## 4 Discussion
\begin{table}
\begin{tabular}{c c c c c c c} \hline \hline
**No.** & **Compound Name** & **Compound** & **Observed** & **Observed** & **Mass Error** & **Reference** \\  & & **Formula** & **RT (min)** & _m/z_ & **(ppm)** & **Reference** \\ \hline
1. & Procyanidin A2 & C\({}_{20}\)H\({}_{23}\)O\({}_{12}\) & 5.56 & 577.1344 & 0.6 & [34] \\
2. & Nor-up-tropine & C\({}_{24}\)H\({}_{35}\)NO & 18.97 & 128.1062 & \(-\)6.1 & - \\
3. & Hydrocovolchic acid & C\({}_{24}\)H\({}_{35}\)O\({}_{4}\) & 18.54 & 393.298 & \(-\)4.9 & [35] \\
4. & Nigakiactone H & C\({}_{22}\)H\({}_{23}\)O\({}_{8}\) & 6.69 & 425.2141 & \(-\)6.8 & [36] \\
5. & Stratatic acid C & C\({}_{25}\)H\({}_{43}\)O\({}_{4}\) & 14.72 & 441.3018 & 4.3 & - \\
6. & 16-O-Acetylisidirogormanal & C\({}_{26}\)H\({}_{35}\)O\({}_{6}\) & 6.98 & 517.3895 & 1.5 & - \\
7. & Biestranjol B & C\({}_{25}\)H\({}_{32}\)O\({}_{7}\) & 19.03 & 589.2231 & 1.7 & - \\
8. & Biaxtryolidice & C\({}_{30}\)H\({}_{38}\)O\({}_{4}\) & 6.43 & 463.2802 & 8.3 & [37] \\
9. & Scutellarin & C\({}_{21}\)H\({}_{3}\)O\({}_{12}\) & 19.11 & 449.1113 & 7.7 & [38,39] \\
10. & Protodiogenin & C\({}_{27}\)H\({}_{23}\)O\({}_{3}\) & 6.33 & 595.389 & 8.3 & [40] \\ \hline \hline \end{tabular} RT, retention time.  
\end{table} 
Table 1: The main identified constituents of the _Artemisia santoliniglia_ ethanol extract (ASE). NRF2 being strongly expressed in nuclei of A549 cells but dramatically decreased in H23 cells [50]. STAT3 is another proto-oncogenic factor that was reported to be over-activated in around half of all NSCLC cell lines and primary tumors; it stimulates various prosurvival genes such as survivin to protect cells against drug-induced apoptosis [51]. Both NRF2 and STAT3 are antioxidant and cellular stress response factors, and they regulate downstream target ferrotptosis-related genes such as solute carrier family 7 member 11 (SLC7A11) of the xCT system to boost cellular resistance to drug-induced death. This indicates that NRF2 and STAT3 might correspond to SLC7A11 expression in ferrotposis, a key gene involved in regulating redox-balancing proteins such as GPX4 [52]. In agreement with previous reports, our study demonstrated that the ASE inhibited NRF2 and GPX4 expressions in A549 cells but slightly increased NRF2 levels in H23 cells, giving the cells a chance to evade oxidative stress. Furthermore, unlike in A549 cells, after the ASE treatment, cleavage of caspase-3 prevailed in H23 cells, suggesting that ASE-induced cell death is possibly potentiated through the induction of apoptosis; at the same time, no significant alterations in the expression of the GPX4 protein or ROS activation were detected. One of the interesting results of this study also was the evaluation of procyanidin A2 (PCA2) in the ASE for the first time using an LC-QTOF analysis. In regard to specific types of proanthocyanidins, which are a class of flavonoids, several studies documented the anti-inflammatory and antioxidative effects of PCA2. A previous study further showed that PCA2 suppresses ROS by upregulating the expressions of Nrf2 and heme oxygenase (HO)-1, which help protect cancer cells against oxidative stress [53; 54]. Additionally, biatractylolide, a double sesquiterpene ester previously isolated from the ethyl acetate extract of _Attractylodes macrocphala_, can effectively attenuate glutamate-induced ROS in PC12 and SH-SYSY cell lines and showed an anticancer effect [37]. Contrarily, another active constitutive of the ASE, scutellarin, a flavonoid isolated from the traditional Chinese herb _Scutellarin altissima_ L., was reported to possess cytotoxic effects against colorectal cancer and bladder cancer cell lines and also exhibited a chemosensitization property in human prostate tumor cells [38; 55]. Scutellarin, isolated from the herbal medicine _Erigeron breviscapus_, inhibited the proliferation and promoted apoptosis in A549 cells, concurrently increasing the intracellular ROS level and cleavage of caspase-3, pointing to controversial results of the bioactivities of the abundant constitutes discussed above [56].