肝癌生成引起的纤维化肾损伤严重影响治疗效果。黄芪提取物IV（AS-IV），一种黄芪提取物，具有多种药理活性，在水肿和纤维化的治疗中很有用。Nrf2/HO-1是一种关键的抗氧化应激途径，有助于治疗肾损伤。Smad3磷酸化与肝癌生成有关。我们之前的研究明确了Smad3由Smad3不同磷酸化形式调控的肝癌生成的差异性。因此，我们对黄芪提取物IV对肝癌生成引起的肾纤维化的治疗贡献进行了调查。重点是在AS-IV治疗期间，Smad3的磷酸化和Nrf2/HO-1途径的调控是否参与，并且Nrf2敲除是否对Smad3的磷酸化产生影响。我们对HK-2细胞进行TGF-β1刺激，并进行AS-IV干预。进一步，我们研究了肝癌生成过程中AS-IV对Nrf2敲除小鼠的肾损伤以及其作用机制。一方面，体外结果表明，AS-IV通过促进pSmad3C/p21的表达和Nrf2/HO-1的表达，降低了HK-2的ROS和α-SMA表达，并抑制了pSmad3L/PAI-1的表达。另一方面，组织病理学特征、血清生物标志物和氧化损伤指标的体内结果表明，Nrf2敲除加重了肾损伤。此外，Nrf2敲除通过抑制pSmad3C/p21途径并促进pSmad3L/PAI-1途径，降低了AS-IV的肾保护作用。实验结果如我们所猜测的那样。我们首次确定Nrf2缺陷增加了肝癌生成引起的肾纤维化，并通过调节pSmad3C/3L信号通路削弱了AS-IV的治疗效果。© 2023. 作者（们），在Springer-Verlag GmbH Germany独家许可下，属于Springer Nature。

Fibrotic kidney injury from hepatocarcinogenesis seriously impacts treatment effect. Astragaloside IV (AS-IV), an extract of Astragalus membranaceus, has several pharmacological activities, which are useful in the treatment of edema and fibrosis. Nrf2/HO-1 is a key antioxidant stress pathway and help treatment of kidney injury. Smad3 phosphorylation is implicated in hepatocarcinogenesis. Our previous study clarified that Smad3 is differentially regulated by different phosphorylated forms of Smad3 on hepatocarcinogenesis. Therefore, we investigated the contribution of AS-IV on the therapy of kidney fibrosis from hepatocarcinogenesis. And the focus was on whether the phosphorylation of Smad3 and the regulation of Nrf2/HO-1 pathway were involved during AS-IV therapy and whether there is an effect of Nrf2 knockout on the phosphorylation of Smad3. We performed TGF-β1 stimulation on HK-2 cells and intervened with AS-IV. Furtherly, we investigated renal injury of AS-IV on Nrf2 knockout mice during hepatocarcinogenesis and its mechanism of action. On the one hand, in vitro results showed that AS-IV reduced the ROS and α-SMA expression of HK-2 by promoting the expression pSmad3C/p21 of and Nrf2/HO-1 and suppressed the expression of pSmad3L/PAI-1. On the other hand, the in vivo results of histopathological features, serological biomarkers, and oxidative damage indicators showed that Nrf2 knockout aggravated renal injury. Besides, Nrf2 deletion decreased the nephroprotective effect of AS-IV by suppressing the pSmad3C/p21 pathway and promoting the pSmad3L/PAI-1 pathway. The experimental results were as we suspected. And we identify for the first time that Nrf2 deficiency increases renal fibrosis from hepatocarcinogenesis and attenuates the therapeutic effects of AS-IV via regulating pSmad3C/3L signal pathway.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.