表达水平。利用癌症基因组图谱（TCGA）数据库综合分析肝癌中 SMAD2 和 SMAD3 的预后价值。探讨肝癌中 SMAD2、SMAD3 与自噬相关评分的相关性。探讨肝癌自噬相关评分的药物预测。
AKF-PD 可减轻 CCl 诱导的肝纤维化模型中的肝损伤和 ECM 沉积。体外实验结果显示，AKF-PD 处理可显著降低 HSCs 的活力和自噬体的数量。同时，FN、α-SMA、胶原 III、Beclin-1 和 LC3 的蛋白表达增加，而 P62 的表达减少，Smad2 和 Smad3 的过表达则逆转了这些效应。SMAD2 和 SMAD3 是肝癌的危险因素。SMAD2 和 SMAD3 与肝癌中的自噬相关评分相关。自噬相关评分可预测肝癌的药物反应。
AKF-PD 通过抑制 TGF-β1/Smad 通路抑制 HSC 自噬来减轻肝纤维化。我们的研究提供了一些关于 SMAD2/SMAD3 和自噬如何与肝癌相关的证据。
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