## 3 Keep1-Nrf2-ARE Signaling System
### Dioscin (DC)  
Dioscin (**9**) is a steroidal saponin that is abundantly present in _Dioscorea__nipponica_, _D. zingiberensis_, _D. opposita_, _D. alata_, and _D. japonica_[48]. It has previously been reported to ameliorate prostate, lung, gastric and skin carcinogenesis [206, 207, 208, 209].  
In HL-60 leukemia cells, it produced anticancer action by activating p38 MAPK and JNK signaling [210]. DC ameliorated LPS-induced inflammation in mouse mammary epithelial cells by enhancing the level of total and nuclear Nrf2 and its downstream enzyme HO-1 [211]. Mechanistically, the AMPK signaling was activated and the expression levels of IL-1\(\beta\), IL-6, TNF-\(\alpha\) and NF-\(\kappa\)B were suppressed. A study suggested ROS production to be an important event in DC-mediated apoptosis in human esophageal cancer Kyese510 cells [212]. This ROS-generating anticancer mechanism implied the Nrf2 inhibitory role of DC, where the cellular antioxidant defense enzymes like PRX1 and PRDX6 were downregulated [213]. The ROS-mediated apoptotic role of DC against colon cancer was accompanied by JNK/p38 MAPK signaling activation [214]. In another report, activation of ERK1/2 signaling was implicated in the DC-regulated apoptotic activity in human hepatoma Huh7 cells [215]. The anti-metastatic role of DC was evident in A549 lung cancer cells, where it suppressed EMT by downregulating TGF-\(\beta\)1 expression [216].  
DC ameliorated hepatic fibrosis by facilitating the nuclear translocation of Nrf2, followed by its dissociation from Keap1 [217]. Consequently, by binding to the AREs, Nrf2 upregulated the expression of antioxidant enzymes HO-1, GST, GCLC and GCLM. DC improved doxorubicin-mediated liver damage by tackling oxidative stress and inflammation, and promoting apoptosis [218]. Here, it markedly increased silent information regulator 1 (Sirt1) and HO-1 expressions by mediating Nrf2 nuclear translocation and abrogating forkhead box protein O1 (FOXO1) and Keap1 expression. In addition, inflammation was inhibited by DC by reduced NF-\(\kappa\)B, TNF-\(\alpha\), IL-1\(\beta\), and IL-6 expressions. In addition to TLR4, these inflammatory mediators were also inhibited by DC during the amelioration of acute lung injury [219,220]. An ample body of other evidence was found supporting DC's capacity to improve liver fibrosis and acute liver injury and damage by suppressing oxidative insult and inflammation [221, 222, 223, 224, 225, 226]. In these instances, DC facilitated Nrf2 nuclear translocation and enhanced the levels of HO-1, NQO1, GSH, GST, SOD1, GCL, GCLC, and Gpx. In addition, inflammatory mediators like IL-1\(\beta\), IL-6, TNF-\(\alpha\), \(\kappa\)B\(\alpha\), NF-\(\kappa\)B, ICAM-1, high mobility group box 1 protein (HMGB1), and COX-2 were suppressed by DC. Several signaling pathways, such as farnesoid X receptor (FXR)/AMPK, Sirt1/Nrf2, TGF-\(\beta\)/Smad, wingless-related integration site (Wnt)/\(\beta\)-catenin, PI3K, AKT, and MAPK, were involved in DC-mediated liver protection. DC induced autophagy at the early stage of DC-induced apoptosis by inhibiting the AKT/PI3K/mTOR and activating ERK1/2 and JNK signaling [227]. Figure 7 presents the mechanism of Nrf-ARE activation by DC.